NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Breast Cancer
Version 4.2024 — July 3, 2024

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NCCN Guidelines Version 4.2024 NCCN Guidelines Index

Table of Contents
Breast Cancer Discussion

*William J. Gradishar, MD/Chair ‡ † *Helen Chew, MD † Sameer A. Patel, MD Ÿ

Robert H. Lurie Comprehensive Cancer UC Davis Comprehensive Cancer Center Fox Chase Cancer Center
Center of Northwestern University Chau Dang, MD † Laura H. Rosenberger, MD, MS ¶
*Meena S. Moran, MD/Vice-Chair § Memorial Sloan Kettering Cancer Center Duke Cancer Institute
Yale Cancer Center/Smilow Cancer Hospital *Anthony D. Elias, MD † Hope S. Rugo, MD †
University of Colorado Cancer Center UCSF Helen Diller Family
Jame Abraham, MD ‡ † Comprehensive Cancer Center
Case Comprehensive Cancer Center/ Sharon H. Giordano, MD, MPH †
University Hospitals Seidman Cancer Center The University of Texas *Cesar Santa-Maria, MD, MSCI †
and Cleveland Clinic Taussig Cancer Institute MD Anderson Cancer Center The Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins
Vandana Abramson, MD † Matthew P. Goetz, MD ‡ †
Vanderbilt-Ingram Cancer Center Mayo Clinic Comprehensive Cancer Center Bryan P. Schneider, MD †
Indiana University Melvin and Bren Simon
*Rebecca Aft, MD, PhD ¶ *Rachel C. Jankowitz, MD † Comprehensive Cancer Center
Siteman Cancer Center at Barnes- Abramson Cancer Center
at the University of Pennsylvania Mary Lou Smith, JD, MBA ¥
Jewish Hospital and Washington Research Advocacy Network
University School of Medicine Sara H. Javid, MD ¶
Fred Hutchinson Cancer Center Hatem Soliman, MD †
Doreen Agnese, MD ¶ Moffitt Cancer Center
The Ohio State University Comprehensive Jairam Krishnamurthy, MD †
Cancer Center - James Cancer Hospital Fred & Pamela Buffett Cancer Center Erica M. Stringer-Reasor, MD † ‡
and Solove Research Institute O'Neal Comprehensive
A. Marilyn Leitch, MD ¶ Cancer Center at UAB
Kimberly H. Allison, MD ≠ UT Southwestern Simmons
Stanford Cancer Institute Comprehensive Cancer Center Melinda L. Telli, MD † Þ
Stanford Cancer Institute
Bethany Anderson, MD § Janice Lyons, MD § Mei Wei, MD †
University of Wisconsin Case Comprehensive Cancer Center/ Huntsman Cancer Institute
Carbone Cancer Center University Hospitals Seidman Cancer Center at the University of Utah
Janet Bailey, MD § and Cleveland Clinic Taussig Cancer Institute
Kari B. Wisinski, MD †
University of Michigan Susie McCloskey, MD, MSHS § University of Wisconsin Carbone Cancer Center
Rogel Cancer Center UCLA Jonsson Comprehensive Cancer Center
Kay T. Yeung, MD, Phd Þ †
Harold J. Burstein, MD, PhD † Melissa McShane, MD † UC San Diego Moores Cancer Center
Dana-Farber/Brigham and Fox Chase Cancer Center
Women’s Cancer Center Jessica S. Young, MD ¶
Joanne Mortimer, MD †
Nan Chen, MD ‡ City of Hope National Medical Center Roswell Park Comprehensive Cancer Center
The UChicago Medicine
Comprehensive Cancer Center ‡ Hematology/Hematology § Radiation oncology/
NCCN Continue oncology
Þ Internal medicine
Radiotherapy
Ÿ Reconstructive surgery
Rashmi Kumar, PhD
Ryan Schonfeld, BA † Medical oncology ¶ Surgery/Surgical oncology
≠ Pathology * Discussion Section Writing
NCCN Guidelines Panel Disclosures ¥ Patient advocacy Committee
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NCCN Guidelines Version 4.2024 NCCN Guidelines Index

Table of Contents
Breast Cancer Discussion

NCCN Breast Cancer Panel Members Fertility and Birth Control (BINV-C)
Summary of Guidelines Updates Considerations for Surgical Axillary Staging (BINV-D) Find an NCCN Member
Axillary Lymph Node Staging (BINV-E) Institution: https://www.nccn.org/
Recommendations for Lobular Carcinoma In Situ were removed Margin Status Recommendations After Breast-Conserving home/member-institutions.
from the NCCN Guidelines for Breast Cancer. See NCCN Surgery (BCS) for Invasive Cancers and DCIS (BINV-F)
Guidelines for Breast Cancer Screening and Diagnosis Special Considerations to Breast Conservation Therapy NCCN Categories of
Noninvasive Breast Cancer Requiring RT (BINV-G) Evidence and Consensus: All
Ductal Carcinoma In Situ (DCIS) Workup and Primary Treatment Principles of Breast Reconstruction Following recommendations are category
(DCIS-1) Surgery (BINV-H) 2A unless otherwise indicated.
DCIS Postsurgical Treatment and Surveillance/Follow-up (DCIS-2) Principles of Radiation Therapy (BINV-I) See NCCN Categories of
Invasive Breast Cancer Special Considerations for Breast Cancer in Males Evidence and Consensus.
Clinical Stage, Workup (BINV-1) (Sex Assigned at Birth) (BINV-J)
Locoregional Treatment of cT1–3,cN0 or N+,M0 Disease Principles of Adjuvant Endocrine Therapy (BINV-K)
• BCS followed by RT (BINV-2) Preoperative/Adjuvant Therapy Regimens (BINV-L)
NCCN Categories of
• Mastectomy Followed by RT (BINV-3) Principles of Preoperative Systemic Therapy (BINV-M)
Gene Expression Assays for Consideration of Adjuvant
Preference:
Systemic Adjuvant Treatment All recommendations are
• HR-Positive – HER2-Positive Disease (BINV-5) Systemic Therapy (BINV-N)
Definition of Menopause (BINV-O) considered appropriate.
• HR-Positive – HER2-Negative Disease:
Postmenopausal Patients (BINV-6) Systemic Therapy for ER- and/or PR-Positive Recurrent See NCCN Categories of
Premenopausal Patients with pT1–3, pN0 (BINV-7) Unresectable (Local or Regional) or Stage IV (M1) Preference.
Premenopausal Patients with pT1–3, pN+ (BINV-8) Disease (BINV-P)
• HR-Negative – HER2-Positive Disease (BINV-9) Systemic Therapy Regimens for Recurrent Unresectable
• HR-Negative – HER2-Negative Disease (BINV-10) (Local or Regional) or Stage IV (M1) Disease (BINV-Q)
• Favorable Histologies (BINV-11) Systemic Chemotherapy for HR-Positive or -Negative and
Workup Prior to Preoperative Systemic Therapy (BINV-12) HER-2 Negative (BINV-Q 5 )
Adjuvant Systemic Therapy After Preoperative Systemic Targeted Therapies and Associated Biomarker Testing for
Therapy (BINV-16) Recurrent Unresectable (Local or Regional) or Stage IV
Surveillance/Follow-up (BINV-17) (M1) Disease (BINV-Q 6)
Recurrent/Stage IV (M1) Disease (BINV-18) Principles of Monitoring Metastatic Disease (BINV-R) Staging (ST-1)
Treatment of Local and Regional Recurrence (BINV-19) Special Considerations Abbreviations (ABBR-1)
Systemic Treatment of Recurrent Unresectable (Local or Phyllodes Tumor (PHYLL-1)
Regional) or Stage IV (M1) Disease (BINV-21) Paget Disease (PAGET-1)
Principles of Biomarker Testing (BINV-A) Breast Cancer During Pregnancy (PREG-1)
Principles of Dedicated Breast MRI Testing (BINV-B) Inflammatory Breast Cancer (IBC-1)

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to
treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual
clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations
or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may
not be reproduced in any form without the express written permission of NCCN. ©2024.
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NCCN Guidelines Version 4.2024 NCCN Guidelines Index

Table of Contents
Breast Cancer Discussion

Terminologies in all NCCN Guidelines are being actively modified to advance the goals of equity, inclusion, and representation.
Updates in Version 4.2024 of the NCCN Guidelines for Breast Cancer from Version 3.2024 include:
BINV-Q (6 of 14)
• Targeted Therapies and Associated Biomarker Testing for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease
NTRK fusion row, column 4: Repotrectinib was added.
Footnote bb added: Repotrectinib is indicated for the treatment of solid tumors that have an NTRK gene fusion and are locally advanced or metastatic or where
surgical resection is likely to result in severe morbidity and have progressed following treatment or have no satisfactory alternative therapy. The recommendation in
the first-line setting is category 2B.
Updates in Version 3.2024 of the NCCN Guidelines for Breast Cancer from Version 2.2024 include:
MS-1
• The discussion section related to Systemic Therapies (Preoperative and Adjuvant) for non-metastatic breast cancer was updated.
BINV-16
• Bottom pathway clarification: "and/" added before "or" after both adjuvant pembrolizumab and adjuvant capecitabine.
• Footnote eee clarified: There are no data on sequencing or combining adjuvant pembrolizumab with capecitabine, pembrolizumab and/ or olaparib in patients who
meet criteria for treatment with one or more of these agents. However, their sequential/combined use may be considered given high-risk of recurrence in certain
patients with residual disease high-risk of recurrence.

Updates in Version 2.2024 of the NCCN Guidelines for Breast Cancer from Version 1.2024 include:
DCIS-2
• Footnote o, last sentence added: An FDA-approved biosimilar is an appropriate substitute for denosumab. (Also for footnote ggg on BINV-17, ttt on BINV-21, and f on
BINV-K 2 of 2)

Updates in Version 1.2024 of the NCCN Guidelines for Breast Cancer from Version 5.2023 include:
DCIS-1
• Diagnosis, revised: DCIS Tis,N0,M0, Encapsulated or solid papillary carcinoma (SPC)
• Primary treatment, bottom pathway revised: Total mastectomy with or without sentinel lymph node biopsy (SLNB) ± reconstruction (optional)
• Footnote a added: Encapsulated papillary carcinoma (EPC) without associated conventional invasion is staged as pTis because behavior is similar to DCIS (per
AJCC). SPC should be specified as in situ or invasive based on WHO criteria but both forms have favorable outcomes.
• Footnote g revised: Surgical axillary staging should not be performed for preoperative (biopsy-determined) pure DCIS unless there is some clinical-pathologic suggestion of
invasion or axillary metastasis. A SLNB should also be considered in the setting of 1) Mastectomy for DCIS, where there is a small risk of detecting invasive disease in the
mastectomy specimen or 2) Excision in an anatomic location compromising the performance of a future SLNB procedure.
DCIS-2
• Surveillance/Follow-up, 2nd bullet revised: Mammogram every 12 mo (First mammogram 6–12 mo, after breast-conservation therapy, (category 2B) and annually
thereafter
• Footnote p revised: The standard dose of tamoxifen is 20 mg/day for 5 years. Low-dose tamoxifen (5 mg/day or 10 mg every other day for 3 years) is an option only in
patients who are symptomatic or unwilling to take standard on the 20-mg dosing. or if patient is unwilling or unable to take standard-dose tamoxifen.
BINV-1
• Diagnosis (Clinical) revised: Non-metastatic (M0) IBC Localized breast cancer: Invasive, non-inflammatory, non-metastatic (M0)
• Workup
Last bullet revised: Consider additional imaging studies only in the presence of signs and symptoms of metastatic disease and in other patients who are clinically
high risk
• Clinical Stage
Bottom pathway revised: cT1–T4T3,≥cN0,M0
• Footnote i revised: Patients with a known genetic predisposition to breast cancer may have an increased risk of contralateral or ipsilateral breast cancers after breast-
conservation therapy. Risk reduction strategies including prophylactic mastectomies should be discussed. (Also for subsequent pages)

Continued
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Table of Contents
Breast Cancer Discussion

Updates in Version 1.2024 of the NCCN Guidelines for Breast Cancer from Version 5.2023 include:
BINV-2
• Locoregional treatment of cT1-3, cN0 or cN+, M0 Disease, modified: BCS with surgical axillary staging (category 1) ± oncoplastic reconstruction
• New node: See BINV-4 to determine whether adjuvant systemic therapy is indicated (Also for BINV-3)
• Negative axillary nodes
Header removed: Radiation therapy After Completion of BCS and axillary staging
Revised: WBRT ± boost to tumor bed, and consider comprehensive regional nodal irradiation (RNI) in patients with central/medial tumors, pT3 tumors, or pT2 tumors
with central/medial tumors, pT3 tumors, or pT2 tumors and one of the following high-risk features: grade 3, extensive lymphovascular invasion (LVI), or ER HR-
negative.
Revised: Consider omitting breast irradiation in patients if adjuvant endocrine therapy is planned and following criteria are met (category 1):
◊ Criterion 2 added: 2) ≥65 y, HR+, HER2-negative, pN0, pT ≤3 cm
Footnote j added: For patients >40 years of age with 2 biopsy proven cTis–cT2 lesions (with at least one invasive site) after MRI evaluation, intending on adjuvant whole
breast radiation + boost, breast conservation therapy may be considered (Boughey JC, et al. J Clin Oncol 2023;41:3184-3193).
Footnote r added: Sentinel node biopsy may be omitted based on the SSO Choosing Wisely recommendation in patients >70 years of age with HR+/HER2-negative
and pT1, cN0 tumors.
Footnote s added: For definition of HR+, see Principles of Endocrine Therapy (BINV-K).
BINV-3
• Header removed: RT After Completion of Mastectomy and Axillary Staging
BINV-4
• Histology, Favorable histologic type
Bullet 4 revised: Adenoid cystic (conventional), secretory carcinoma, and other salivary carcinomas (Also for BINV-11)
Removed: Encapsulated or solid papillary carcinoma (SPC)
Removed: Secretory carcinoma
• Systemic Adjuvant Treatment
Postmenopausal, new node added: pT1–3 AND pN0 or pN+
• Footnote x removed: Encapsulated papillary carcinoma (EPC) without associated conventional invasion is staged as pTis because behavior is similar to
DCIS (per AJCC). SPC should be specified as in situ or invasive based on WHO criteria but both forms have favorable outcomes. (Also for subsequent
pages)
BINV-5
• pN0 revised: Consider adjuvant endocrine therapy ± or Consider adjuvant chemotherapy with trastuzumab (category 2B) and endocrine therapy
• Footnote dd revised: Principles of Adjuvant Endocrine Therapy. (Also for subsequent pages)
BINV-6
• Footnote kk added: Two years of adjuvant abemaciclib in combination with endocrine therapy can be considered in patients with HR+/HER2-negative,
high-risk breast cancer (see eligibility criteria listed on (BINV-K). In patients eligible for both adjuvant olaparib and abemaciclib, the optimal choice of
therapy and sequencing is not known. (Also for BINV-8)
BINV-7
• Not done: Adjuvant chemotherapy followed by endocrine therapy ± ovarian suppression/ablation (category 1) (Also for Recurrence score 16–25 and
Recurrence score ≥26)
BINV-8
• Top pathway revised: Adjuvant endocrine therapy ± ovarian suppression/ablation
• Middle pathway revised: Adjuvant chemotherapy followed by endocrine therapy ± ovarian suppression/ablation (Also for bottom pathway)
BINV-11
• Top pathway, last bullet removed: Encapsulated or solid papillary carcinoma
• Footnote removed: EPC without associated conventional invasion is staged as pTis because behavior is similar to DCIS (per AJCC). SPC should be
specified as in situ or invasive based on WHO criteria but both forms have favorable outcomes.
BINV-12
• Additional Workup, Additional tests to consider as clinically indicated
Bullet 4 revised: FDG-PET/CT (useful in certain circumstances)
• Footnote uu revised: At the time of biopsy of the most suspicious axillary lymph node(s) sampling, a marker clip or tattoo should be placed to allow for
identification and removal that the biopsy-positive lymph node has been removed at the time of definitive surgery.
BINV-13
• Column 1, last bullet revised: Biopsy + marker clip placement recommended of the most suspicious and/or clinically positive axillary lymph nodes, if not
previously done; only the most suspicious node should be marked and retrieved along with SLNs Continued
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NCCN Guidelines Version 4.2024 NCCN Guidelines Index

Table of Contents
Breast Cancer Discussion

Updates in Version 1.2024 of the NCCN Guidelines for Breast Cancer from Version 5.2023 include:
BINV-14
• Surgical Treatment
BCS not possible revised: Mastectomy and surgical axillary staging ± reconstruction (optional)
• Adjuvant Therapy (BCS possible) revised: post-lumpectomy adjuvant WBRT RT
• Adjuvant Therapy (BCS not possible)
Sub-bullet 2 added: cT4, any N: RT is indicated to the chest wall + comprehensive RNI with inclusion of any portion of the undissected axilla at risk.
Sub-bullet 3 added: cT3, cN0, and ypN0: Consider RT to the chest wall + comprehensive RNI with inclusion of any portion of the undissected axilla at
risk.
• Footnote aaa added: Based on emerging data, there maybe subsets of patients who achieve pCR in nodes that may not benefit from RNI (in BCS
setting) or PMRT + RNI (in mastectomy setting). (Mamounas E, Bandos H, White J, et al. Loco-regional irradiation in patients with biopsy-proven axillary
node Involvement at presentation who become pathologically node-negative after neoadjuvant chemotherapy: Primary outcomes of NRG Oncology/
NSABP B-51/RTOG 1304; Abstract GS02-07; SABCS 2023)
BINV-18
• Footnote kkk revised: Tumor tissue or plasma-based circulating tumor DNA (ctDNA) assays may be used and each of these have benefits and
limitations for diagnosis and disease progression. Tissue-based assays have greater sensitivity, but ctDNA may reflect tumor heterogeneity more
accurately. If one specimen is negative for actionable biomarkers, testing on the alternative specimen can be considered.
BINV-19
• Section significantly revised.
BINV-A (2 of 2)
• Correlation of ER and Histology: Highly Unusual Results, Highly Unusual ER-Positive Results
Last row revised: Carcinomas with apocrine differentiation (apocrine carcinoma)
BINV-B
• Clinical indications and applications, bullet 5 revised: The utility of MRI in follow-up screening of most patients with prior breast cancer is undefined and
annual MRI is recommended in patients with personal history of breast cancer who: 1) were diagnosed age <50 or 2) have dense breasts. It should
generally be considered for:
Bullet 5, sub-bullets removed:
◊ 1) Patients with dense breasts treated with BCS + RT
◊ 2) Those diagnosed before the age of 50
◊ 3) Whose lifetime risk of a second primary breast cancer is >20% based on models largely dependent on family history, such as in those with the
risk associated with inherited susceptibility to breast cancer.
• Reference removed: Monticciolo DL, Newell MS, Moy L, et al. Breast cancer screening in women at higher-than-average risk: Recommendations from
the ACR. J Am Coll Radiol 2018;15:408-414.
• Reference added: Monticciolo DL, Newell MS, Moy L, Lee CS, Destounis SV. Breast cancer screening for women at higher-than-average risk: Updated
recommendations from the ACR. J Am Coll Radiol. 2023 Sep;20(9):902-914.

Continued
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Breast Cancer Discussion

Updates in Version 1.2024 of the NCCN Guidelines for Breast Cancer from Version 5.2023 include:
BINV-C
• Bullet 4 revised: Patients should be advised not to become pregnant while on any systemic therapy and specific drug package inserts should be
consulted for recommendations. Patients should not become pregnant during treatment with RT, chemotherapy, endocrine therapy, or within 6 months
of completing trastuzumab or pertuzumab.
• Bullet 5 added: A prospective trial evaluated premenopausal women who had completed between 18–30 months of endocrine therapy before
temporarily interrupting endocrine therapy for up to 2 years to allow for pregnancy. At short-term follow-up, the risk of recurrence was not increased
among those women who enrolled or those who became pregnant. This approach is an option for women who desire pregnancy, although long-term
safety is still unknown.
BINV-D
• Section significantly revised.
BINV-F (2 of 2)
• Row 4 in table added: Invasive breast cancer (treated with neoadjuvant chemotherapy followed by breast conservation therapy)
• Reference 4 added: Choi J, Laws A, Hu J, et al. Margins in breast-conserving surgery after neoadjuvant therapy. Ann Surg Oncol 2018;25:3541-3547.
• Reference 5 added: Wimmer K, Bolliger M, Bago-Horvath Z, et al. Impact of surgical margins in breast cancer after preoperative systemic
chemotherapy on local recurrence and survival. Ann Surg Oncol 2020;27:1700-1707.
BINV-G
• Section significantly revised.
BINV-H (4 of 7)
• No adjuvant chemotherapy planned, RT planned node revised: Tissue expansion followed by RT; and conversion to permanent implant or autologous
tissue reconstruction ≥6 months after completion of RT (category 2B) or Tissue expansion followed by exchange to permanent implant before RT (if no
delay to initiation of RT) (prior to RT), followed by exchange to permanent implant before (if no delay to initiation of RT) or after RT (can be considered
prior to RT if no delay to initiation of treatment)
BINV-H (5 of 7)
• Bullet 1 revised: "...However, breast reconstruction should not interfere with the appropriate surgical, medical, and radiation management of the cancer
or the scope of appropriate surgical treatment for this disease...The availability of or the practicality of breast reconstruction should not result in the
delay or refusal of appropriate surgical, medical, and radiation intervention."
BINV-I (2 of 3)
• Heading revised: Chest Wall Post-mastectomy Radiation (including breast reconstruction)
Bullet 1 revised: The target includes the ipsilateral chest wall and the entire mastectomy scar, and ± drain sites when indicated.
Bullet 1, sub-bullet 1 added: Regional nodal RT is typically delivered with the chest wall. See below.
Bullet 2 added: In the case of cT3N0, high-risk features for considering PMRT include, but are not limited to, young age and/or LVI.
Bullet 3 added: Based on anatomic considerations and presence of reconstruction, various 3D-, IMRT, or VMAT techniques using photons and/or
electrons are appropriate.
Bullet removed: Depending on whether or not the patient has had breast reconstruction, several techniques using photons and/or electrons are
appropriate.
◊ Sub-bullet removed: Special consideration should be given to the use of bolus material to ensure that the skin dose is adequate, particularly in the
case of IBC.

Continued
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Breast Cancer Discussion

Updates in Version 1.2024 of the NCCN Guidelines for Breast Cancer from Version 5.2023 include:
Bullet 4 revised: RT PMRT details and dosing:
◊ Sub-bullet 1 added: The routine use of bolus is not recommended. Bolus should be considered in the use of IBC or clinical-pathologic situations
with the dose delivered to the skin is not adequate.
◊ Sub-bullet 3, sub-sub-bullet removed: Boost: 10–16 Gy at 1.8 to 2.0 Gy/fx total 5–8 fractions.
• Regional Nodal Radiation
Bullet 3, sub-bullet revised: A supplemental boost of RT can be delivered to grossly involved or enlarged lymph nodes (ie, internal mammary, supra/
infra-clavicular) that have not been surgically addressed removed.
• RT with Preoperative or Adjuvant Systemic Therapy
Sequencing of RT with systemic therapy:
◊ Bullet 2, sub-bullet 1 revised: CMF (cyclophosphamide/methotrexate/fluorouracil) is the only standard regimen that can be given concurrently with
RT. and RT may be given concurrently, or CMF may be given first.
◊ Bullet 2, sub-bullet 2, sub-sub-bullet added: Abemaciclib should be initiated after completion of surgery/RT/chemotherapy, concurrently with
endocrine therapy.
BINV-K
• Section significantly revised.
BINV-L (1 of 9)
• Preoperative/adjuvant therapy regimens, HER2-Negative:
• HER2- Other Recommended Regimens:
Bullet 4 revised: Select patients with For TNBC:
Bullet 4, sub-bullet 1 revised: Paclitaxel + carboplatin (various schedules) (category 2A)
Bullet 4, sub-bullet 2 revised: Docetaxel + carboplatin (preoperative setting only) (category 2A)
• Footnote c, bullet 2 revised: HR-positive, HER2-negative tumors, if 1) ≥4 positive lymph nodes after adjuvant chemotherapy (category 2A), or 2)
residual disease after preoperative therapy and a clinical stage, pathologic stage, ER status, and tumor grade (CPS+EG) score ≥3 (category 2A).
• Footnote removed and text listed above the table: The regimens listed in the table for HER2-negative disease are all category 1 (except where
indicated) when used in the adjuvant setting.
• Footnote removed: The inclusion of platinum agents as neoadjuvant chemotherapy for TNBC remains controversial. Several studies have shown
improved pCR rates with incorporation of platinum. However, long-term outcomes remain unknown. The routine use of platinum agents as part of
neoadjuvant therapy for TNBC is not recommended for most patients (including BRCA mutation carriers), but it may be considered in select patients
(such as those for whom achieving better local control is necessary). The use of platinum agents in the adjuvant setting is not recommended. If
platinum agents are included in an anthracycline-based regimen, the optimal sequence of chemotherapy and choice of taxane agent is not established.
Carboplatin may be used as part of the pembrolizumab regimen.
BINV-L (2 of 9)
• Preoperative/adjuvant therapy regimens, HER2-Positive:
Other Recommended Regimens:
◊ Bullet 3 added: Paclitaxel/carboplatin + trastuzumab + pertuzumab

Continued
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NCCN Guidelines Version 4.2024 NCCN Guidelines Index

Table of Contents
Breast Cancer Discussion

Updates in Version 1.2024 of the NCCN Guidelines for Breast Cancer from Version 5.2023 include:
BINV-L (5 of 9)
• Preoperative/adjuvant therapy regimens, HER2- Negative Regimens:
Other Recommended Regimens:
◊ Last bullet revised: Docetaxel + carboplatin (4–6 cycles) (preoperative setting only)
BINV-L (6 of 9)
• Preoperative/adjuvant therapy regimens, HER2- Positive Regimens: Preferred Regimens
TDM-1 regimen added
BINV-L (8 of 9)
• Preoperative/adjuvant therapy regimens, HER2- Positive Regimens: Other Recommended Regimens
Paclitaxel/carboplatin + trastuzumab + pertuzumab regimen added
BINV-L (9 of 9)
• Reference 28 added: van Ramshorst MS, van der Voort A, van Werkhoven ED, et al. Neoadjuvant chemotherapy with or without anthracyclines in
the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol
2018;19:1630-1640.
BINV-M (2 of 2)
• Section significantly revised.
BINV-N (4 of 5)
• Row 2, bullet removed: In contrast, BCI (H/I) low patients derived no benefit from extended adjuvant therapy.
• Footnote e added: The benefit of testing BCI (H/I) for extended adjuvant endocrine therapy is unknown in patients who had ovarian function
suppression, CDK4/6 inhibitors, or olaparib in addition to adjuvant endocrine therapy.
BINV-P
• Systemic therapy for ER- and/or PR-positive Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease
Other Recommended Regimens: Bullet 2 revised: Selective ER down-regulator (fulvestrant, category 1) + non-steroidal aromatase inhibitor
(anastrozole, letrozole) (category 1)
BINV-Q (2 of 14)
• Footnote i revised: Sacituzumab govitecan-hziy may be used for patients who have received at least 1 prior regimen in the metastatic setting and adult
patients with metastatic TNBC who have received at least 2 prior therapies, at least one of which was for metastatic disease. It may be considered for
later line if not used as second line therapy.
BINV-Q (4 of 14)
• Reference 1 added: Sphar BG, Bowe C, Dains JE. The impact of peripheral cooling on chemotherapy-induced peripheral neuropathy: An integrative
review. J Adv Pract Oncol 2020;11:845-857.
• Reference 2 added: Hanai A, Ishiguro H, Sozu T, et al. Effects of cryotherapy on objective and subjective symptoms of paclitaxel-induced neuropathy:
Prospective self-controlled trial. J Natl Cancer Inst 2018;110:141-148.
BINV-Q (6 of 14)
• Targeted Therapies and Associated Biomarker Testing for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease: This section has been
extensively revised.

Continued
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Breast Cancer Discussion

Updates in Version 1.2024 of the NCCN Guidelines for Breast Cancer from Version 5.2023 include:
BINV-Q (8 of 14)
• Dosing: Systemic Therapy Regimens for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease
Antimetabolites added: Capecitabine 1500 mg PO twice daily days 1–7 and days 15–21 cycled every 28 days
BINV-Q (11 of 14)
• Reference 7 added: Khan QJ, Bohnenkamp C, Monson T, et al. Randomized trial of fixed dose capecitabine compared to standard dose capecitabine in
metastatic breast cancer: The X-7/7 trial. J Clin Oncol 2023;41:1007-1007.
BINV-R (3 of 3)
• Principles of Monitoring Metastatic Disease: Suggested Intervals of Follow-up for Patients with Metastatic Disease
Last row, added: Brain MRI with contrast
PHYLL-1
• Section significantly revised.
PREG-1
• Workup
"If indicated" moved above options from abdominal ultrasound.
• Footnote b revised: Considerations and selection of optimal local therapy and systemic therapy are similar to that recommended in non–pregnancy-
associated breast cancer; see other sections of this guideline. However, the selection and timing of chemotherapy, endocrine therapy, and RT is
different in the pregnant versus non-pregnant patient. BCS during the first trimester of pregnancy can be considered in women who will require adjuvant
chemotherapy and can have adjuvant radiation therapy delayed until after delivery (See Discussion)...
• Footnote e added: Survival outcomes of BCT are equivalent to mastectomy in both non-pregnancy and pregnancy-associated BCs. Therapeutic RT is
generally avoided during pregnancy due to potential risks to the fetus. Mastectomy may be preferred, particularly for early (1st trimester) gestational
diagnosis, as early BCS may preclude timely administration of RT. Generally, intervals of 12–16 weeks between treatment modalities (surgery, RT, and
chemotherapy) are considered acceptable.

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Ductal Carcinoma In Situ (DCIS) Discussion

DIAGNOSIS WORKUP PRIMARY TREATMENT

Whole breast radiation therapy

(WBRT) (category 1) with or
• History and physical exam without boost to tumor bedh,j,k,l
Breast-conserving
• Diagnostic bilateral or Postsurgical
surgeryf (BCS) without
mammogram Accelerated partial breast Treatment (DCIS-2)
DCIS lymph node surgeryg
• Pathology reviewb irradiation/partial breast
Tis,N0,M0, • Determination of tumor radiation (APBI/PBI)h,j,k,l
Encapsulated or or
estrogen receptor (ER)
solid papillary No RTh,j,k,l (category 2B)
carcinoma (SPC)a status
• Genetic counseling
for patients at riskc of Total mastectomy with sentinel lymph node biopsy Postsurgical
hereditary breast cancer (SLNB)g,h ± reconstructioni Treatment (DCIS-2)
• Breast MRId,e as indicated

g Surgical axillary staging should not be performed for preoperative (biopsy-

determined) pure DCIS unless there is some clinical-pathologic suggestion
of invasion or axillary metastasis. A SLNB should also be considered
in the setting of 1) mastectomy for DCIS, where there is a small risk of
a Encapsulated papillary carcinoma (EPC) without associated conventional invasion detecting invasive disease in the mastectomy specimen or 2) Excision
is staged as pTis because behavior is similar to DCIS (per AJCC). SPC should be in an anatomic location compromising the performance of a future SLNB
specified as in situ or invasive based on WHO criteria but both forms have favorable procedure.
outcomes. h Invasive disease at total mastectomy or re-excision should be managed as
b The panel endorses the College of American Pathologists Protocol for pathology clinical stage l or stage ll disease (BINV-1).
reporting for all invasive and noninvasive carcinomas of the breast. http://www.cap.org. i Principles of Breast Reconstruction Following Surgery (BINV-H).
c For risk criteria, see NCCN Guidelines for Genetic/Familial High-Risk Assessment: j Principles of Radiation Therapy (BINV-I).
Breast, Ovarian, and Pancreatic. k Special Considerations to Breast-Conservation Therapy Requiring
d Principles of Dedicated Breast MRI Testing (BINV-B). Radiation Therapy (BINV-G).
e The use of MRI has not been shown to increase likelihood of negative margins or l WBRT following BCS reduces ipsilateral breast tumor recurrence rates in
decrease conversion to mastectomy. Data to support improved long-term outcomes DCIS by 50%–70%. Approximately half of the recurrences are invasive
are lacking. and half are DCIS. The risk of local relapse increases with larger DCIS,
f Re-resection(s) may be performed in an effort to obtain negative margins in patients palpable mass, grade III disease, margins ≤2mm, ER-negative tumors,
desiring breast-conservation therapy. Patients in whom adequate surgical margins and age <50. Select patients with "low" risk DCIS may be considered
cannot be achieved with BCS should undergo a total mastectomy. For definition suitable for APBI/PBI or omission of radiation (endocrine therapy alone, if
of adequate surgical margins, see Margin Status Recommendations After BCS for all RTOG 9804 criteria are met: screen-detected, grade I/II, size ≤2.5cm,
Invasive Cancers and DCIS (BINV-F). margins ≥3mm).

Note: All recommendations are category 2A unless otherwise indicated.

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Ductal Carcinoma In Situ (DCIS) Discussion

DCIS POSTSURGICAL TREATMENT SURVEILLANCE/FOLLOW-UP

Risk reduction therapy for ipsilateral breast following BCS:

• Consider endocrine therapy for 5 years for patients with ER-
positive DCIS, if:
Treated with BCS and RTm (category 1)
Treated with excision alonen • Interval history and physical exam every 6–12 mo for 5 y,
• Endocrine therapyo: then annually
Tamoxifenm,p for premenopausal patients • First mammogram 6–12 mo, after breast-conservation
Tamoxifenm,p or aromatase inhibitor for postmenopausal therapy (category 2B) and annually thereafter
patients with some advantage for aromatase inhibitor therapy
in patients <60 years or with concerns for thromboembolism
Risk reduction therapy for contralateral breast:
• Counseling regarding risk reduction

m CYP2D6 genotype testing is not recommended for patients considering tamoxifen.

n Available data suggest endocrine therapy provides risk reduction in the ipsilateral breast treated with breast conservation and in the contralateral breast in patients
with mastectomy or breast conservation with ER-positive primary tumors. Since a survival advantage has not been demonstrated, individual consideration of risks and
benefits is important.
o The use of a bisphosphonate (PO/IV) or denosumab is acceptable to maintain or improve bone mineral density and reduce risk of fractures in postmenopausal (natural
or induced) patients receiving adjuvant aromatase inhibitor therapy. Optimal duration of either therapy has not been established. Benefits from duration beyond
3 years or optimal duration beyond 3 years is not known. Factors to consider for duration of anti-osteoporosis therapy include bone mineral density, response to
therapy, and risk factors for continued bone loss or fracture. There are case reports of spontaneous fractures after denosumab discontinuation. Patients treated with a
bisphosphonate or denosumab should undergo a dental examination with preventive dentistry prior to the initiation of therapy, and should take supplemental calcium
and vitamin D. An FDA-approved biosimilar is an appropriate substitute for denosumab.
p The standard dose of tamoxifen is 20 mg/day for 5 years. Low-dose tamoxifen (5 mg/day or 10 mg/every other day, for 3 years) is an option in patients who are
symptomatic or unwilling to take standard 20-mg dosing.

Note: All recommendations are category 2A unless otherwise indicated.

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Invasive Breast Cancer Discussion

DIAGNOSIS WORKUPa CLINICAL STAGE

(CLINICAL) • History and physical exam
• Imaging:
Diagnostic bilateral mammogram
Ultrasound as necessary See NCCN Guidelines for
cT0,cN+,M0
Breast MRIb (optional), with special Occult Primary
consideration for mammographically occult
tumors
• Pathology reviewc
• Determination of tumor estrogen/
Localized breast progesterone receptor (ER/PR) status and Locoregional treatmenti
cancer: HER2 statusd Not
• BCS Followed by RT
Invasive, • Genetic counseling and testing if patient is at considering
(BINV-2)
non-inflammatory, riske for hereditary breast cancer, has triple- preoperative
or
non-metastatic (M0) negative breast cancer (TNBC) (at any age), or Criteria for systemic
is a candidate for adjuvant olaparib • Mastectomy Followed
preoperative therapy
• Address fertility and sexual health concerns cT1–T4, by RT (BINV-3)
as appropriatef systemic
≥cN0,M0
• Pregnancy test in all patients of childbearing therapy
(BINV-M) Considering Additional Workup
potentialf (If pregnant, see PREG-1)
• Assess for distressg preoperative Prior to Preoperative
• Consider additional imaging studies only systemic Systemic Therapy
in the presence of signs and symptoms of therapy (BINV-12)
metastatic disease and for patients who are
clinically high risk (BINV-18)h

Inflammatory breast cancer (IBC) Workup for IBC (IBC-1)

Stage IV (M1) or Workup for Recurrent or
Metastatic (M1) invasive breast cancer
Recurrent disease Stage IV (M1) Disease (BINV-18)

a For tools to aid optimal assessment and management e For risk criteria, see NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic.
of older adults, see NCCN Guidelines for Older Adult f For Fertility and Birth Control, see BINV-C. The general considerations for fertility and sexual health/function outlined for specific
Oncology. populations in NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology and NCCN Guidelines for Survivorship are
b Breast MRI may be useful for characterizing axillary and/ applicable to all patients diagnosed with breast cancer.
or internal mammary nodal disease. See Principles of g See NCCN Guidelines for Distress Management.
Dedicated Breast MRI Testing (BINV-B). h Routine systemic staging is not indicated for non-metastatic (M0) cancer in the absence of systemic symptoms. If metastatic
c The panel endorses the College of American Pathologists disease is suspected, see Workup on BINV-18.
Protocol for pathology reporting for all invasive and i Patients with a known genetic predisposition to breast cancer may have an increased risk of contralateral or ipsilateral breast
noninvasive carcinomas of the breast. http://www.cap.org. cancers after breast-conservation therapy. Risk reduction strategies including prophylactic mastectomies should be discussed.
d Principles of Biomarker Testing (BINV-A). See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic.

Note: All recommendations are category 2A unless otherwise indicated.

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Invasive Breast Cancer Discussion

LOCOREGIONAL TREATMENT OF cT1–3, cN0 or cN+, M0 DISEASEa: BREAST-CONSERVING SURGERY (BCS) FOLLOWED BY RT

WBRT ± boostp to tumor bed, and consider comprehensive regional nodal

irradiation (RNI) in patients with central/medial tumors, pT3 tumors, or pT2 tumors
and one of the following high-risk features: grade 3, extensive lymphovascular
invasion (LVI), or hormone-receptor (HR)-negative.s
Negative or
Consider APBI/PBI in selected patients who are low risk (category 1)p,q
axillary nodes or
Consider omitting breast irradiation if adjuvant endocrine therapy is planned and
following criteria are met (category 1):
1) ≥70 y, HR+, HER2-negative, cN0, pT1r,s
2) ≥65 y, HR+, HER2-negative, pN0, pT ≤3 cms
WBRT ± boost (use of comprehensive
Yes RNI with or without intentional inclusion
See BINV-4 Meets ALL of the following to all of axilla at the discretion of the radiation
BCSj with surgical to determine criteria: oncologist) (category 1)
axillary staging whether • cT1–T2, cN0
(category 1)i,k,l,m adjuvant 1–3 positive • No preoperative
systemic axillary nodes chemotherapy WBRT with inclusion of any portion of
± oncoplastic • 1–2 positive sentinel
reconstructionn therapy is the undissected axilla at risk ± boostp
lymph nodes (SLNs) No to tumor bed (category 1). Strongly
indicated • WBRT planned
consider comprehensive RNI, including
any portion of the undissected axilla.
≥4 positiveo WBRT ± boostp to tumor bed (category 1) + comprehensive RNI,
axillary nodes including any portion of the undissected axilla at risk (category 1)

l Axillary Lymph Node Staging (BINV-E) and Margin Status Recommendations After BCS for
Invasive Cancers and DCIS (BINV-F).
a For tools to aid optimal assessment and management of older adults, see NCCN m Special Considerations to Breast-Conservation Therapy Requiring Radiation Therapy
Guidelines for Older Adult Oncology. (BINV-G).
i Patients with a known genetic predisposition to breast cancer may have an n Includes techniques such as local tissue rearrangement, local flaps, regional flaps, breast
increased risk of contralateral or ipsilateral breast cancers after breast-conservation reduction, and mastopexy to allow for greater volumes of resection while optimizing aesthetic
therapy. Risk reduction strategies including prophylactic mastectomies should be outcomes in patients undergoing BCS.
discussed. See NCCN Guidelines for Genetic/Familial High-Risk Assessment: o Consider imaging for systemic staging, including chest/abdomen ± pelvis diagnostic CT with
Breast, Ovarian, and Pancreatic. contrast, bone scan, and optional FDG-PET/CT.
j For patients >40 years of age with 2 biopsy proven cTis–cT2 lesions (with at p Principles of Radiation Therapy (BINV-I).
least one invasive site) after MRI evaluation, intending on adjuvant whole breast q APBI/PBI may be administered prior to chemotherapy.
radiation + boost, breast conservation therapy may be considered (Boughey JC, et r Sentinel node biopsy may be omitted based on the SSO Choosing Wisely recommendation in
al. J Clin Oncol 2023;41:3184-3193). See BINV-G. patients ≥70 years of age with HR+/HER2-negative and pT1, cN0 tumors.
k Considerations for Surgical Axillary Staging (BINV-D). s For definition of HR+, see Principles of Endocrine Therapy (BINV-K).

Note: All recommendations are category 2A unless otherwise indicated.

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Invasive Breast Cancer Discussion

LOCOREGIONAL TREATMENT OF cT1–3, cN0 or cN+, M0 DISEASEa,t: MASTECTOMY FOLLOWED BY RT

Negative axillary nodes

and tumor ≤5 cm and No RTw
margins ≥1 mm

Negative axillary
Consider RTp to chest wall. For patients with additional high-risk features,w
nodes and tumor
consider addition of comprehensive RNI (including any portion of the
≤5 cm and negative
undissected axilla at risk).
margins but <1 mm
See BINV-4
Total mastectomy to determine Negative axillary
with surgical whether Consider RTp to chest wall ± comprehensive RNI (including any portion of
nodes and tumor
axillary stagingi,k,l adjuvant the undissected axilla at risk).
>5 cm
(category 1) ± systemic
reconstructionu therapy is 1–3 positive Strongly consider RTp to chest wall + comprehensive RNI (including
indicated axillary nodesv any portion of the undissected axilla at risk).

≥4 positive RTp to chest wall + comprehensive RNI (including any portion of the
axillary nodeso undissected axilla at risk) (category 1)

Re-excision to negative margins is preferred. If not feasible, then strongly

Margins positive consider RTp to chest wall ± comprehensive RNI (including any portion of
the undissected axilla at risk).

a For o Consider imaging for systemic staging, including chest/abdomen ± pelvis diagnostic CT
tools to aid optimal assessment and management of older adults, see
NCCN Guidelines for Older Adult Oncology. with contrast, bone scan, and optional FDG-PET/CT.
i Patients with a known genetic predisposition to breast cancer may have p Principles of Radiation Therapy (BINV-I).
t Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J).
an increased risk of contralateral or ipsilateral breast cancers after breast- u Principles of Breast Reconstruction Following Surgery (BINV-H).
conservation therapy. Risk reduction strategies including prophylactic
mastectomies should be discussed. See NCCN Guidelines for Genetic/ v In the case of a micrometastasis (>0.2 to ≤2.0 mm), and no axillary dissection, evaluate
Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. other patient risk factors when considering RT.
k Considerations for Surgical Axillary Staging (BINV-D). w Postmastectomy RT may be considered for patients with multiple high-risk recurrence
l See Axillary Lymph Node Staging (BINV-E) and Margin Status factors, including central/medial tumors or tumors ≥2 cm and at least one of the
Recommendations After BCS for Invasive Cancers and DCIS (BINV-F). following: grade 3, ER-negative, or LVI.

Note: All recommendations are category 2A unless otherwise indicated.

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Invasive Breast Cancer Discussion

HISTOLOGY HR STATUS HER2 STATUS SYSTEMIC ADJUVANT TREATMENT

HER2-positiveaa BINV-5
ER-positiveaa,bb
pT1–3 AND pN0
and/or Postmenopausalcc or pN+ BINV-6
PR-positiveaa,bb
• Ductal/NSTx HER2-negativeaa pT1–3 AND pN0 BINV-7
• Lobular Premenopausalcc
• Mixed pT1–3 AND pN+ BINV-8
• Micropapillary
• Metaplasticy HER2-positiveaa BINV-9
ER-negative
and
PR-negativeaa,bb HER2-negativeaa BINV-10
Favorable histologic typez:
• Pure tubular
• Pure mucinous
• Pure cribriform
• Adenoid cystic ER-positivebb and/or PR-positivebb
(conventional), secretory or Favorable Histologies (BINV-11)
carcinoma, and other ER-negative and PR-negative
salivary carcinomas
• Rare low-grade forms of
metaplastic carcinomay
• Other rare forms

aa Correlation of histology, HR, and HER2 status should always be done with
awareness of unusual/discordant or borderline results. See Principles of
x According to WHO, carcinoma of no special type (NST) encompasses Biomarker Testing (BINV-A).
multiple patterns including medullary pattern, cancers with neuroendocrine bb Although patients with cancers with 1%–100% ER immunohistochemistry (IHC)
expression, and other rare patterns. staining are considered ER-positive and eligible for endocrine therapies, there are
y There are rare subtypes of metaplastic carcinoma (eg, low-grade more limited data on the subgroup of cancers with ER-low–positive (1%–10%)
adenosquamous and low-grade fibromatosis-like carcinoma) that are results. The ER-low–positive group is heterogeneous with reported biologic
considered to have a favorable prognosis without adjuvant systemic therapies. behavior often similar to ER-negative cancers; thus, individualized consideration
z To be associated with favorable prognosis, the favorable histologic type of risks versus benefits of endocrine therapy and additional adjuvant therapies
should not be high grade, should be pure (>90% as classified on the surgical should be incorporated into decision-making. See Principles of Biomarker Testing
excision, not core biopsy alone), and should be HER2 negative. If atypical (BINV-A).
pathologic or clinical features are present, consider treating as ductal/NST. cc Definition of Menopause (BINV-O).

Note: All recommendations are category 2A unless otherwise indicated.

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Invasive Breast Cancer Discussion

SYSTEMIC ADJUVANT TREATMENT: HR-POSITIVE – HER2-POSITIVE DISEASEd,t,bb

Consider adjuvant endocrine therapydd
or
pN0 Consider adjuvant chemotherapya,ee
with trastuzumabff,gg (category 2B) and
Tumor ≤0.5 cm endocrine therapydd,hh
Adjuvant endocrine therapydd,hh
pT1, pT2, or pT3; pN1mi or
and pN0 or pN1mi Adjuvant chemotherapya,dd,ee with
Tumor 0.6–1.0 cm
(≤2 mm axillary trastuzumabff and endocrine therapydd,hh
node metastasis) Follow-Up
Adjuvant chemotherapya,ee
with (BINV-17)
• Ductal/NSTx Tumor >1 cm
• Lobular trastuzumab (category 1) and endocrine therapydd,hh
• Mixed
• Micropapillary Adjuvant chemotherapya,ee with trastuzumabff
pN+ (≥1 ipsilateral (category 1) and endocrine therapydd,hh,ii
metastases >2 mm) or
Adjuvant chemotherapya,ee with trastuzumabff +
pertuzumabjj (category 1, preferred) and endocrine
a For tools to aid optimal assessment and management of older adults, see NCCN therapydd,hh,ii
Guidelines for Older Adult Oncology.
d Principles of Biomarker Testing (BINV-A).
t Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J).
x According to WHO, carcinoma of NST encompasses multiple patterns including
medullary pattern, cancers with neuroendocrine expression, and other rare patterns. gg Adjuvant chemotherapy with weekly paclitaxel and trastuzumab can be
bb Although patients with cancers with 1%–100% ER IHC staining are considered considered for pT1,N0,M0, HER2-positive cancers, particularly if the primary
ER-positive and eligible for endocrine therapies, there are more limited data on the cancer is HR-negative. The absolute benefit of HER2-based systemic
subgroup of cancers with ER-low–positive (1%–10%) results. The ER-low–positive chemotherapy is likely negligible in patients with HR-positive cancers and tumor
group is heterogeneous with reported biologic behavior often similar to ER-negative size bordering on T1mic (<1 mm), when the estimated recurrence risk is less than
cancers; thus, individualized consideration of risks versus benefits of endocrine 5% and endocrine therapy remains a viable option for systemic treatment.
therapy and additional adjuvant therapies should be incorporated into decision- hh Consider adjuvant bisphosphonate therapy for risk reduction of distant
making. See Principles of Biomarker Testing (BINV-A). metastasis for 3–5 years in postmenopausal patients (natural or induced) with
dd See Adjuvant Endocrine Therapy and Principles of Adjuvant Endocrine Therapy high-risk node-negative or node-positive tumors.
(BINV-K). ii Consider extended adjuvant neratinib following adjuvant trastuzumab-containing
ee Preoperative/Adjuvant Therapy Regimens (BINV-L). therapy for patients with HR-positive, HER2-positive disease with a perceived high
ff The
 prognosis of patients with pT1a and pT1b tumors that are pN0 is uncertain even risk of recurrence. The benefit or toxicities associated with extended neratinib in
when HER2 is amplified or overexpressed. This is a population of patients with breast patients who have received pertuzumab is unknown.
cancer that was not studied in the available randomized trials. The decision for use jj Updated results from the adjuvant APHINITY trial in HER2-positive early
of trastuzumab therapy in this cohort of patients must balance the known toxicities of breast cancer, with a median follow-up of 8.4 years, have confirmed the
trastuzumab, such as cardiac toxicity, and the uncertain, absolute benefits that may benefit of adding pertuzumab to trastuzumab plus chemotherapy in preventing
exist with trastuzumab therapy. recurrences.

Note: All recommendations are category 2A unless otherwise indicated.

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SYSTEMIC ADJUVANT TREATMENT: HR-POSITIVE – HER2-NEGATIVE DISEASEd,t,bb

POSTMENOPAUSALcc PATIENTS with pT1–3 AND pN0 or pN+ TUMORS
Tumor ≤0.5 cm
Consider adjuvant endocrine
and
therapy (category 2B)dd
pN0
Adjuvant chemotherapya,ee followed
by endocrine therapydd,hh,kk
Not done (category 1)
Strongly or
Tumor >0.5 cm Adjuvant endocrine therapydd,hh,kk Follow-Up
• Ductal/NSTx consider
or (BINV-17)
• Lobular 21-gene RT-
pN1mi (≤2 mm axillary Recurrence Adjuvant endocrine therapy
PCR assay if
• Mixed node metastases) score <26 (category 1)dd,hh,kk
• Micropapillary candidate for
or
chemotherapy Adjuvant chemotherapya,ee followed
pN1 (1–3 positive nodes)kk Recurrence
(category 1) by
mm,nn score ≥26 endocrine therapydd,hh,kk (category 1)
Adjuvant chemotherapya,ee,oo
pN2/pN3 (≥4 ipsilateral followed by
metastases >2 mm)kk,ll endocrine therapydd,hh,kk (category 1)
a For tools to aid optimal assessment and management of older
adults, see NCCN Guidelines for Older Adult Oncology.
d Principles of Biomarker Testing (BINV-A).
t Special Considerations for Breast Cancer in Males (Sex Assigned at hh 
Consider adjuvant bisphosphonate therapy for risk reduction of distant metastasis for 3–5 years
Birth) (BINV-J). in postmenopausal patients (natural or induced) with high-risk node-negative or node-positive
x According to WHO, carcinoma of NST encompasses multiple
tumors.
patterns including medullary pattern, cancers with neuroendocrine kk Two years of adjuvant abemaciclib in combination with endocrine therapy can be considered
expression, and other rare patterns. in patients with HR+/HER2-negative, high-risk breast cancer (see eligibility criteria listed on
bb Although patients with cancers with 1%–100% ER IHC staining are
(BINV-K). In patients eligible for both adjuvant olaparib and abemaciclib, the optimal choice of
considered ER-positive and eligible for endocrine therapies, there are therapy and sequencing is not known.
more limited data on the subgroup of cancers with ER-low–positive ll There are few data regarding the role of gene expression assays in those with ≥4 ipsilateral
(1%–10%) results. The ER-low–positive group is heterogeneous with axillary lymph nodes. Decisions to administer adjuvant chemotherapy for this group should be
reported biologic behavior often similar to ER-negative cancers; thus based on clinical factors.
individualized consideration of risks versus benefits of endocrine mm Other
 prognostic gene expression assays may be considered to help assess risk of recurrence
therapy and additional adjuvant therapies should be incorporated into but have not been validated to predict response to chemotherapy. See Gene Expression
decision-making. See Principles of Biomarker Testing (BINV-A). Assays for Consideration of Adjuvant Systemic Therapy (BINV-N).
cc See Definition of Menopause (BINV-O). nn Patients with T1b tumors with low-grade histology and no LVI should be treated with endocrine
dd See Adjuvant Endocrine Therapy and Principles of Adjuvant monotherapy as the TAILORx trial did not include patients with such tumors.
Endocrine Therapy (BINV-K). oo Addition of 1 year of adjuvant olaparib is an option for select patients with germline BRCA1/2
ee Preoperative/Adjuvant Therapy Regimens (BINV-L). mutation after completion of adjuvant chemotherapy. See BINV-L.

Note: All recommendations are category 2A unless otherwise indicated.

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SYSTEMIC ADJUVANT TREATMENT: HR-POSITIVE - HER2-NEGATIVE DISEASEd,t,bb

PREMENOPAUSALcc PATIENTS with pT1–3 AND pN0 TUMORS
Consider adjuvant endocrine
Tumor ≤0.5 cm and pN0
therapy (category 2B)dd

Adjuvant chemotherapyee followed

by endocrine therapydd,hh ± ovarian
• Ductal/NSTx suppression/ablation (category 1)
Not done
• Lobular or
• Mixed Adjuvant endocrine therapydd,hh ±
• Micropapillary ovarian suppression/ablationdd,hh
Recurrence Adjuvant endocrine therapydd,hh ± Follow-Up
Strongly consider score ≤15 ovarian suppression/ablationdd,hh,pp
Tumor >0.5 cm 21-gene RT-PCR (BINV-17)
and assay if candidate Adjuvant endocrine therapydd,hh ±
pN0 for chemotherapy ovarian suppression/ablationdd,hh,pp
(category 1)mm,nn Recurrence or
score 16–25 Adjuvant chemotherapyee followed by
endocrine therapydd,hh,pp ± ovarian
suppression/ablation
Adjuvant chemotherapyee followed
Recurrence
by endocrine therapydd,hh ± ovarian
score ≥26
suppression/ablation

d Principles of Biomarker Testing (BINV-A).

t Special Considerations for Breast Cancer in Males (Sex Assigned at dd See Adjuvant Endocrine Therapy and Principles of Adjuvant Endocrine Therapy (BINV-K).
Birth) (BINV-J). ee Preoperative/Adjuvant Therapy Regimens (BINV-L).
x According to WHO, carcinoma of NST encompasses multiple hh Consider adjuvant bisphosphonate therapy for risk reduction of distant metastasis for
patterns including medullary pattern, cancers with neuroendocrine 3–5 years in postmenopausal patients (natural or induced) with high-risk node-negative or
expression, and other rare patterns. node-positive tumors.
bb Although patients with cancers with 1%–100% ER IHC staining are mm Other
 prognostic gene expression assays may be considered to help assess risk of
considered ER-positive and eligible for endocrine therapies, there are recurrence but have not been validated to predict response to chemotherapy. See Gene
more limited data on the subgroup of cancers with ER-low–positive Expression Assays for Consideration of Adjuvant Systemic Therapy (BINV-N).
(1%–10%) results. The ER-low–positive group is heterogeneous with nn Patients with T1b tumors with low-grade histology and no LVI should be treated with
reported biologic behavior often similar to ER-negative cancers; thus endocrine monotherapy as the TAILORx trial did not include patients with such tumors.
individualized consideration of risks versus benefits of endocrine pp In premenopausal patients with recurrence score <26, the addition of chemotherapy to
therapy and additional adjuvant therapies should be incorporated into endocrine therapy was associated with a lower rate of distant recurrence compared with
decision-making. See Principles of Biomarker Testing (BINV-A). endocrine monotherapy, but it is unclear if the benefit was due to the ovarian suppression
cc Definition of Menopause (BINV-O). effects promoted by chemotherapy.

Note: All recommendations are category 2A unless otherwise indicated.

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SYSTEMIC ADJUVANT TREATMENT: HR-POSITIVE - HER2-NEGATIVE DISEASEd,t,bb

PREMENOPAUSALcc PATIENTS with pT1–3 AND pN+ TUMORS

Not a candidate Adjuvant endocrine therapy

pN1mi (≤2 mm for chemotherapy ± ovarian suppression/
axillary node
Assess to ablationdd,hh,kk,pp
metastasis)
determine if
or
candidate for
pN1 (1–3 Adjuvant chemotherapyee followed
chemotherapy If candidate for
positive by endocrine therapy ± ovarian
nodes)kk chemotherapy consider
gene expression suppression/ablationdd,hh,kk,pp
or Follow-Up
• Ductal/NSTx assay to assess (BINV-17)
Adjuvant endocrine therapy + ovarian
• Lobular prognosispp,rr
suppression/ablationdd,hh,kk,pp
• Mixed
• Micropapillary
Adjuvant chemotherapyee
pN2/pN3 (≥4 ipsilateral followed by endocrine therapy
metastases >2 mm)kk,qq ± ovarian suppression/
ablationdd,hh,kk,oo (category 1)

d Principles of Biomarker Testing (BINV-A).

t Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J). kk Two years of adjuvant abemaciclib in combination with endocrine therapy
x According to WHO, carcinoma of NST encompasses multiple patterns including can be considered in patients with HR+/HER2-negative, high-risk breast
medullary pattern, cancers with neuroendocrine expression, and other rare patterns. cancer (see eligibility criteria listed on (BINV-K). In patients eligible for
bb Although patients with cancers with 1%–100% ER IHC staining are considered both adjuvant olaparib and abemaciclib, the optimal choice of therapy and
ER-positive and eligible for endocrine therapies, there are more limited data on the sequencing is not known.
subgroup of cancers with ER-low–positive (1%–10%) results. The ER-low–positive oo Addition of 1 year of adjuvant olaparib is an option for select patients with
group is heterogeneous with reported biologic behavior often similar to ER-negative germline BRCA1/2 mutation after completion of adjuvant chemotherapy.
cancers; thus individualized consideration of risks versus benefits of endocrine See BINV-L.
therapy and additional adjuvant therapies should be incorporated into decision- pp In premenopausal patients with RS <26, the addition of chemotherapy to
making. See Principles of Biomarker Testing (BINV-A). endocrine therapy was associated with a lower rate of distant recurrence
cc Definition of Menopause (BINV-O). compared with endocrine monotherapy, but it is unclear if the benefit was
dd See Adjuvant Endocrine Therapy and Principles of Adjuvant Endocrine Therapy due to the ovarian suppression effects promoted by chemotherapy.
(BINV-K). qq There are few data regarding the role of gene expression assays in those
ee Preoperative/Adjuvant Therapy Regimens (BINV-L). with ≥4 ipsilateral axillary lymph nodes. Decisions to administer adjuvant
hh Consider adjuvant bisphosphonate therapy for risk reduction of distant metastasis chemotherapy for this group should be based on clinical factors.
for 3–5 years in postmenopausal patients (natural or induced) with high-risk node- rr Gene Expression Assays for Consideration of Adjuvant Systemic Therapy
negative or node-positive tumors. (BINV-N).

Note: All recommendations are category 2A unless otherwise indicated.

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SYSTEMIC ADJUVANT TREATMENT: HR-NEGATIVE – HER2-POSITIVE DISEASEd,t

Consider adjuvant chemotherapya,ss
pN0 with trastuzumabff,gg (category 2B)
Tumor ≤0.5 cm
Consider adjuvant chemotherapya,ss
pN1mi with trastuzumabff,gg,hh
pT1, pT2, or pT3; and
Consider adjuvant chemotherapya,ss
pN0 or pN1mi (≤2 mm Tumor 0.6–1.0 cm with trastuzumabff,gg,hh
axillary node metastasis)
Follow-Up
(BINV-17)
• Ductal/NSTx Adjuvant chemotherapya,ss
• Lobular Tumor >1 cm with trastuzumabhh (category 1)
• Mixed
• Micropapillary Adjuvant chemotherapya,ss with
trastuzumabhh (category 1)
or
pN+ (≥1 ipsilateral metastases >2 mm) Adjuvant chemotherapya,ss with
trastuzumabhh + pertuzumabjj
(category 1, preferred)

a For tools to aid optimal assessment and management of older adults, see NCCN Guidelines for Older Adult Oncology.
d Principles of Biomarker Testing (BINV-A).
t Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J).
x According to WHO, carcinoma of NST encompasses multiple patterns including medullary pattern, cancers with neuroendocrine expression, and other rare patterns.
ff The
 prognosis of patients with T1a and T1b tumors that are pN0 is uncertain even when HER2 is amplified or overexpressed. This is a population of patients with
breast cancer that was not studied in the available randomized trials. The decision for use of trastuzumab therapy in this cohort of patients must balance the known
toxicities of trastuzumab, such as cardiac toxicity, and the uncertain, absolute benefits that may exist with trastuzumab therapy.
gg Adjuvant chemotherapy with weekly paclitaxel and trastuzumab can be considered for pT1,N0,M0, HER2-positive cancers, particularly if the primary cancer is HR-
negative. The absolute benefit of HER2-based systemic chemotherapy is likely negligible in patients with HR-positive cancers and tumor size bordering on T1mic (<1
mm), when the estimated recurrence risk is less than 5% and endocrine therapy remains a viable option for systemic treatment.
hh Consider adjuvant bisphosphonate therapy for risk reduction of distant metastasis for 3–5 years in postmenopausal patients (natural or induced) with high-risk node-
negative or node-positive tumors.
jj Updated results from the adjuvant APHINITY trial in HER2-positive early breast cancer, with a median follow-up of 8.4 years, have confirmed the benefit of adding
pertuzumab to trastuzumab plus chemotherapy in preventing recurrences.
ss Preoperative/Adjuvant Therapy Regimens (BINV-L).

Note: All recommendations are category 2A unless otherwise indicated.

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SYSTEMIC ADJUVANT TREATMENT: HR-NEGATIVE – HER2-NEGATIVE DISEASEd,t

pN0 No adjuvant therapytt

Tumor ≤0.5 cm
pN1mi Consider adjuvant chemotherapya,ee,hh,oo
pT1, pT2, or pT3; and pN0 or
pN1mi (≤2 mm axillary node Tumor 0.6–1.0 cm Consider adjuvant chemotherapya,ee,hh,oo
metastasis)
Follow-Up
(BINV-17)
• Ductal/NSTx Tumor >1 cm Adjuvant chemotherapya,ee,hh,oo (category 1)
• Lobular
• Mixed
• Micropapillary
• Metaplasticy

pN+ (≥1 ipsilateral metastases >2 mm) Adjuvant chemotherapya,ee,hh,oo (category 1)

a For tools to aid optimal assessment and management of older adults, see NCCN Guidelines for Older Adult Oncology.
d Principles of Biomarker Testing (BINV-A).
t Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J).
x According to WHO, carcinoma of NST encompasses multiple patterns including medullary pattern, cancers with neuroendocrine expression, and other rare patterns.
y There are rare subtypes of metaplastic carcinoma (eg, low-grade adenosquamous and low-grade fibromatosis-like carcinoma) that are considered to have a favorable
prognosis without adjuvant systemic therapies.
ee Preoperative/Adjuvant Therapy Regimens (BINV-L).
hh Consider adjuvant bisphosphonate therapy for risk reduction of distant metastasis for 3–5 years in postmenopausal patients (natural or induced) with high-risk node-
negative or node-positive tumors.
oo Addition of 1 year of adjuvant olaparib is an option for select patients with germline BRCA1/2 mutation after completion of adjuvant chemotherapy. See BINV-L.
tt In select patients with high-risk features (eg, young patients with high-grade histology), adjuvant chemotherapy may be considered (category 2B). See BINV-L.

Note: All recommendations are category 2A unless otherwise indicated.

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SYSTEMIC ADJUVANT TREATMENT: FAVORABLE HISTOLOGIESt,z

Consider adjuvant endocrine

<1 cm therapydd for risk reduction
pT1, pT2, or pT3;
and pN0 or pN1mi Consider adjuvant endocrine
1–2.9 cm
(≤2 mm axillary therapydd
node metastasis)
ER-positive
• Pure tubular ≥3 cm Adjuvant endocrine therapydd,hh
and/or
• Pure mucinous
PR-positive,
• Pure cribriform
HER2-negativeaa
pN+ (≥1 ipsilateral Adjuvant endocrine therapydd,hh Follow-Up
metastases >2 mm) ± adjuvant chemotherapya,ee (BINV-17)
• Adenoid cystic
(conventional),
secretory
• Carcinoma, and ER-negative
Limited available data support local therapy
other salivary and
only with consideration for systemic/targeted
carcinomas PR-negative,
therapies only in pN+ disease
• Rare low- HER2-negativeaa
grade forms
of metaplastic
carcinomay

a For tools to aid optimal assessment and management of older adults, see NCCN
Guidelines for Older Adult Oncology.
t Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) aa Correlationof histology, HR, and HER2 status should always be done with
(BINV-J). awareness of unusual/discordant or borderline results. See Principles of
y There are rare subtypes of metaplastic carcinoma (eg, low-grade Biomarker Testing (BINV-A).
adenosquamous and low-grade fibromatosis-like carcinoma) that are considered dd Adjuvant Endocrine Therapy and Principles of Adjuvant Endocrine Therapy
to have a favorable prognosis without adjuvant systemic therapies. (BINV-K).
z To be associated with favorable prognosis, the favorable histologic type should ee Preoperative/Adjuvant Therapy Regimens (BINV-L).
not be high grade, should be pure (>90% as classified on the surgical excision, hh Consider adjuvant bisphosphonate therapy for risk reduction of distant
not core biopsy alone), and should be HER2 negative. If atypical pathologic or metastasis for 3–5 years in postmenopausal patients (natural or induced) with
clinical features are present, consider treating as ductal/NST. high-risk node-negative or node-positive tumors.

Note: All recommendations are category 2A unless otherwise indicated.

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WORKUP PRIOR TO PREOPERATIVE SYSTEMIC THERAPY

CLINICAL STAGE ADDITIONAL WORKUPa

For operable breast

• Axillary assessment with exam cancers: see Breast and
Consider ultrasound Axillary Evaluation Prior
c≥T2vv or cN+ and M0 Percutaneous biopsy of suspicious nodesuu to Preoperative Systemic
or • CBC Therapy (BINV-13)
cT1c, cN0 HER2-positive • Comprehensive metabolic panel, including liver function tests and
disease alkaline phosphatase
or Additional tests to consider as clinically indicated
cT1c, cN0 TNBC • Chest diagnostic CT ± contrast
(For preoperative • Abdomen ± pelvis diagnostic CT with contrast or MRI with contrast
systemic therapy criteria, • Bone scan or sodium fluoride PET/CT (category 2B) For inoperable
see BINV-M 1) • FDG-PET/CTww breast cancers: see
• Breast MRIb (optional), with special consideration for Preoperative Systemic
mammographically occult tumors, if not previously done Therapy (BINV-15)

a For tools to aid optimal assessment and management of older adults, see NCCN Guidelines for Older Adult Oncology.
b Breast MRI may be useful for characterizing axillary and/or internal mammary nodal disease. See Principles of Dedicated Breast MRI Testing (BINV-B).
uu At the time of biopsy of the most suspicious axillary lymph node(s), a marker should be placed to allow for identification and removal at the time of definitive surgery.
vv If considering preoperative therapy, consider use of a gene expression assay during workup for postmenopausal patients with cN0, operable ER-positive, HER2-
negative disease (Iwata H, et al. Breast Cancer Res Treat 2019;173:123-133; Pease AM, et al. Ann Surg Oncol 2019;26:366-371).
ww FDG-PET/CT is most beneficial and accurate for advanced disease (stage III) and invasive ductal (compared to lobular) histology, but may be useful in selected
circumstances of earlier stage disease (stage IIA disease: T1N1, T2N0) such as: equivocal CT+ bone scan results; suspicion of undetected nodal and/or distant
disease; and treatment response assessment. An FDG-PET/CT may be utilized as an adjunct to, or in lieu of, initial standard staging and may be performed
simultaneously with diagnostic CT. Conversely, a bone scan or sodium fluoride PET/CT may not be needed if an upfront FDG-PET/CT clearly indicates consistent
findings on both PET and CT components.

Note: All recommendations are category 2A unless otherwise indicated.

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OPERABLE DISEASE: BREAST AND AXILLARY EVALUATION PRIOR TO PREOPERATIVE SYSTEMIC THERAPY

Prior to preoperative systemic therapy, perform:

• Core biopsy of breast with placement of image-
detectable clips or marker(s), if not previously
performed, should be performed prior to
preoperative therapy to demarcate the tumor bed
• Axillary imaging with ultrasound or MRI (if not Preoperative systemic Surgical Treatment and Adjuvant
previously done) therapy based on HR and Therapy After Preoperative Systemic
and HER2 statusee (BINV-M 1) Therapy (BINV-14)
• Biopsy + marker placement recommended of the
most suspicious and/or clinically positive axillary
lymph node, if not previously done; only the most
suspicious node should be marked and retrieved
along with SLNs

ee Preoperative/Adjuvant Therapy Regimens (BINV-L).

Note: All recommendations are category 2A unless otherwise indicated.

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OPERABLE DISEASE:
SURGICAL TREATMENT AND ADJUVANT THERAPY AFTER PREOPERATIVE SYSTEMIC TREATMENTxx
SURGICAL TREATMENT ADJUVANT THERAPY

Adjuvant systemic therapyyy (BINV-16) + WBRTp

• cN+ and ypN0: Adjuvant RT to the whole breast ± boost to the tumor bedzz;
BCS with and strongly consider comprehensive RNI with inclusion of any portion of the
surgical axillary undissected axilla at risk.aaa
staging (BINV-D) • Any ypN+: Adjuvant RT to the whole breast ± boost to the tumor bedzz; and
± oncoplastic comprehensive RNI with inclusion of any portion of the undissected axilla at
reconstructionn risk.
• Any cN0, ypN0: Adjuvant RT to whole breast ± boost to tumor bedzz
BCS possible
Adjuvant systemic therapyyy (BINV-16) + post-mastectomy RTp
• cN+ and ypN0: Strongly consider RT to the chest wall and comprehensive
RNI with inclusion of any portion of the undissected axilla at risk.aaa
• Any ypN+: RT is indicated to the chest wall + comprehensive RNI with
inclusion of any portion of the undissected axilla at risk.
• cT4, any N: RT is indicated to the chest wall + comprehensive RNI with
Mastectomy and surgical inclusion of any portion of the undissected axilla at risk.
• cT3, cN0, and ypN0: Consider RT to the chest wall + comprehensive RNI with
axillary staging (BINV-D) inclusion of any portion of the undissected axilla at risk.
± reconstructionu
BCS not possible Adjuvant systemic therapyyy (BINV-16), no RT
• Any cN0,ypN0: If axilla was assessed by SLNB or axillary node dissectionk

n Includes techniques such as local tissue rearrangement, local flaps, regional flaps, breast reduction, and mastopexy to allow for greater volumes of resection while
optimizing aesthetic outcomes in patients undergoing BCS.
p Principles of Radiation Therapy (BINV-I).
u Principles of Breast Reconstruction Following Surgery (BINV-H).
xx The
 accurate assessment of in-breast tumor or regional lymph node response to preoperative systemic therapy is difficult, and should include physical examination
and performance of imaging studies (mammogram and/or breast ultrasound and/or breast MRI) that were abnormal at the time of initial tumor staging. Selection of
imaging methods prior to surgery should be determined by the multidisciplinary team. MRI is more accurate than mammography for assessing tumor response to
neoadjuvant therapy.
yy Complete planned systemic therapy regimen course if not completed preoperatively.
zz Strongly consider RT boost for high-risk features (eg, high-grade disease, age <50 years).
aaa Based on emerging data, there may be subsets of patients who achieve pCR in nodes that may not benefit from RNI (in BCS setting) or PMRT + RNI (in mastectomy
setting). (Mamounas E, Bandos H, White J, et al. Loco-regional irradiation in patients with biopsy-proven axillary node Involvement at presentation who become
pathologically node-negative after neoadjuvant chemotherapy: Primary outcomes of NRG Oncology/NSABP B-51/RTOG 1304; Abstract GS02-07; SABCS 2023.)

Note: All recommendations are category 2A unless otherwise indicated.

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INOPERABLE OR LOCALLY ADVANCED DISEASE (NON-INFLAMMATORY):

PREOPERATIVE SYSTEMIC THERAPY AND SUBSEQUENT TREATMENT
RESPONSExx LOCOREGIONAL TREATMENT

Mastectomy and surgical

axillary stagingk Adjuvant systemic therapyyy (BINV-16)
Response to
+ reconstruction (optional)u and
preoperative
or Adjuvant RTp to the whole breast or chest
systemic therapyxx
BCS with surgical axillary wall and comprehensive RNI with inclusion of
and tumor is operable
stagingk,bbb ± oncoplastic any portion of the undissected axilla at risk.
reconstructionn
Preoperative
systemic
therapyee Response to
see BINV-M 1 preoperative Follow pathway
systemic therapyxx above
No response to and tumor is operable
Consider additional systemic
preoperative systemic
therapy and/or preoperative
therapyxx and/or tumor
radiationp
remains inoperable No response to
preoperative systemic Individualize
therapyxx and tumor treatment
is inoperable

k Considerations for Surgical Axillary Staging (BINV-D).

n Includes techniques such as local tissue rearrangement, local flaps, regional
flaps, breast reduction, and mastopexy to allow for greater volumes of resection
while optimizing aesthetic outcomes in patients undergoing BCS.
p Principles of Radiation Therapy (BINV-I).
u Principles of Breast Reconstruction Following Surgery (BINV-H). yy Complete
 planned systemic therapy regimen course, if not completed
ee Preoperative/Adjuvant Therapy Regimens (BINV-L). preoperatively.
xx The
 accurate assessment of in-breast tumor or regional lymph node response bbb For patients with skin and/or chest wall involvement (T4 non-inflammatory)
to preoperative systemic therapy is difficult, and should include physical prior to preoperative systemic therapy, breast conservation may be performed
examination and performance of imaging studies (mammogram and/or breast in carefully selected patients based on a multidisciplinary assessment of local
ultrasound and/or breast MRI) that were abnormal at the time of initial tumor recurrence risk. In addition to standard contraindications to breast conservation
staging. Selection of imaging methods prior to surgery should be determined (BINV-G), exclusion criteria for breast conservation include: inflammatory (T4d)
by the multidisciplinary team. MRI is more accurate than mammography for disease before preoperative systemic therapy and incomplete resolution of skin
assessing tumor response to preoperative therapy. involvement after preoperative systemic therapy.

Note: All recommendations are category 2A unless otherwise indicated.

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ADJUVANT SYSTEMIC THERAPY AFTER PREOPERATIVE SYSTEMIC THERAPYhh

RESPONSE/PATHOLOGIC STAGE ADJUVANT SYSTEMIC THERAPYdd,ee,hh,ii
AFTER PREOPERATIVE THERAPY

ypT0N0 or pCR Adjuvant endocrine therapy (category 1)

HR-positive/
HER2-negative ypT1–4,N0 Adjuvant endocrine therapy (category 1)
or + adjuvant olaparib if germline BRCA1/2 mutation CPS+EG score ≥3, and residual disease (category 1).
ypN≥1 Select patients may be eligible for adjuvant abemaciclib, see BINV-K for eligibility criteria.

ypT0N0 or pCR Complete up to 1 year of HER2-targeted therapy with trastuzumab (category 1) ± pertuzumab. If
node positive at initial staging, trastuzumab + pertuzumab (category 1).
HR-negative/
HER2-positive Ado-trastuzumab emtansine (category 1) alone for 14 cycles.ccc
If ado-trastuzumab emtansine discontinued for toxicity, then complete (up to) 1 year of HER2-directed
ypT1–4,N0 therapy with trastuzumab (category 1) ± pertuzumab. If node positive at initial staging, trastuzumab +
or pertuzumabjj (category 1)
ypN≥1 and Follow-Up
If HR-positive, adjuvant endocrine therapyii (category 1) (BINV-17)
HR-positive/
HER2-positive
ypT0N0 or pCR Endocrine therapy (category 1) + complete (up to) 1 year of HER2-directed therapy with trastuzumab
(category 1) ± pertuzumab. If node positive at initial staging, trastuzumab + pertuzumab (category 1)

ypT0N0 or pCR For high-riskddd: Adjuvant pembrolizumab (if pembrolizumab-containing regimen was given
preoperatively)
HR-negative/ Adjuvant pembrolizumab (if pembrolizumab-containing regimen was given preoperatively)eee
HER2-negative and/or
ypT1–4,N0
or Adjuvant capecitabine (6–8 cycles)ccc,eee
ypN≥1 and/or
Adjuvant olaparib for 1 year if germline BRCA1/2 mutationeee (category 1)

dd Principles of Adjuvant Endocrine Therapy (BINV-K). jj Updated results from the adjuvant APHINITY trial in HER2-positive early breast cancer,
ee Preoperative/Adjuvant Therapy Regimens (BINV-L). with a median follow-up of 8.4 years, have confirmed the benefit of adding pertuzumab to
hh Consider adjuvant bisphosphonate therapy for risk reduction of distant trastuzumab plus chemotherapy in preventing recurrences.
metastasis for 3–5 years in postmenopausal patients (natural or ccc Recommendations do not apply to residual DCIS (ypTis).
induced) with high-risk node-negative or node-positive tumors. ddd High-risk criteria include stage II–III TNBC. The use of adjuvant pembrolizumab (category
ii Consider extended adjuvant neratinib following adjuvant trastuzumab- 2A) may be individualized.
containing therapy for patients with HR-positive, HER2-positive disease eee There are no data on sequencing or combining adjuvant pembrolizumab with
with a perceived high risk of recurrence. The benefit or toxicities capecitabine or olaparib in patients who meet criteria for treatment with one or more of
associated with extended neratinib in patients who have received these agents. However, their sequential/combined use may be considered given high-risk
pertuzumab or ado-trastuzumab emtansine is unknown. of recurrence in patients with residual disease.

Note: All recommendations are category 2A unless otherwise indicated.

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SURVEILLANCE/FOLLOW-UP
Exam: Endocrine therapy:
• History and physical exam 1–4 times per year as clinically • For fertility concerns, see BINV-C.
appropriate for 5 y, then annually • Assess and encourage adherence to adjuvant endocrine
Genetic screening: therapy
• Periodic screening for changes in family history and genetic • Patients on tamoxifen:
testing indications and referral to genetic counseling as indicated, Age-appropriate gynecologic screening
see NCCN Guidelines for Genetic/Familial High-Risk Assessment: Routine annual pelvic ultrasound is not recommended
Breast, Ovarian, and Pancreatic • Patients on an aromatase inhibitor or who experience
Post surgical management: ovarian failure secondary to treatment should have
• Educate, monitor, and refer for lymphedema management, see monitoring of bone health with a bone mineral density
NCCN Guidelines for Survivorship: Lymphedema determination at baseline and periodically thereafterggg
Breast imaging: Lifestyle:
• Mammography every 12 mo, beginning 6 months or more after • Evidence suggests that active lifestyle, healthy diet,
Recurrent
completion of BCTfff limited alcohol intake, and achieving and maintaining an
Disease
• Routine imaging of reconstructed breast is not indicated ideal body weight (20–25 BMI) may lead to optimal breast
(BINV-18)
• For patients with germline mutations or family history of breast cancer outcomes
cancer, please refer to NCCN Guidelines for Genetic/Familial High- Communication:
Risk Assessment: Breast, Ovarian, and Pancreatic • Coordination of care between the primary care provider
Screening for metastases: and specialists is encouraged. Additionally, a personalized
• In the absence of clinical signs and symptoms suggestive of survivorship treatment plan including personalized
recurrent disease, there is no indication for laboratory or imaging treatment summary of possible long-term toxicity and
studies for metastases screening. clear follow-up recommendations is recommended. See
Post treatment monitoring: NCCN Guidelines for Survivorship
• Cardiotoxicity monitoring for patients who received left-sided Engagement:
radiation therapy, anthracyclines, or HER2-targeted therapy. • Patients frequently require follow-up encouragement in
For anthracycline-induced toxicity, see NCCN Guidelines for order to improve adherence to ongoing screening and
Survivorship medication adherence
• Provide guidance on risk of comorbidities

Studies indicate that annual mammograms are the appropriate frequency for surveillance of patients with breast cancer who have had BCS and RT with no clear advantage to shorter
fff
interval imaging. Patients should wait 6 to 12 months after the completion of RT to begin their annual mammogram surveillance. Suspicious findings on physical examination or
surveillance imaging might warrant a shorter interval between mammograms.

ggg The use of estrogen, progesterone, or selective ER modulators to treat osteoporosis or osteopenia in patients with breast cancer is discouraged. The use of a bisphosphonate (oral/IV)
or denosumab is acceptable to maintain or to improve bone mineral density and reduce risk of fractures in postmenopausal (natural or induced) patients receiving adjuvant aromatase
inhibitor therapy. Optimal duration of either therapy has not been established. Benefits of duration beyond 3 years or optimal duration beyond 3 years is not known. Factors to consider
for duration of anti-osteoporosis therapy include bone mineral density, response to therapy, and risk factors for continued bone loss or fracture. There are case reports of spontaneous
fractures after denosumab discontinuation. Patients treated with a bisphosphonate or denosumab should undergo a dental examination with preventive dentistry prior to the initiation of
therapy, and should take supplemental calcium and vitamin D. An FDA-approved biosimilar is an appropriate substitute for denosumab.

Note: All recommendations are category 2A unless otherwise indicated.

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RECURRENT/STAGE IV (M1) DISEASE

CLINICAL WORKUPa
STAGE
• History and physical exam
• Discuss goals of therapy, adopt shared decision-making, and document course of care
• CBC Treatment
• Comprehensive metabolic panel, including liver function tests and alkaline phosphatase of Local and
• Imaging for systemic staging: Regional Recurrence
Chest diagnostic CT ± contrast (BINV-19)
Abdomen ± pelvis diagnostic CT with contrast or MRI with contrast and
Brain MRI with contrast if suspicious CNS symptomshhh Supportive carelll
Spine MRI with contrast if back pain or symptoms of cord compression
Stage IV (M1) Bone scan or sodium fluoride PET/CT (category 2B)
or Useful in certain circumstances:
Recurrent ◊ FDG-PET/CT (consider FES-PET/CT for ER-positive disease)
X-rays of symptomatic bones and long and weight-bearing bones abnormal on bone scan Systemic Treatment of
• Biomarker testing: Recurrent Unresectable
Biopsy of at least first recurrence of disease (consider re-biopsy if progression) (local or regional) or
Evaluation of ER/PR and HER2 statusd,iii,jjj Stage IV (M1) (BINV-21)
Comprehensive germline and somatic profiling to identify candidates for targeted and
therapies,kkk see BINV-Q 6 Supportive carelll
• Genetic counseling if patient is at riske for hereditary breast cancer
• Assess for distressg
a For tools to aid optimal assessment and management of older adults, see NCCN
Guidelines for Older Adult Oncology.
d Principles of Biomarker Testing (BINV-A). jjj Inclinical situations where a biopsy cannot safely be obtained but the clinical
e For risk criteria, see NCCN Guidelines for Genetic/Familial High-Risk evidence is strongly supportive of recurrence, treatment may commence based
Assessment: Breast, Ovarian, and Pancreatic. on the ER/PR/HER2 status of the primary tumor. Since ER/PR and HER2 status
g See NCCN Guidelines for Distress Management. can change with treatment and metastatic progression, it may be appropriate to
hhh For the treatment of brain metastases, see NCCN Guidelines for Central consider repeat testing on new samples in these scenarios if management will
Nervous System Cancers. change.
iii False-negative ER and/or PR determinations occur, and there may be kkk Tumor tissue or plasma-based circulating tumor DNA (ctDNA) assays may be
discordance between the ER and/or PR determination between the primary used and each of these have benefits and limitations for diagnosis and disease
and metastatic tumor(s). Therefore, endocrine therapy with its low attendant progression. Tissue-based assays have greater sensitivity, but ctDNA may reflect
toxicity may be considered in patients with non-visceral or asymptomatic visceral tumor heterogeneity more accurately. If one specimen is negative for actionable
tumors, especially in patients with clinical characteristics predicting for an HR- biomarkers, testing on the alternative specimen can be considered.
positive tumor (eg, long disease-free interval, limited sites of recurrence, indolent lll See NCCN Guidelines for Palliative Care and NCCN Guidelines for Supportive
disease, older age). Care.

Note: All recommendations are category 2A unless otherwise indicated.

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TREATMENT OF LOCAL RECURRENCE: In-breast or Chest wall recurrencemmm (Without clinically overt axillary recurrence)

(For REGIONAL ± LOCAL RECURRENCE see BINV-20)

INITIAL (PRIOR SURGERY) PRIOR RT LOCAL-REGIONAL (CURRENT) TREATMENT

Repeat BCS + surgical axillary staging if no prior

No
ALNDnnn + RTp
BCS
Total mastectomyooo + surgical axillary staging if no
Yes
prior ALNDnnn + repeat RT if feasiblep,ppp Consider appropriate
systemic therapyrrr
(See BINV-K, BINV-L,
Surgical resection if feasibleqqq + surgical axillary
No BINV-P, BINV-Q)
stagingnnn + postmastectomy radiotherapy (PMRT)p
Mastectomy
Surgical resection if feasibleqqq + surgical axillary
Yes staging if no prior ALNDnnn +repeat RT, if feasiblep,ppp

p Principles of Radiation Therapy (BINV-I).

mmm Multidisciplinary approach is especially important in the management of breast cancer recurrence to consider all potential treatment options for optimal outcomes.
nnn In patients with a local breast recurrence after BCS who had a prior SLNB, a repeat SLNB may be considered although the accuracy of repeat SLNB is unproven.
After mastectomy, repeat SLNB may be considered although there are limited data in this setting.
ooo In selected patients who decline mastectomy and otherwise meet consensus criteria for radiotherapy omission or APBI/PBI, repeat BCS +/- adjuvant APBI/PBI may
be considered. There are limited data for a repeat BCS in this setting.
ppp The decision to use RT to treat locoregional recurrence must factor in any prior radiation to the area and the risk of late normal tissue toxicity from the sum of the
prior and planned radiation courses.
qqq Consider systemic therapy to best response, then resect if possible.
rrr See the Discussion for additional information.

Note: All recommendations are category 2A unless otherwise indicated.

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TREATMENT OF REGIONAL ± LOCAL RECURRENCEmmm

(For LOCAL ONLY RECURRENCE see BINV-19)

RECURRENCE INITIAL (PRIOR) LOCAL-REGIONAL (CURRENT) TREATMENT

TYPE TREATMENT

Surgical resection if feasibleqqq with

SLNB only ALND (for axillary recurrence) + RT if
feasiblep,ppp
Axillary
Surgical resection of gross diseaseqqq
ALND ± ALND (for axillary recurrence) if Consider appropriate systemic
feasible + RT if feasiblep,ppp therapyrrr
(See BINV-K, BINV-L, BINV-P,
BINV-Q)
Prior RT Repeat RT, if feasiblep,ppp
Supra/infra-clavicular,
Internal mammary
No prior RT RT (comprehensive or localized)

p See Principles of Radiation Therapy (BINV-I).

mmm Multidisciplinary approach is especially important in the management of breast cancer recurrence to consider all potential treatment options for optimal outcomes.
ppp The decision to use RT to treat locoregional recurrence must factor in any prior radiation to the area and the risk of late normal tissue toxicity from the sum of the
prior and planned radiation courses.
qqq Consider systemic therapy to best response, then resect if possible.
rrr See the Discussion for additional information.

Note: All recommendations are category 2A unless otherwise indicated.

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SYSTEMIC TREATMENT OF RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASEt

ER- and/or PR-positive; HER2-negatived,bb,uuu BINV-22

Add denosumab
zoledronic acid,
Bone disease present
or pamidronatettt
ER- and/or PR-positive; HER2-positived,bb,uuu BINV-24

Recurrent
unresectable
(local or
regional) or
stage IV (M1)
diseasesss
ER- and PR-negative; HER2-positived,bb BINV-26

Bone disease not present

ER- and PR-negative; HER2-negatived,bb BINV-27

d Principles of Biomarker Testing (BINV-A).
t Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J).
bb Although patients with cancers with 1%–100% ER IHC staining are considered ER-positive and eligible for endocrine therapies, there are more limited data on the
subgroup of cancers with ER-low–positive (1%–10%) results. The ER-low–positive group is heterogeneous with reported biologic behavior often similar to ER-negative
cancers; thus, individualized consideration of risks versus benefits of endocrine therapy and additional adjuvant therapies should be incorporated into decision-making.
See Principles of Biomarker Testing (BINV-A).
sss Routine surgical resection of the primary breast tumor is generally not indicated in the management of patients presenting with de novo stage IV (M1) disease.
Although there is no survival benefit, it may be considered for local control of the primary tumor. Discussion regarding management of the primary tumor in this setting
must be individualized.
ttt Denosumab, zoledronic acid, or pamidronate (all with calcium and vitamin D supplementation) should be given (category 1) in addition to systemic therapy or
endocrine therapy if bone metastasis is present, expected survival is ≥3 months, and renal function is adequate. Patients should undergo a dental examination
with preventive dentistry prior to initiation of this therapy. The optimal schedule for zoledronic acid is every 12 weeks. An FDA-approved biosimilar is an appropriate
substitute for denosumab.
uuu Baseline assessment of bone density recommended for patients receiving an aromatase inhibitor who are at risk of osteoporosis (eg, age >65, family history, chronic
steroids).

Note: All recommendations are category 2A unless otherwise indicated.

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SYSTEMIC TREATMENT OF RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE:

ER- AND/OR PR-POSITIVE; HER2-NEGATIVEd
Continue
therapy until
Progression
Visceral crisisvvv Consider initial systemic therapywww progressionzzz
(BINV-23)
or unacceptable
toxicityaaaa

Premenopausalcc Ovarian ablation or suppression + systemic therapyxxx,yyy

No visceral crisis
and
Prior endocrine
therapy within 1 y
Postmenopausalcc Systemic therapyxxx,yyy
Continue
endocrine
therapy until Progression
Ovarian ablation or suppression + systemic therapyxxx progressionzzz (BINV-23)
Premenopausalcc or or unacceptable
Selective ER modulatorsxxx toxicity
No visceral crisis
and
No prior
endocrine
therapy within 1 y
Postmenopausalcc Systemic therapyxxx

d Principles of Biomarker Testing (BINV-A).

cc Definition of Menopause (BINV-O).
vvv According to the 5th ESO-ESMO international consensus guidelines (Cardoso F, et al. Ann Oncol 2020;31:1623-1649) for advanced breast cancer visceral crisis
is defined as: “severe organ dysfunction, as assessed by signs and symptoms, laboratory studies and rapid progression of disease. Visceral crisis is not the mere
presence of visceral metastases but implies important organ compromise leading to a clinical indication for the most rapidly efficacious therapy.”
www Systemic Therapy Regimens for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-Q).
xxx Systemic Therapy for ER- and/or PR-Positive Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-P).
yyy If progression on initial endocrine therapy, switch to a different endocrine therapy option.
zzz Principles of Monitoring Metastatic Disease (BINV-R).
aaaa It is acceptable to switch to endocrine-based therapy (BINV-P) after disease stabilizes or response is observed

Note: All recommendations are category 2A unless otherwise indicated.

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SYSTEMIC TREATMENT OF RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE:

ER- AND/OR PR-POSITIVE; HER2-NEGATIVEd

If not endocrine therapy

refractory, consider: No clinical benefit after up to 3 sequential
Alternate endocrine endocrine therapy regimenszzz
Systemic therapywww,zzz
therapyiii,xxx ± targeted or
Progressionzzz therapy Symptomatic visceral disease
or unacceptable (see second-line therapy
toxicity on first-line options on BINV-P)
endocrine therapy

or
Most patients will be candidates for
multiple lines of systemic therapy to
Consider no further
palliate advanced breast cancer. At
Systemic therapywww cytotoxic therapybbbb
each reassessment clinicians should
and
assess value of ongoing treatment,
For those with Continue supportive care
the risks and benefits of an additional
visceral crisis: (See NCCN Guidelines for Palliative
line of systemic therapy, patient
Progressionzzz Alternate systemic Care and NCCN Guidelines for
performance status, and patient
or unacceptable therapywww Supportive Care)
preferences through a shared decision-
toxicity on first-line making process.
systemic therapy

d Principles of Biomarker Testing (BINV-A).

iii False-negative ER and/or PR determinations occur, and there may be discordance between the ER and/or PR determination between the primary and metastatic
tumor(s). Therefore, endocrine therapy with its low attendant toxicity may be considered in patients with non-visceral or asymptomatic visceral tumors, especially in
patients with clinical characteristics predicting for a HR-positive tumor (eg, long disease-free interval, limited sites of recurrence, indolent disease, older age).
www Systemic Therapy Regimens for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-Q).
xxx Systemic Therapy for ER- and/or PR-Positive Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-P).
zzz Principles of Monitoring Metastatic Disease (BINV-R).
bbbb The potential side effects of additional lines of therapy may outweigh any clinical benefit in a patient who has a compromised performance status. Patient
preference must be taken into account.

Note: All recommendations are category 2A unless otherwise indicated.

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SYSTEMIC TREATMENT OF RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE:

ER- and/or PR-POSITIVE; HER2-POSITIVEd

Systemic therapy + HER2-targeted therapywww,xxx

or Continue therapy until
Progression
Endocrine therapycccc ± HER2-targeted therapy progressionzzz
(BINV-25)
(if premenopausal,cc consider ovarian ablation or or unacceptable toxicity
suppression)xxx,dddd

d Principles of Biomarker Testing (BINV-A).

cc Definition of Menopause (BINV-O).
www Systemic Therapy Regimens for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-Q).
xxx Systemic Therapy for ER- and/or PR-Positive Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-P).
zzz Principles of Monitoring Metastatic Disease (BINV-R).
cccc If prior endocrine therapy within 1 y, consider a different endocrine therapy.
dddd For premenopausal patients, tamoxifen alone (without ovarian ablation/suppression) + HER2-targeted therapy is also an option.

Note: All recommendations are category 2A unless otherwise indicated.

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SYSTEMIC TREATMENT OF RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE:

ER- and/or PR-POSITIVE; HER2-POSITIVEd

No clinical Most patients will

benefit after up be candidates for
Consider alternate multiple lines of
Progressionzzz to 3 sequential Systemic therapy
endocrine therapy, systemic therapy to
on first-line endocrine therapy + HER2-targeted
if not endocrine palliate advanced Consider no further
endocrine regimens ± HER2- therapy until
refractoryiii,xxx breast cancer. At HER2-targeted
therapy ± HER2- targeted therapyzzz progression
targeted therapy
± HER2-targeted
or www,xxx,zzz each reassessment therapybbbb and
therapywww clinicians should continue supportive
Symptomatic
visceral disease assess value of care
ongoing treatment, See NCCN Guidelines
the risks and benefits for Palliative Care
Progressionzzz of an additional line and
Alternate of systemic therapy, NCCN Guidelines for
on systemic
systemic therapy Continue HER2-targeted therapy patient performance Supportive Care
therapy
+ HER2-targeted until progressionzzz,eeee status, and patient
+ HER2-targeted
therapywww preferences through
therapy
a shared decision-
making process.

d Principles of Biomarker Testing (BINV-A).

iii False-negative ER and/or PR determinations occur, and there may be discordance between the ER and/or PR determination between the primary and metastatic
tumor(s). Therefore, endocrine therapy with its low attendant toxicity may be considered in patients with non-visceral or asymptomatic visceral tumors, especially in
patients with clinical characteristics predicting for a HR-positive tumor (eg, long disease-free interval, limited sites of recurrence, indolent disease, older age).
www Systemic Therapy Regimens for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-Q).
xxx Systemic Therapy for ER- and/or PR-Positive Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-P).
zzz Principles of Monitoring Metastatic Disease (BINV-R).
bbbb The potential side effects of additional lines of therapy may outweigh any clinical benefit in a patient who has a compromised performance status. Patient
preference must be taken into account.
eeee Continue HER2-targeted therapy following progression on first-line HER2-targeted chemotherapy for metastatic breast cancer. The optimal duration of trastuzumab
in patients with long-term control of disease is unknown.

Note: All recommendations are category 2A unless otherwise indicated.

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SYSTEMIC TREATMENT OF RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE:

ER- and/or PR-NEGATIVE; HER2-POSITIVEd

Most patients will be candidates

Consider no further
for multiple lines of systemic
HER2-targeted
therapy to palliate advanced breast
therapybbbb and
Continue cancer. At each reassessment
Alternate continue supportive
Systemic therapy therapy until clinicians should assess value
systemic therapy care
+ HER2-targeted progressionzzz Progressionzzz of ongoing treatment, the risks
+ HER2-targeted NCCN Guidelines for
therapywww or unacceptable and benefits of an additional
therapywww,zzz,eeee Palliative Care
toxicity line of systemic therapy, patient
and
performance status, and patient
NCCN Guidelines for
preferences through a shared
Supportive Care
decision-making process.

d Principles of Biomarker Testing (BINV-A).

www Systemic Therapy Regimens for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-Q).
zzz Principles of Monitoring Metastatic Disease (BINV-R).
bbbb The potential side effects of additional lines of therapy may outweigh any clinical benefit in a patient who has a compromised
performance status. Patient
preference must be taken into account.
eeee Continue HER2-targeted therapy following progression on first-line HER2-targeted chemotherapy for metastatic breast cancer. The optimal duration of trastuzumab
in patients with long-term control of disease is unknown.

Note: All recommendations are category 2A unless otherwise indicated.

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SYSTEMIC TREATMENT OF RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE:

ER- AND/OR PR-NEGATIVE; HER2-NEGATIVEd

Most patients will be

candidates for multiple
lines of systemic therapy
to palliate advanced
Consider no further cytotoxic
breast cancer. At each
therapybbbb and continue
Continue reassessment clinicians
supportive care
therapy until should assess value
Alternative systemic NCCN Guidelines for
Systemic therapywww,ffff progressionzzz of ongoing treatment,
therapywww,ffff Palliative Care
or unacceptable the risks and benefits
and
toxicity of an additional line of
NCCN Guidelines for
systemic therapy, patient
Supportive Care
performance status,
and patient preferences
through a shared
decision-making process.

d Principles of Biomarker Testing (BINV-A).

www Systemic Therapy Regimens for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-Q).
zzz Principles of Monitoring Metastatic Disease (BINV-R).
bbbb The potential side effects of additional lines of therapy may outweigh any clinical benefit in a patient who has a compromised
performance status. Patient
preference must be taken into account.
ffff Targeted Therapies and Associated Biomarker Testing for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease BINV-Q (6).

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF BIOMARKER TESTING

HER2 TESTINGa,b
• HER2 testing should be performed on all new primary or newly metastatic breast cancers using methodology outlined in the ASCO/CAP HER2 testing
guideline.a
• A re-review of the pathology with consideration for repeat or consultative HER2 testing should be made if a Grade 1 (any histologic type), pure mucinous, pure
tubular, or pure cribriform carcinoma tests HER2-positive.a
• After a negative HER2 test result on initial biopsy sample, consider retesting on subsequent surgical or other additional sample if the initial sample was
suboptimal (eg, minimal invasive cancer was present, cold ischemic time or fixation was suboptimal), testing error is expected, additional samples contain
higher grade morphologically distinct cancer from the biopsy, to rule out heterogeneity in a high grade cancer, or if it will otherwise aid in clinical decision-
making.a
IHC 0,1+d HER2 (-)
Must reflex test with ISH (if same specimen),
HER2 testing Equivocal result or order new test with IHC or dual probe ISH (if
IHC 2+
by validated new specimen available).
immunohistochemistry IHC 3+ HER2 (+)
b,c
(IHC) assay
HER2-Negative:
• (Group 5) HER2/CEP17 ratio <2.0 AND average HER2 copy number <4.0 signals/cell
HER2-Negativef (Determined by concurrent IHC and ISH results):
• (Group 2) HER2/CEP17 ratio ≥2.0 AND average HER2 copy number <4.0 signals/cell and concurrent IHC 0-1+ or 2+
• (Group 3) HER2/CEP17 ratio <2.0 AND average HER2 copy number ≥6.0 signals/cell and concurrent IHC 0-1+
• (Group 4) HER2/CEP17 ratio <2.0 AND average HER2 copy number ≥4.0 and <6.0 signals/cell and concurrent IHC 0-1+ or 2+
HER2 testing by validated
dual-probee ISH assayb,c HER2-Positivef (Determined by concurrent IHC and ISH results):
• (Group 2) HER2/CEP17 ratio ≥2.0 AND average HER2 copy number <4.0 signals/cell and concurrent IHC 3+
• (Group 3) HER2/CEP17 ratio <2.0 AND average HER2 copy number ≥6.0 signals/cell and concurrent IHC 2+ or 3+
• (Group 4) HER2/CEP17 ratio <2.0 AND average HER2 copy number ≥4.0 and <6.0 signals/cell and concurrent IHC 3+

HER2-Positive:
• (Group 1) HER2/CEP17 ratio ≥2.0 AND average HER2 copy number ≥ 4.0 signals/cell

d The
distinction between HER2 IHC 0 and 1+ is currently clinically relevant in
the metastatic setting since patients with HER2 1+ or 2+/ISH negative results
a NCCN endorses the ASCO/CAP HER2 testing guideline. “Principles of HER2 Testing” (on primary or metastatic samples) may be eligible for treatment targeting
modified with permission from Wolff AC, Hammond MEH, Allison KH, et al. Human non-amplified levels of HER2 expression.
Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of e Single-probe ISH assays are not preferentially recommended but if used,
Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused cases with average HER2 copy number ≥4.0 and <6.0 signals/cell should
Update. J Clin Oncol 2018;36:2105-2122. base final results on concurrent IHC and if 2+ reflexed to dual probe ISH
b Laboratory must participate in a quality assurance accreditation program for HER2 testing.
f For ISH Groups 2–4 final ISH results are based on review of concurrent IHC,
testing. Otherwise, tissue specimen should be sent to an accredited laboratory for testing.
Health care systems and providers must cooperate to ensure the highest quality testing. with recounting of the ISH test by a second reviewer if IHC is 2+ (per 2018
c Evidence from trastuzumab adjuvant trials show that HER2 testing by ISH or IHC have CAP/ASCO Update recommendations). Additional report comments are
similar utility to predict clinical benefit from HER2-targeted therapy. recommended for negative final results in these ISH groups.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF BIOMARKER TESTING

HR TESTING
• HR testing (ER and PR) by IHC should be performed on any new primary • Laboratories should have standard operating procedures to maximize
or newly metastatic breast cancer using methodology outlined in the accuracy and reproducibility of results for cases with <10% ER staining
latest ASCO/CAP HR testing guideline.g DCIS should be tested for ER or weak intensity staining (to avoid false negatives). The status of
(PR not required). controls should be reported for cases with these results.
• ER testing should be used to determine if a patient is a candidate for • PR testing by IHC on invasive cancers can aid in the prognostic
endocrine therapies. classification of cancers and serve as a control for possible false-
Cancers with 1%–100% of cells positive for ER expression are negative ER results. Patients with ER-negative, PR-positive cancers may
considered ER-positive. Patients with these results are considered be considered for endocrine therapies, but the data on this group are
eligible for endocrine therapies (applies to DCIS and invasive cancers). noted to be limited. The same overall interpretation principles apply but
Invasive cancers with between 1%–10% ER positivity are considered PR should be interpreted as either positive (if 1%–100% of cells have
ER-low–positive. There are more limited data on the benefit of nuclear staining) or negative (if <1% or 0% of cells have nuclear staining).
endocrine therapies in this group, but they suggest possible benefit • Interpretation of any ER result by pathology should include evaluation
from endocrine treatment, so patients are considered eligible for this of the concordance with the histologic findings of each case. Clinicians
treatment (as above). However, this group is noted to be heterogeneous should be aware of when results are unusual and work with pathologists
and the biologic behavior of ER-low–positive cancers may be more to attempt to resolve (eg, repeat testing, consultative review) or explain
similar to ER-negative cancers. This should be considered in decision- atypical reported findings. See table below.
making for other adjuvant therapy and overall treatment pathway.
Cancers with <1% staining are considered ER-negative. Patients
with cancers with these results have not been shown to benefit from
endocrine therapies.
Summary of ER IHC Scoring/Interpretation Correlation of ER and Histology: Highly Unusual Results
Results Interpretation/ Highly Unusual ER-Negative Results Highly Unusual ER-Positive Results
(following ER testing by Report As: Low-grade invasive carcinomas of no Metaplastic carcinomas of all subtypes
validated IHC assay) special type (also known as invasive
ductal carcinoma)
0% to <1% of nuclei stain ER-negative
Lobular carcinomas (classic type) Adenoid cystic carcinomas and other
ER-low–positive salivary gland-like carcinomas of the breast
1%–10% of nuclei
1%–100% of stain (with recommended
comment) Pure tubular, cribriform, or mucinous Secretory carcinoma
nuclei stain carcinomas
>10% of nuclei stain ER-positive
Encapsulated papillary and solid Carcinomas with apocrine differentiation
papillary carcinomas (apocrine carcinoma)

g Allison
KH, Hammond MEH, Dowsett M, et al. Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update. J Clin Oncol
2020;38:1346-1366; Arch Pathol Lab Med 2020;144:545-563.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF DEDICATED BREAST MRI TESTING

See NCCN Guidelines for Breast Cancer Screening and Diagnosis for indications for screening MRI in patients at increased breast cancer risk.

Personnel, Facility, and Equipment Clinical Indications and Applications

• Breast MRI examinations are performed with IV contrast and should • May be used for staging evaluation to define extent of cancer or
be performed and interpreted by an expert breast imaging team presence of multifocal or multicentric cancer in the ipsilateral
working in concert with the multidisciplinary treatment team. breast, or as screening of the contralateral breast cancer at time
• Breast MRI examinations require a dedicated breast coil and breast of initial diagnosis (category 2B). There are no high-level data to
imaging radiologists familiar with the optimal timing sequences and demonstrate that the use of MRI to facilitate local therapy decision-
other technical details for image interpretation. The imaging center making improves local recurrence or survival.1
should have the ability to perform MRI-guided needle sampling and/ • May be helpful for breast cancer evaluation before and after
or image-guided localization of MRI-detected findings. preoperative systemic therapy to define extent of disease, response
to treatment, and potential for breast-conservation therapy.
• May be useful in identifying otherwise clinically occult disease
in patients presenting with axillary nodal metastases (cT0, cN+),
with Paget disease, or with invasive lobular carcinoma poorly (or
inadequately) defined on mammography, ultrasound, or physical
examination.
• False-positive findings on breast MRI are common. Surgical
decisions should not be based solely on the MRI findings. Additional
tissue sampling of areas of concern identified by breast MRI is
recommended.
• The utility of MRI in follow-up screening of most patients with prior
breast cancer is undefined and annual MRI is recommended in
patients with personal history of breast cancer who:
1) were diagnosed age ≤ 50 or
2) have dense breasts

1 Houssami N, Ciatto S, Macaskill P, et al. Accuracy and surgical impact of magnetic resonance imaging in breast cancer staging: systematic review and meta-analysis
in detection of multifocal and multicentric cancer. J Clin Oncol 2008;26:3248-3258.
2 Monticciolo DL, Newell MS, Moy L, Lee CS, Destounis SV. Breast cancer screening for women at higher-than-average risk: Updated recommendations from the ACR.
J Am Coll Radiol 2023;20:902-914.

Note: All recommendations are category 2A unless otherwise indicated.

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FERTILITY AND BIRTH CONTROL

See NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology

• All premenopausal patients should be informed about the potential • Although data are limited, hormone-based birth control is
impact of chemotherapy on fertility and asked about their desire discouraged regardless of the HR status of the patient's cancer.
for potential future pregnancies. Patients who may desire future • Alternative methods of birth control include intrauterine devices
pregnancies should be referred to fertility specialists before (IUDs), barrier methods, or, for patients with no intent of future
chemotherapy and/or endocrine therapy to discuss the options pregnancies, tubal ligation or vasectomy for the partner.
based on patient specifics, disease stage, and biology (which • Randomized trials have shown that ovarian suppression with
determine the urgency, type, and sequence of treatment). Timing GnRH agonist therapy administered during adjuvant chemotherapy
and duration allowed for fertility preservation, options inclusive in premenopausal patients with breast tumors (regardless of HR
of oocyte and embryo cryopreservation as well as evolving status) may preserve ovarian function and diminish the likelihood of
technologies, and the probability of successful pregnancies chemotherapy-induced amenorrhea.
subsequent to completion of breast cancer therapy are also to be • Smaller historical experiences in patients with ER-positive disease
discussed. have reported conflicting results with regard to the protective effect
• Although amenorrhea frequently occurs during or after of GnRH agonist therapy on fertility.
chemotherapy, it appears that the majority of patients <35 years • Breastfeeding following breast-conservation cancer treatment is
resume menses within 2 years of finishing adjuvant chemotherapy. not contraindicated. However, the quantity and quality of breast
• Menses and fertility are not necessarily linked. Absence of regular milk produced by the conserved breast may not be sufficient or
menses, particularly if the patient is taking tamoxifen, does not may be lacking some of the nutrients needed. Breastfeeding is
necessarily imply infertility. Conversely, the presence of menses not recommended during active treatment with chemotherapy and
does not guarantee fertility. There are limited data regarding endocrine therapy or within 6 months of completing trastuzumab or
continued fertility after chemotherapy. pertuzumab.
• Patients should be advised not to become pregnant while on any
systemic therapy and specific drug package inserts should be
consulted for recommendations.
• A prospective trial evaluated premenopausal women who had
completed between 18–30 months of endocrine therapy before
temporarily interrupting endocrine therapy for up to 2 years to
allow for pregnancy. At short-term follow-up, the risk of recurrence
was not increased among those women who enrolled or those who
became pregnant. This approach is an option for women who desire
pregnancy, although long-term safety is still unknown.

Note: All recommendations are category 2A unless otherwise indicated.

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CONSIDERATIONS FOR SURGICAL AXILLARY STAGING

No palpable lymph SLN not identified ALND level I/IIf
node at diagnosis
and limited
axillary lymph SLN negativec No further axillary surgery (category 1)
node involvement SLN
on imaging mapping and Meets ALL of the following criteriag: No ALND level I/IIf
confirmed by • cT1–T2, cN0
needle biopsy excisionb,c • No preoperative chemotherapy
± marker a Breast- • 1–2 positive SLNs
placement in the conserving • WBRT planned Yes
most suspicious to all No further
node surgery
SLN positivec axillary surgery
Micrometastases seen in SLNh

Clinically Mastectomye
suspicious Meets ALL of the following criteria:i
• cT1–T2, cN0 No ALND level I/IIf
(palpable) lymph
nodes FNA or • No preoperative chemotherapy
or core • 1–2 positive SLNsj
Significant axillary US-guided FNA biopsy • Adjuvant RT planned with intentional Consider no
lymph node Yes
or core biopsy inclusion of undissected axilla at risk further axillary
disease burden on negatived to all
imaging + marker surgeryk
or placement No preoperative chemotherapy
Preoperative recommendeda
systemic therapy FNA or
Consider ALND level I/IIf
being considered in the most core cN+ remains clinically
and suspicious preoperative Yes,
suspicious biopsy positive
lymph nodes at chemotherapy preoperative
diagnosis on exam node positive
chemotherapy
or imaging
cN+ converts to clinically SLNB
a If
node negative (category 2B)l
a positive lymph node is clipped or tattooed during biopsy, every effort
should be made to remove the clipped or tattooed node at the time of
surgery. Only the most suspicious node should be marked and retrieved g ACOSOG Z0011: Giuliano AE, et al. JAMA 2017;318:918-926.
along with SLNs to reduce the false negative rate. h Galimberti V, et al. Lancet Oncol 2013;14:297-305.
b SLN mapping injections may be peritumoral, subareolar, or subdermal. i EORTC AMAROS: Donker M, et al. Lancet Oncol 2014;15:1303-1310; Ruters E, et al.
c Sentinel node involvement is defined by multilevel node sectioning with Cancer Res 2019;79 GS4-01-GS04-01.
hematoxylin and eosin (H&E) staining. Cytokeratin IHC may be used j Limited data exist for ≥3 positive SLNs.
for equivocal cases on H&E. Routine cytokeratin IHC to define node k In the mastectomy setting, in patients who were initially cN0, who have positive
involvement is not recommended in clinical decision-making. nodes on SLNB, and have no axillary dissection, RT to the chest wall should include
d If clinically negative axilla before chemotherapy and then have a positive undissected axilla at risk ± RNI.
sentinel node after chemotherapy, consider completion axillary lymph node l Among patients shown to be N+ prior to preoperative systemic therapy, SLNB has
dissection or multidisciplinary tumor board discussion on appropriateness a >10% false-negative rate when performed after preoperative systemic therapy,
of radiation of axilla without further surgery. which can be improved by marking and removing the most suspicious biopsied node,
e Limited data exist for patients with mastectomy. using dual tracers, and by obtaining ≥3 sentinel nodes (targeted axillary lymph node
f Axillary Lymph Node Staging (BINV-E). dissection). (Caudle AS, et al. J Clin Oncol 2016;34:1072-1078.)

Note: All recommendations are category 2A unless otherwise indicated.

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AXILLARY LYMPH NODE STAGING

SLNB should be performed and is the preferred method of axillary lymph node staging if the patient is an appropriate SLNB candidate
(BINV-D).

In the absence of definitive data demonstrating superior survival, the performance of axillary staging may be considered optional in patients
who have particularly favorable tumors, patients for whom the selection of adjuvant systemic and/or RT is unlikely to be affected, those ≥70
years of age, or those with serious comorbid conditions.a

Level III dissection to the thoracic inlet should be performed only in cases with gross disease in level II and/or lll.
In the absence of gross disease in level II nodes, lymph node dissection should include tissue inferior to the axillary vein from the latissimus
dorsi muscle laterally to the medial border of the pectoralis minor muscle (level I/II).

Lymphedema is a potential side effect after the treatment of axillary lymph node surgery resulting from damage to the lymphatic system.
Early detection/diagnosis of lymphedema is key for optimal management. Consider pretreatment measurement of both arms as a baseline for
patients with risk factors for lymphedema. See NCCN Guidelines for Survivorship: Lymphedema (SLYMPH-1).

a Sentinel node biopsy may be omitted based on the SSO Choosing Wisely recommendation in patients ≥70 years of age with HR+/HER2-negative and pT1, cN0
tumors.

Note: All recommendations are category 2A unless otherwise indicated.

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MARGIN STATUS RECOMMENDATIONS AFTER BREAST-CONSERVING SURGERY (BCS) FOR INVASIVE CANCERS AND DCIS
• Margins should be evaluated on all surgical specimens from BCS. Requirements for optimal margin evaluation include:
Orientation of the surgical specimens
Description of the gross and microscopic margin status
Reporting of the distance, orientation, and type of tumor (invasive or DCIS) in relation to the closest margin.
• For mammographically detected DCIS with microcalcifications, complete resection should be documented by analysis of margins and
specimen radiography. Post-excision mammography can be considered if there is uncertainty.
• The NCCN Panel accepts the definitions of negative margins after breast-conservation therapy from the 2014 SSO/ASTRO Margins
Guideline1 for Stage I/II Invasive Cancers and the 2016 SSO/ASTRO/ASCO Guideline for DCIS.2 For patients with stage I or II invasive cancers
after BCS, a positive margin is defined as “ink on tumor” (any invasive cancer or DCIS cells on ink). These patients generally require further
surgery—either a re-excision to achieve a negative margin or a mastectomy. If re-excision is technically feasible to allow for BCS to achieve
“no ink on tumor,” this can be done with resection of the involved margin guided by the orientation of the initial resection specimen or re-
excision of the entire original excision cavity. There may be select patients with stage III invasive cancers who may be eligible for BCS. For
these patients, the margins status would be accessed with similar definitions.
DCIS
• For patients with pure DCIS treated by BCS and WBRT, a quantitative description of any tumor close to margin resection width of at least
2 mm is associated with a reduced risk of ipsilateral breast tumor recurrence (IBTR) relative to narrower negative margin widths, while
the routine practice of obtaining margins greater than 2 mm to further improve outcomes is not supported by the evidence. When there is
only minimal or focal DCIS involvement near the margin, clinical judgment should be utilized to weigh the risks of re-excision with risk of
recurrence for an individual patient.
• For patients with DCIS treated with excision alone (no WBRT), regardless of margin width, there is a substantially higher rate of IBTR than
treatment with excision and WBRT, even in predefined, patients who are low risk. Although the optimal margin width for treatment with
excision alone is unknown, it should be at least 2 mm, with some evidence suggesting improved IBTR rates with margin widths wider than 2
mm.
• DCIS with microinvasion (DCIS-M), defined as an invasive focus ≤1 mm in size, should refer to the DCIS margin definition when considering
the optimal margin width (>2 mm), given that the majority of DCIS-M is comprised of DCIS and systemic therapy utilization for this lesion
more closely reflects the treatment pattern for DCIS than for invasive carcinoma.

Continued

1 Moran MS, Schnitt SJ, Giuliano AE, et al. Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-
conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer. J Clin Oncol 2014;32:1507-1515.
2 Morrow M, Van Zee KJ, Solin LJ, et al. Society of Surgical Oncology-American Society for Radiation Oncology-American Society of Clinical Oncology Consensus
Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation in Ductal Carcinoma In Situ. J Clin Oncol 2016;34:4040-4046.

Note: All recommendations are category 2A unless otherwise indicated.

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MARGIN STATUS RECOMMENDATIONS AFTER BCS FOR INVASIVE CANCERS AND DCIS
Invasive Breast Cancer
• For invasive breast cancers that have a component of DCIS, regardless of the extent of DCIS, the negative margin definition of “no ink on
tumor” should be based on the invasive margin guideline. In this setting, “no ink on tumor” is recommended for either DCIS or invasive
cancer cells, primarily because the natural history, treatment, and outcomes of these lesions are more similar to invasive cancer than DCIS.
For specifically challenging cases, clinical judgment and discussion with the patient should precede routine re-excision.
• These margin recommendations cannot be applied directly to patients undergoing APBI/PBI,1 where data regarding local recurrence are
more limited. Furthermore, individualized clinical judgment should be utilized on a case-by-case basis, using postoperative mammography
to identify residual calcifications and clinical-pathologic factors such as quantitative extent of disease near margin, presence of extensive
intraductal component (EIC),3 young age, or multiple close margins to assist in identifying patients who may have an increased risk of IBTR
and therefore may be selected to benefit from re-excision.
• For patients with invasive breast cancer after BCS, with microscopically focally positive margins (in the absence of an EIC),3 the use of a
higher radiation boost dose to the tumor bed may be considered, since generally a boost to the tumor bed is recommended for patients at
higher risk of recurrence. See BINV-I.

No ink on tumor 2-mm margin No margin necessary

Invasive breast cancer X
Invasive breast cancer + DCIS X
Invasive breast cancer + extensive DCIS X
Invasive breast cancer (treated with neoadjuvant chemotherapy
X
followed by breast conservation therapy)4,5
Pure DCIS X
DCIS with microinvasion X
Pure LCIS* at surgical margin X
Atypia at surgical margin X

*For pleomorphic Lobular Carcinoma In Situ (LCIS), the optimal width of margins is not known.

1 Moran MS, Schnitt SJ, Giuliano AE, et al. Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-
conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer. J Clin Oncol 2014;32:1507-1515.
3 EIC is defined as an infiltrating ductal cancer where >25% of the tumor volume is DCIS and DCIS extends beyond the invasive cancer into surrounding normal breast
parenchyma.
4 Choi J, Laws A, Hu J, et al. Margins in breast-conserving surgery after neoadjuvant therapy. Ann Surg Oncol 2018;25:3541-3547.
5 Wimmer K, Bolliger M, Bago-Horvath Z, et al. Impact of surgical margins in breast cancer after preoperative systemic chemotherapy on local recurrence and survival.
Ann Surg Oncol 2020;27:1700-1707.

Note: All recommendations are category 2A unless otherwise indicated.

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SPECIAL CONSIDERATIONS TO BREAST-CONSERVATION THERAPY REQUIRING RT

Contraindications for breast-conservation therapy (BCT), defined as breast-conserving surgery followed by RT:
Absolute (mastectomy is recommended)
• Inflammatory breast cancer or invasive breast cancer with extensive skin or dermal lymphatic involvement
• Diffuse suspicious or malignant-appearing microcalcifications
• Inability to clear multiple positive pathologic margins after one or more re-excision attempts, see BINV-F
• Homozygous ATM mutation (often leads to ataxia-telangiectasia syndrome) (category 2B)a
• Multicentric disease with any of the following criteria1,b:
Receipt of neoadjuvant chemotherapy or endocrine therapy
Age ≤ 40
Triple negative breast cancer (ER-, PR-, and HER2-negative)
More than 2 lesions involving more than 2 quadrants by MRI evaluation
Any individual lesion ≥5 cm
BRCA mutation carrier
Multicentric pure DCIS
Inability to achieve negative margins (defined as no ink on tumor for invasive cancers ± DCIS), see BINV-F
cN2–N3
Any reason for precluding the delivery of adjuvant WBRT+ boost
• Patients diagnosed with gestational breast cancer who cannot receive RT within 12–16 weeksa. See PREG-1.

Relative (mastectomy should be considered, but BCT may be appropriate)

• Patients with a known genetic predisposition to breast cancerb
• Pathologic p53 mutation (Li-Fraumeni syndrome) (category 2B)a,b
(See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic)
• Active connective tissue disease involving the skin (eg, scleroderma or lupus)a
• A history of prior radiation therapy to the affected area; knowledge of doses and volumes prescribed is importanta,c,2

1 Boughey JC, Rosenkranz KM, Ballman KV, et al. Local recurrence after breast-conserving therapy in patients with multiple ipsilateral breast cancer: Results from
ACOSOG Z11102 (Alliance). J Clin Oncol 2023;41:3184-3193.
2 Arthur DW, Winter KA, Kuerer HM, et al. Effectiveness of breast-conserving surgery and 3-dimensional conformal partial breast reirradiation for recurrence of breast
cancer in the ipsilateral breast: The NRG Oncology/RTOG 1014 Phase 2 Clinical Trial. JAMA Oncol 2020;6:75-82.
a Contraindications to radiation delivery where toxicity may be increased.
b Patients with a known genetic predisposition to breast cancer may have an increased risk of contralateral or ipsilateral breast cancers after breast-conservation
therapy. Risk reduction strategies including prophylactic mastectomies should be discussed. See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast,
Ovarian, and Pancreatic.
c For patients >40 years of age with 2 biopsy proven cTis-cT2 lesions (with at least one site invasive) after MRI evaluation, intending on adjuvant whole breast radiation
+ boost, breast conservation therapy may be considered. See Boughey JC, et al. J Clin Oncol 2023;41:3184-3193.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF BREAST RECONSTRUCTION FOLLOWING SURGERY

No reconstruction required if ratio of
tumor to breast volume is small and
Breast-conserving minimal cosmetic deformity will result
surgeryc or Delayed fat grafting
(mark cavity with Consider oncoplastic reduction or
clips for subsequent mastopexy and simultaneous or delayed Delayed flap for correction of contour
RT planning, contralateral matching procedure RT
or defects performed ≥ 6 months after RT
particularly in cases
of oncoplastic tissue Consider bilateral breast reduction if
symptoms warrant breast reduction Contralateral reduction/mastopexy
rearrangement/ for symmetry
reduction)d or
Local tissue rearrangement, regional
flap (LD, partial LD, TDAP) Reconstruction Based on Planned
Adjuvant RT (BINV-H 2)
History of RT or adjuvant RT needed or
Carcinoma Reconstruction Based on History of
in situa,b RT (BINV-H 3)
or Mastectomye No history of RT/no adjuvant RT needed Implant, autologous, or combination reconstruction
Invasive
carcinoma Reconstruction Based on Unknown
Unknown RT history or need for RT History of RT or Unknown Need for
Postmastectomy RT (BINV-H 4)
IBC Delayed reconstruction
(Special Cases, [BINV-H 7])

a General Principles of Breast Reconstruction (BINV-H 5).

b Patient Factors Affecting Choice of Reconstruction (BINV-H 6).
c An evaluation of the likely cosmetic outcome of BCS should be performed prior to surgery.
Oncoplastic techniques for breast conservation can extend breast-conserving surgical options
in situations where the resection by itself would likely yield an unacceptable cosmetic outcome. d Consider staged partial mastectomy reconstruction (oncoplastic
Application of these oncoplastic techniques may reduce the need for mastectomy and decrease approaches) if preoperative margin status is unclear (lobular,
the need for a secondary surgery to minimize breast deformity. Patients should be informed of multifocal/centric).
the possibility of positive margins and potential need for secondary surgery, which could include e As with any mastectomy, there is a risk of locoregional cancer
either segmental re-excision, or mastectomy with or without loss of the nipple. Systematic recurrence, and evidence suggests skin-sparing or skin- and
oncoplastic reduction specimen orientation as well as highly specific operative documentation nipple-sparing mastectomy is probably equivalent to standard
regarding tissue rearrangement should be conducted. Enhanced communication between the mastectomy in this regard. Indications for post-mastectomy RT
radiation oncology team and reconstructive team will be necessary for boost cavity localization following skin-sparing mastectomy should not differ from standard
for RT treatment planning (Shah C, et al. Ann Surg Oncol 2018;25:2509-2511). mastectomy.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF BREAST RECONSTRUCTION FOLLOWING SURGERY

RECONSTRUCTION BASED ON PLANNED ADJUVANT RTa,b

Tissue expansion followed by exchange to implant prior to the initiation of RTk

2 stage: tissue expander
followed by permanent
implant (prepectoral, partial
submuscular, or total
submuscular tissue expander)
Implant-based Tissue expansion followed by RT and delayed exchange to implantj,k
reconstruction ≥ 6 months after completion of RT
plannedf

1 stage: direct to implanth

Immediate autologous reconstructioni

Autologous
reconstruction Delayed reconstruction ≥ 6 months after the completion of RTi
plannedg

Place tissue expander at the time of surgery, followed by expansion, RT, and delayed autologous reconstructioni,j
≥ 6 months after completion of RT

a General Principles of Breast Reconstruction (BINV-H 5).

b Patient Factors Affecting Choice of Reconstruction (BINV-H 6).
f The use of RT significantly increases the baseline risk of capsular contracture, i Consider delaying autologous reconstruction until after RT is completed, as RT to
aesthetic deformity, malposition, implant exposure, infection, and reconstructive a flap may cause loss of cosmesis and/or fat necrosis.
failure. j Consultation with radiation oncologists may be necessary to determine if volume
g Common donor sites for autologous tissue include the abdomen (ie, DIEP, MS- of contralateral tissue expander will affect RT treatment planning. In some cases,
TRAM, SIEA, free TRAM, pedicled TRAM), gluteal region (ie, SGAP, IGAP), thigh contralateral deflation may be required prior to CT simulation. Radiation oncology
(ie, TUG, VUG, DUG, PAP), or the back (ie, LD, TDAP). consultation should also be requested in cases of an anticipated close or positive
h Determined by preoperative size and ptosis, patient desire of postoperative size, deep margin, as this may impact the optimal placement of the expander (pre- vs.
and assessment intraoperatively of skin and soft tissue quality and perfusion, with subpectoral). Clips to identify the close/positive margins should be placed to
consideration for patient-specific relative contraindications (eg, smoking, obesity) assist in delineating the tumor bed boost.
to single-stage versus two-stage approaches. Healing issues may occur and k Exchange of tissue expander to implant should be timed to avoid any delay in
delay initiation of RT. adjuvant RT.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF BREAST RECONSTRUCTION FOLLOWING SURGERY

RECONSTRUCTION BASED ON PRIOR HISTORY OF RTa,b
Autologous (preferred) or combinationn

Adequatem 1 stage: direct to implant

Recurrent 2 stage: tissue expander

carcinoma after Assess soft tissue preoperatively followed by implant
breast conservation and intraoperativelyl
including RT

Inadequatem Autologous (preferred) or combinationn,o

Autologous (preferred) or combinationn,o

Adequatem
2 stage: tissue expander followed by
Delayed implant or autologous tissue
Assess soft tissue preoperatively
reconstruction after
and intraoperativelyl
mastectomy and RT

Inadequatem Autologous (preferred) or combinationn,o

a General Principles of Breast Reconstruction (BINV-H 5).

b Patient Factors Affecting Choice of Reconstruction (BINV-H 6). n Addition of latissimus flap to prosthetics in the patient who has previously had
l Assessment includes clinical examination and may also include intraoperative irradiation mitigates many of the effects specified in the previous footnote.
technologies to assess perfusion. o In the patient with delayed reconstruction, there is often limited soft tissue even
m In patients with a history of RT to the breast, implant-based reconstruction with the addition of a latissimus flap. Therefore, latissimus flap + tissue expander
carries a significantly increased risk of capsular contracture, aesthetic deformity, placement may be required if a permanent implant cannot be accommodated
malposition, implant exposure, infection, and reconstructive failure. under the latissimus flap.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF BREAST RECONSTRUCTION FOLLOWING SURGERY

RECONSTRUCTION BASED ON NO OR UNKNOWN HISTORY OF RT OR
UNKNOWN NEED FOR POSTMASTECTOMY RTa,b Exchange tissue expander to implant
No RT planned or
Tissue Convert to autologous tissue reconstruction
Adjuvant
expansion Exchange tissue expander to permanent implantf,j
chemotherapy
during (prior to initiation of RT, if no delay to initiation of RT or
Immediate placement planned
chemotherapy ≥ 6 months after RT)
of tissue expander at RT planned
the time of mastectomy or
(prepectoral, partial Conversion to autologous tissue reconstruction
submuscular, total ≥ 6 months after RT
submuscular tissue
No RT planned Tissue expansion followed by exchange to permanent
expander placement)f No adjuvant implant or autologous tissue reconstruction
chemotherapy
planned
RT planned Tissue expansion followed by RT; conversion
to permanent implant or autologous tissue ≥6
1 stage: direct to implanth months after completion of RT (category 2B)j
or Consider revisional surgeries or
Immediate autologous to the ipsilateral or contralateral Tissue expansion followed by exchange to
reconstruction or latissimus dorsi breast after RT if needed permanent implant before RT (if no delay to
with implant at time of mastectomyi initiation of RT)

RT not required Reconstruction with implant, autologous tissue, or a combination

Delayed reconstruction
RT required Reconstruction Based on History of RT (BINV-H 3)
a General Principles of Breast Reconstruction (BINV-H 5).
b Patient Factors Affecting Choice of Reconstruction (BINV-H 6). i Consider delaying autologous reconstruction until after RT is completed, as RT to
f The use of RT significantly increases the baseline risk of capsular contracture, a flap may cause loss of cosmesis and/or fat necrosis.
aesthetic deformity, malposition, implant exposure, infection, and reconstructive j Consultation with radiation oncologists may be necessary to determine if volume
failure. of contralateral tissue expander will affect RT treatment planning. In some
h Determined by preoperative size and ptosis, patient desire of postoperative size, cases, contralateral deflation may be required prior to CT simulation. Radiation
and assessment intraoperatively of skin and soft tissue quality and perfusion, oncology consultation should also be requested in cases of an anticipated
with consideration for patient-specific relative contraindications (eg, smoking, close or positive deep margin, as this may impact the optimal placement of
obesity) to single-stage versus two-stage approaches. Healing issues may occur the expander (pre- vs. subpectoral). Clips to identify the close/positive margins
and delay initiation of RT. should be placed to assist in delineating the tumor bed boost.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF BREAST RECONSTRUCTION FOLLOWING SURGERY

General Principles of Breast Reconstruction
• Breast reconstruction may be an option for any patient receiving surgical treatment for breast cancer. All patients undergoing breast
cancer treatment should be educated about breast reconstructive options as adapted to their individual clinical situation. However,
breast reconstruction should not interfere with the appropriate surgical, medical, and radiation management of the cancer or the scope of
appropriate surgical treatment for this disease. Coordinating consultation and surgical treatment with a reconstructive surgeon should be
executed within a reasonable time frame. The process of breast reconstruction should not govern the timing or the scope of appropriate
surgical treatment for this disease. The availability of or the practicality of breast reconstruction should not result in the delay or refusal of
appropriate surgical, medical, and radiation intervention.
• Some patients may choose not to have reconstruction after mastectomy. The option to undergo mastectomy alone with a surgically
optimized closure should be offered to all patients as part of a comprehensive discussion of reconstructive options. Achieving the optimal
result in this scenario may require additional procedures beyond the initial mastectomy. See BINV-H (6) for patient factors influencing choice
of reconstruction.
• Selection of reconstruction option is based on an assessment of cancer treatment, body habits of patients, obesity, smoking history,
comorbidities, and patient concerns. Smoking and obesity (WHO Class 2 and 3) increase the risk of perioperative complications for all types
of breast reconstruction. Patients with these high risk factors should be counseled about their increased risk for complications following
breast reconstruction, including donor site complications/hernias and bulges of the abdominal wall, delayed healing, mastectomy skin flap
necrosis, total flap failure (obesity), and implant failure (smoking).
• Nipple areolar reconstruction should be offered to patients if the nipple-areolar complex (NAC) has been removed as part of their cancer
treatment. Various techniques are available for nipple reconstruction. Three-dimensional (3-D) tattooing can be offered to patients as an
option for NAC reconstruction.
• Additionally, patients who are not satisfied with the cosmetic outcome following completion of breast cancer treatment should be offered
reconstructive surgery consultation.
• Patients known to harbor genetic mutations that increase the risk of breast cancer may opt to undergo bilateral prophylactic mastectomies
with reconstruction. Reconstruction can be performed with prosthetic, autologous tissue, or a combination of implant with autologous
tissue.
• Skin-sparing mastectomy should be performed by an experienced breast surgery team that works in a coordinated, multidisciplinary fashion
to guide proper patient selection for skin-sparing mastectomy, determine optimal sequencing of the reconstructive procedure(s) in relation
to adjuvant therapies, and perform a resection that achieves appropriate surgical margins.
• Revisional surgery may be necessary after breast reconstruction. This may include procedures such as fat grafting, mastopexy, direct
excision/suction-assisted lipectomy, contralateral procedures (in cases of unilateral reconstruction), and others. Patients should be informed
before reconstruction that revision surgery may be necessary.

Continued

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF BREAST RECONSTRUCTION FOLLOWING SURGERY

Patient Factors Influencing Breast Reconstruction
• Breast reconstruction is elective and patients may choose to not have breast reconstruction. Individual patients present preoperatively with
a variety of factors that may impact the choice of reconstruction, the risk of complications, donor site morbidity, and aesthetic result. Each
of these factors must be taken into account, along with patient desire, to choose the optimal method of reconstruction.
• Patient desire
The patient may have a strong feeling towards one form of reconstruction after being given the options. Breast reconstruction should be a
shared decision.
• Medical comorbidities
Medical comorbidities may preclude longer reconstructive procedures such as autologous tissue reconstruction in some patients.
The selection of the reconstructive method of choice should take into consideration patient comorbidities.
Poorly controlled diabetes is a risk factor for postoperative complications in both implant and autologous tissue reconstruction.
Patients should be screened for personal or familial thrombophilia. Thrombophilia may result in reconstructive failure of microsurgical
reconstruction or thromboembolic events.
• Tobacco use
Smoking has been associated with increased risk of delayed wound healing, mastectomy flap necrosis, NAC necrosis in the setting of
nipple-sparing mastectomy, infection, and failure of implant-based reconstruction. In free flap reconstruction, smoking increases the risk
of donor complications. Patients should be encouraged to stop smoking prior to reconstruction.
Smoking has not definitively been shown to increase the risk of microvascular thrombosis in free flap breast reconstruction.
• Breast size/shape
If patient has significant macromastia or ptosis, consideration can be given to a reduction pattern mastectomy with either implant-based or
autologous tissue reconstruction, or oncoplastic reduction techniques.
The volume limitations of implants may preclude an acceptable reconstruction in patients with macromastia if preservation of volume is a
priority.
• BMI
Patients with a markedly elevated BMI may be at increased risk of infectious complications and seromas as well as donor site
complications from autologous reconstruction, including delayed healing and hernia formation. Immediate reconstruction can be
performed, but delayed reconstruction can be considered if the patient is motivated to lose weight. Oncoplastic reduction techniques can
be considered if the breast is large/ptotic.
• Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL)
There exists an association between certain types of textured breast implants and BIA-ALCL. The risk appears to vary based on the
method of texturing. Patients with a past or current history of textured implants should follow up with their reconstructive surgeon.
See NCCN Guidelines for T-Cell Lymphomas.

Continued

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF BREAST RECONSTRUCTION FOLLOWING SURGERY

Special Cases
• Nipple-sparing mastectomy
NAC-sparing procedures may be an option in patients with cancer who are carefully selected by experienced multidisciplinary teams.
Retrospective data support the use of NAC-sparing procedures for early-stage breast cancer, DCIS, risk-reduction procedures, and in
some locally advanced invasive cancers (ie, with complete clinical response to preoperative chemotherapy and no nipple involvement with
cancer).
Contraindications to NAC include: Preoperative clinical or radiographic evidence of nipple involvement, including Paget disease, bloody
nipple discharge associated with malignancy, IBC, and/or imaging findings suggesting malignant involvement of the nipple or subareolar
tissues.
Nipple margin assessment is mandatory and should be clearly designated on the specimen.
Preoperative breast size, shape, and nipple position should also be considered in the decision to perform NAC-sparing mastectomy.
Patients with small to moderate breast volume with good nipple position are ideal candidates. In patients with large or significantly ptotic
breasts, NAC-sparing mastectomies may be offered in select cases by using various reduction patterns or delay techniques to augment
the NAC perfusion, either in an immediate or delayed fashion, as long as it does not delay oncologic care. Intraoperative assessment of the
NAC perfusion should also guide the decision to preserve the NAC or remove it.
Patients should be counseled on the risk of delayed healing, nipple necrosis, loss of pigmentation, loss of sensation, loss of projection,
and need for subsequent removal of the NAC.
Topical 2% nitroglycerine (45 mg total dose) used prophylactically has been shown to reduce mastectomy skin flap necrosis in both skin-
sparing mastectomy and nipple sparing mastectomy in one randomized control trial.
• Inflammatory breast cancer
Delayed reconstruction after mastectomy for IBC remains the clinical standard, for several reasons. The need to resect involved skin
negates the benefit of skin-sparing mastectomy for immediate reconstruction, and high rates of local and distant recurrence warrant
comprehensive, RNI in a timely fashion, which may be technically more challenging or subject to delay after immediate reconstruction.
Advances in multimodal therapy have improved 5-year survival in patients with IBC, justifying clinical studies to see if immediate
reconstruction may be appropriate for certain patients with IBC, but neither the outcomes nor the clinical features to predict such
outcomes are known at this time.
In the uncommon clinical circumstance that the extent of skin excision at the time of mastectomy precludes primary or local closure,
reconstruction of the chest wall defect with autologous tissue is necessary, and concomitant immediate reconstruction may be
accomplished.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF RADIATION THERAPY

Optimizing Delivery of Individual Therapy
• It is important to individualize RT planning and delivery.
3-D CT-based treatment planning should routinely be utilized to delineate target volumes & organs at risk, and assess dose distribution
across the entire treatment volume.
Radiation to the breast/chest wall and nodal regions is generally delivered with single energy or mixed energy photons ± electrons.
Treatment planning should be optimized to maximally improve homogeneity across the target volume while minimizing dose to organs at
risk.
Additional techniques such as respiratory control (deep inspiration breath-hold), prone positioning, and cardiac blocks may also be used
to try to further reduce dose to heart, lung, and adjacent normal tissue.
At a minimum, weekly imaging to verify treatment setup should be utilized. More frequent imaging may be needed for selected cases with
inconsistent reproducibility. Image-guided radiation therapy (IGRT) may be utilized with deep inspiration breath-hold (DIBH) technique to
reduce normal tissue exposure of the heart, lung or liver.
Dose-volume histograms (DVHs) should be used to evaluate, dose and constraints to normal tissues (ie, heart, lung), and planning target
volumes (PTVs).
• It is common for RT to follow chemotherapy when chemotherapy is indicated.
Whole Breast Radiation
• Target definition is the breast tissue at risk.
• RT dosing:
The whole breast should receive a hypofractionated dose of 40–42.5 Gy in 15–16 fractions; in selected cases 45–50.4 Gy in 25–28 fractions
may be considered.
A boost to the tumor bed is recommended in patients at higher risk for recurrence. Typical boost doses are 10–16 Gy in 4–8 fractions.
Ultra-hypofractionated WBRT of 28.5 Gy in 5 (once-a-week) fractions may be considered for selected pts over 50 years following BCS with
early-stage, node-negative disease, particularly those in whom a boost is not intended.a,b
• Lumpectomy cavity boost can be delivered using enface electrons, photons, or brachytherapy.

a Alternatively,
26 Gy in 5 daily fractions over one week may be considered, though data beyond 5 years for local relapse or toxicity are not yet available for this
regimen. [Murray Brunt A, Haviland JS, Wheatley DA, et al. Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late
normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial. Lancet 2020;395:1613-1626.]
b Brunt AM, Haviland JS, Sydenham M, et al. Ten-year results of FAST: A randomized controlled trial of 5-fraction whole-breast radiotherapy for early breast cancer. J
Clin Oncol 2020;38:3261-3272.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF RADIATION THERAPY

Post-mastectomy Radiation (including breast reconstruction)

• The target includes the ipsilateral chest wall and the entire mastectomy scar ± drain sites.
Regional nodal RT is typically delivered with the chest wall. See below.
• In the case of cT3N0, high-risk features for considering PMRT include, but are not limited to, young age and/or LVI.
• Based on anatomic considerations and presence of reconstruction, various 3-D-, IMRT, or VMAT techniques using photons and/or electrons are appropriate.
• PMRT details and dosing:
The routine use of bolus is not recommended. Bolus should be considered in the use of IBC or clinical-pathologic situations where the dose to the skin
may not be adequate.
Chest wall scar boost of 10-16 Gy/fx at 1.8 to 2.0 Gy/fx total 5-8 fractions may be delivered with or without bolus using electrons or photons.
Chest wall RT dose is 45-50.4 Gy at 1.8-2 Gy/fx in 25-28 fractions. Patients not undergoing breast reconstruction may alternatively receive 40 Gy at 2.67
Gy/fx or 42.5 Gy at 2.66 Gy/fx
Regional Nodal Radiation
• For supra/infra-clavicular and axillary nodes, prescription depth varies based on the patient anatomy.
• Regional nodes should be contoured when considering regional nodal RT. Refer to breast atlases for contouring guidelines.c,d
• RT dosing:
Regional node dose is 45–50.4 Gy at 1.8–2 Gy/fx; patients not undergoing breast reconstruction may alternatively receive 40 Gy at 2.67 Gy/fx or 42.5 Gy at
2.66 Gy/fx
A supplemental boost of RT can be delivered to grossly involved or enlarged lymph nodes (ie, internal mammary, supra/infra-clavicular) that have not
been surgically removed.
RT with Preoperative or Adjuvant Systemic Therapy
• In patients treated with preoperative systemic therapy, adjuvant RT is based on the maximal disease stage (ie, clinical stage, pathologic stage, tumor
characteristics) at diagnosis (before preoperative systemic therapy) and pathology results after preoperative systemic therapy.
• Sequencing of RT with systemic therapy:
It is common for RT to follow chemotherapy when chemotherapy is indicated. However,
– CMF (cyclophosphamide/methotrexate/fluorouracil) is the only standard regimen that can be given concurrently with RT.
– Capecitabine is typically given after completion of RT.
– Olaparib should be given after completion of RT.
Available data suggest that sequential or concurrent endocrine therapy with RT is acceptable. Due to compounding side effects, initiating endocrine
therapy at the completion of RT may be preferred.
◊ Abemaciclib should be initiated after completion of surgery/RT/chemotherapy, concurrently with endocrine therapy.
Adjuvant HER2-targeted therapy ± endocrine therapy may be delivered concurrently with RT.

c Offersen BV, Boersma LJ, Kirkove C, et al. ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer.
Radiother Oncol 2015;114:3-10.
d Gentile MS, Usman AA, Neuschler EI, et al. Contouring guidelines for the axillary lymph nodes for the delivery of radiation therapy in breast cancer: Evaluation of the
RTOG Breast Cancer Atlas. Int J Radiat Oncol Biol Phys 2015;93:257-265.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF RADIATION THERAPY

Accelerated Partial Breast Irradiation (APBI)/Partial Breast Irradiation (PBI)
• APBI/PBI offers comparable local control to WBRT in selected patients with low-risk early-stage breast cancer. However, the optimal
external beam-APBI/PBI technique/fractionation for minimizing long-term cosmesis effects has not been determined.
Patients are encouraged to participate in clinical trials.
The NCCN Panel recommends APBI/PBI for any patient with no BRCA 1/2 mutations meeting the criteria outlined in the 2016 ASTRO
consensus statement for guidance on APBI/PBI use.
According to the 2016 ASTRO criteria, patients aged ≥50 years are "suitable" for APBI/PBI if they have:
◊ Invasive ductal carcinoma measuring ≤2 cm (pT1 disease) with negative margin widths of ≥2 mm, no LVI, and ER-positive tumors
or
◊ Low/intermediate nuclear grade, screening-detected DCIS measuring size ≤2.5 cm with negative margin widths of ≥3 mm.
• RT dosing:

Regimen Method Reference

30 Gy/5 fractions QOD External Livi L, Meattini I, Marrazzo L, et al. Accelerated partial breast irradiation using intensity-modulated radiotherapy
(preferred) beam RT versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised controlled trial. Eur J Cancer
(EBRT)e 2015;51:451-463.
Meattini I, Marrazzo L, Saieva C, et al. Accelerated partial-breast irradiation compared with whole-breast
irradiation for early breast cancer: Long-term results of the randomized phase III APBI-IMRT-Florence Trial. J
Clin Oncol 2020;38:4175-4183.
40 Gy/15 fractions EBRT Coles CE, Griffin CL, Kirby AM, et al. Partial-breast radiotherapy after breast conservation surgery for patients
with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled,
phase 3, non-inferiority trial. Lancet 2017;390:1048-1060.
34 Gy/10 fractions BID Balloon/ Vicini FA, Cecchini RS, White JR, et al. Long-term primary results of accelerated partial breast irradiation after
Interstitial breast-conserving surgery for early-stage breast cancer: a randomised, phase 3, equivalence trial. Lancet
2019;394:2155-2164.
38.5 Gy/10 fractions BID EBRT Whelan TJ, Julian JA, Berrang TS, et al. External beam accelerated partial breast irradiation versus whole breast
irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast
cancer (RAPID): a randomised controlled trial. Lancet 2019;394:2165-2172.

e The protocol mandated IMRT.

Note: All recommendations are category 2A unless otherwise indicated.

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SPECIAL CONSIDERATIONS FOR BREAST CANCER IN MALES (SEX ASSIGNED AT BIRTH)

NCCN recommendations have been developed to be inclusive of individuals of all sexual and gender identities to the greatest extent
possible. On this page, the terms males and females refer to sex assigned at birth.
• Few males have been included in breast cancer trials.1 Therefore, recommendations regarding management of breast cancer in males are
generally extrapolated from findings of clinical trials focusing on breast cancer in females.
• Although there are some biologic and clinical differences between breast cancer in males and females, management of breast cancer in
males is similar overall to management of breast cancer in females, with the following special considerations pertinent to male patients2:
Genetics: The NCCN Panel recommends consideration of genetic testing for all males with breast cancer (See NCCN Guidelines for
Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic).
Breast surgery: Historically, males with breast cancer have undergone mastectomy more often than BCS. However, breast-conservation
therapy is increasingly being performed in males and evolving data indicate that breast conservation in males is associated with
equivalent outcomes to mastectomy and that it is safe and feasible. Decisions about breast conservation versus mastectomy in males
should be made according to similar criteria as for females.2-9
Axillary lymph node surgery: As in females, SLNB should be performed in the setting of male breast cancer with a clinically node-negative
axilla.2,4
RT: Indications for radiation after breast surgery in males with breast cancer are the same as for females with breast cancer.2,5,10,11
Use of molecular assays: Data are limited regarding the use of molecular assays to assess prognosis and to predict benefit from
chemotherapy in males with breast cancer.2 Available data suggest the 21-gene assay recurrence score provides prognostic information
in males with breast cancer.12,13
Preoperative/adjuvant systemic therapy: Chemotherapy with/without HER2-targeted therapy should be recommended for males with
breast cancer according to guidelines for females with breast cancer.2 Options for adjuvant endocrine therapy for males with breast
cancer include tamoxifen for 5–10 years or, if tamoxifen is contraindicated, a GnRH analog plus an aromatase inhibitor. In males, single-
agent adjuvant treatment with an aromatase inhibitor has been associated with inferior outcomes compared to tamoxifen alone, likely due
to inadequate estradiol suppression, and is not recommended.2,14-17
Follow-up after treatment for early-stage disease: There are only limited data to support screening for breast cancer in males.2 The NCCN
Panel recommends that bone density be assessed at baseline and every 2 years in males with breast cancer who receive adjuvant GnRH
analog therapy. Low bone density should be managed according to standard guidelines.18
Systemic therapy for advanced disease: Management of advanced breast cancer in males is similar to that in females; however, it is
preferred that when an aromatase inhibitor is used, a GnRH analog should be given concurrently.2 Available data suggest single-agent
fulvestrant has similar efficacy in males as in females.19 Newer agents such as CDK4/6 inhibitors in combination with an aromatase
inhibitor or fulvestrant, mTOR inhibitors, and PIK3CA inhibitors have not been systematically evaluated in clinical trials in males with
breast cancer. However, available real-world data suggest comparable efficacy and safety profiles and it is reasonable to recommend
these agents to males based on extrapolation of data from studies comprised largely of female participants with advanced breast cancer.
Indications for and recommendations regarding chemotherapy, HER2-targeted therapy, immunotherapy, and PARP inhibitors for advanced
breast cancer in males are similar to those for advanced breast cancer in females.1

References

Note: All recommendations are category 2A unless otherwise indicated.

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SPECIAL CONSIDERATIONS FOR BREAST CANCER IN MALES (SEX ASSIGNED AT BIRTH)

REFERENCES
1 Duma N, Hoversten KP, Ruddy KJ. Exclusion of male patients in breast cancer clinical trials. JNCI Cancer Spectr 2018;2:pky018.
2 Gao Y, Goldberg JE, Young TK, et al. Breast cancer screening in high-risk men: A 12-year longitudinal observational study of male breast imaging utilization and
outcomes. Radiology 2019;293:282-291.
3 Cardoso F, Bartlett JMS, Slaets L, et al. Characterization of male breast cancer: results of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast
Cancer Program. Ann Oncol 2018;29:405-417.
4 Cloyd JM, Hernandez-Boussard T, Wapnir IL. Outcomes of partial mastectomy in male breast cancer patients: analysis of SEER, 1983-2009. Ann Surg Oncol
2013;20:1545-1550.
5 Bateni SB, Davidson AJ, Arora M, et al. Is breast-conserving therapy appropriate for male breast cancer patients? A National Cancer Database analysis. Ann Surg
Oncol 2019;26:2144-2153.
6 Zaenger D, Rabatic BM, Dasher B, Mourad WF. Is breast conserving therapy a safe modality for early-stage male breast cancer? Clin Breast Cancer
2016;16:101-104.
7 Leone J, Zwenger AO, Leone BA, et al. Overall survival of men and women with breast cancer according to tumor subtype: A population-based study. Am J Clin
Oncol 2019;42:215-220.
8 Elmi M, Sequeira S, Azin A, et al. Evolving surgical treatment decisions for male breast cancer: an analysis of the National Surgical Quality Improvement Program
(NSQIP) database. Breast Cancer Res Treat 2018;171:427-434.
9 Fields EC, DeWitt P, Fisher CM, Rabinovitch R. Management of male breast cancer in the United States: a surveillance, epidemiology and end results analysis.
Int J Radiat Oncol Biol Phys 2013;87:747-752.
10 Flynn LW, Park J, Patil SM, et al. Sentinel lymph node biopsy is successful and accurate in male breast carcinoma. J Am Coll Surg 2008;206:616-621.
11 Jardel P, Vignot S, Cutuli B, et al. Should adjuvant radiation therapy be systematically proposed for male breast cancer? A systematic review. Anticancer Res
2018;38:23-31.
12 Massarweh SA, Sledge GW, Miller DP, et al. Molecular characterization and mortality from breast cancer in men. J Clin Oncol 2018;36:1396-1404.
13 Grenader T, Yerushalmi R, Tokar M, et al. The 21-gene recurrence score assay (Oncotype DX) in estrogen receptor-positive male breast cancer: experience in
an Israeli cohort. Oncology 2014;87:1-6.
14 Hayes FJ, Seminara SB, Decruz S, et al. Aromatase inhibition in the human male reveals a hypothalamic site of estrogen feedback. J Clin Endocrinol Metab
2000;85:3027-3035.
15 Mauras N, O'Brien KO, Klein KO, Hayes V. Estrogen suppression in males: metabolic effects. J Clin Endocrinol Metab 2000;85:2370-2377.
16 Eggemann H, Ignatov A, Smith BJ, et al. Adjuvant therapy with tamoxifen compared to aromatase inhibitors for 257 male breast cancer patients. Breast Cancer
Res Treat 2013;137:465-470.
17 Harlan LC, Zujewski JA, Goodman MT, Stevens JL. Breast cancer in men in the United States: a population-based study of diagnosis, treatment, and survival.
Cancer 2010;116:3558-3568.
18 Gralow JR, Biermann JS, Farooki A, et al. NCCN Task Force Report: Bone Health In Cancer Care. J Natl Compr Canc Netw 2013;11 Suppl 3:S1-50; quiz S51.
19 Zagouri F, Sergentanis TN, Chrysikos D, et al. Fulvestrant and male breast cancer: a case series. Ann Oncol 2013;24:265-266.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF ADJUVANT ENDOCRINE THERAPY

(for pT1-3pN+M0)
General Principles Ovarian function assessment
• Hormone receptor-positive (HR+) tumors: Breast tumors may be positive for • Menopausal status cannot be determined while receiving OFS.a
estrogen receptors (ER+), progesterone receptors (PR+) or both (ER+/PR+). See • Monitor estradiol and follicle-stimulating hormone (FSH)/LH levels:
Principles of Biomarker Testing (BINV-A). If under 60 y and amenorrheic for ≤12 months prior to treatment
ER+ tumors: ER testing should be used to determine if a patient is a candidate with adjuvant endocrine therapy
for endocrine therapies.a Patients with cancers with 1%–100% ER IHC staining Amenorrheic after chemotherapy or after tamoxifen +/- ovarian
are considered ER+ and eligible for endocrine therapies, there are limited function suppression (OFS).
efficacy data on the subgroup of cancers with ER-low-positive (1%–10%) results. After switching from tamoxifen to an AI, or if taken off OFS
The ER-low-positive group is heterogeneous with reported biologic behavior Prior to next dose of GNRH agonist, particularly in women under
often similar to ER-negative cancers; thus, individualized consideration of risks the age of 45. Frequency of testing of estradiol and FSH/LH levels
versus benefits of endocrine therapy and additional adjuvant therapies should should be individualized.
be incorporated into decision-making. • AI can stimulate ovarian function. If vaginal bleeding occurs while
PR+ tumors: Patients with ER-negative, PR+ cancers may be considered for on AI, contact physician immediately.
endocrine therapies, but the data on this group are noted to be limited. The same Methods for OFS
overall interpretation principles apply but PR should be interpreted as either • GNRH agonists
positive (if 1%–100% of cells have nuclear staining) or negative (if <1% or 0% of Goserelin 3.6 mg SC every 4w or 10.8 mg SC every 12w
cells have nuclear staining). Leuprolide 3.75–7.5 mg IM every 4w or 11.25–22.5 mg IM every 12w
• Considering that majority of all HR+ breast cancers are ER+ or ER+/PR+ and ER- • Radiation therapy
negative/PR+ tumors are relatively uncommon, ER and/or PR+ tumors are referred • Bilateral oophorectomy
to as HR+ throughout the guidelines. Initiation of OFS
• The magnitude of risk reduction from adjuvant endocrine therapy is dependent on: • With start of chemotherapy (neoadjuvant or adjuvant)
Level of ER expression: Low ER+ expression is less likely to benefit from • If no chemotherapy planned, then OFS should be started alone for
endocrine therapy. at least 1-2 cycles or concurrently with tamoxifen until estradiol
Recurrence score (RS) on gene expression assay test results: Patients with high level in postmenopausal range at which time an aromatase inhibitor
RS will gain relatively less benefit from adjuvant endocrine alone compared to could considered.
those with low RS. Concurrently with RT or upon completion
Candidates for ovarian suppression + endocrine therapy Duration of OFS
• Premenopausal • 5 years optimal according to SOFT and TEXT trial. No efficacy or
• Endocrine sensitive tumors with high enough recurrence risk where the additional safety date to support prolonged OFS. It is encouraged to complete
absolute decrease in recurrence compared with tamoxifen alone is worth the a minimum 2 years of OFS (The 8-year DFS was 85.4% with OFS +
additional toxicity (young age, high-grade tumor, lymph node involvement).b tamoxifen versus 80.2% with tamoxifen alone.c
• Premenopausal patients wishing to continue adjuvant endocrine
therapy after OFS stopped should use tamoxifen.

a Definition of Menopause (BINV-O).

b A balanced discussion of the risks and benefits associated with ovarian suppression therapy is critical, including the potential side effects of premature menopause.
Aromatase inhibitor or tamoxifen for 5 years plus ovarian suppression should be considered, based on SOFT and TEXT clinical trial outcomes, for premenopausal
patients at higher risk of recurrence (ie, young age, high-grade tumor, lymph node involvement).
c Baek SY, Noh WC, Ahn SH, et al. Adding ovarian suppression to tamoxifen for premenopausal women with hormone receptor-positive breast cancer after
chemotherapy: An 8-year follow-up of the ASTRRA Trial. J Clin Oncol 2023;41:4864-4871.

Note: All recommendations are category 2A unless otherwise indicated.

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ADJUVANT ENDOCRINE THERAPYd,e,f,g Aromatase inhibitor for 5 yk (category 1)

Postmenopausala or
Tamoxifenj for 5 y (category 1) Consider tamoxifenj for an additional 5 y to complete 10 y
± ovarian suppression or
ablationb,h (category 1) Consider tamoxifenj for an additional 5 y to complete 10 y
Premenopausal Premenopausala,i or
at diagnosisa,h,i or No further endocrine therapy
Aromatase inhibitor for 5 yk
+ ovarian suppression or
ablationb,h (category 1) Consider aromatase inhibitor
for an additional 3–5 yk
Aromatase inhibitork for 5 y (category 1)
or
Aromatase inhibitork for 2–3 y (category 1) Tamoxifenj to complete 5 y of endocrine therapy (category 1)
or Aromatase inhibitor to complete 5 yk of endocrine
therapy (category 1)
Tamoxifenj for 2–3 y or
Up to 5 y of an aromatase inhibitork (category 2B)
Postmenopausal Aromatase inhibitor for 5 yk (category 1)
Tamoxifenj for 4.5–6 y or
at diagnosisa
Consider tamoxifenj for an additional 5 y to complete 10 y
Patients with a contraindication to aromatase Tamoxifenj for 5 y (category 1)
inhibitors, who decline aromatase inhibitors, or or
who are intolerant to aromatase inhibitors Consider tamoxifenj for up to 10 y
a Definition of Menopause (BINV-O).
b A balanced discussion of the risks and benefits associated with ovarian suppression
therapy is critical, including the potential side effects of premature menopause. Aromatase
inhibitor or tamoxifen for 5 years plus ovarian suppression should be considered, based h Evidence
 suggests that the magnitude of benefit from surgical or radiation ovarian
on SOFT and TEXT clinical trial outcomes, for premenopausal patients at higher risk of ablation in premenopausal patients with HR-positive breast cancer is similar to that
recurrence (ie, young age, high-grade tumor, lymph node involvement).d If patient is not achieved with CMF alone.
postmenopausal, sequential evaluation of hormonal status is recommended to consider i Safety data support administration of GnRH agonists before or with chemotherapy,
an alternative endocrine agent. especially if there is a goal to enhance fertility preservation. They can also be
e Baseline assessment of bone density recommended for patients receiving an aromatase initiated after chemotherapy in patients who remain premenopausal.
inhibitor who are at risk of osteoporosis (eg, age >65, family history, chronic steroids). j Some SSRIs like fluoxetine and paroxetine decrease the formation of endoxifen,
f The use of a bisphosphonate (oral/IV) or denosumab is acceptable to maintain or to 4-OH tamoxifen, and active metabolites of tamoxifen, and may impact its efficacy.
improve bone mineral density and reduce risk of fractures in postmenopausal (natural Caution is advised about coadministration of these drugs with tamoxifen. However,
or induced) patients receiving adjuvant aromatase inhibitor therapy. An FDA-approved SNRIs (citalopram and venlafaxine) appear to have minimal impact on tamoxifen
biosimilar is an appropriate substitute for denosumab. metabolism. At this time, based on current data the panel recommends against
g In patients with HR-positive/HER2-negative, high-risk breast cancer (ie, those with ≥4 CYP2D6 gene testing for patients being considered for tamoxifen therapy.
positive lymph nodes (confirmed preoperatively and/or at surgery), or 1–3 positive lymph k The three selective aromatase inhibitors (ie, anastrozole, letrozole, exemestane)
nodes with either grade 3 disease or tumor size ≥5 cm (on pre-operative imaging and/ have shown similar anti-tumor efficacy and toxicity profiles in randomized studies in
or at surgery), 2 years of adjuvant abemaciclib can be considered in combination with the adjuvant and preoperative settings. The optimal duration of aromatase inhibitors
endocrine therapy (category 1, preferred). In patients eligible for both adjuvant olaparib in adjuvant therapy is uncertain. Patients with lymph node involvement may benefit
and abemaciclib, the optimal sequence is not known. from extended aromatase inhibitor duration (7.5–10 years total).

Note: All recommendations are category 2A unless otherwise indicated.

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PREOPERATIVE/ADJUVANT THERAPY REGIMENSa

The regimens listed in the table for HER2-negative disease are all category 1 (except where indicated) when used in the adjuvant setting.

HER2-Negative
Preferred Regimens:
• Dose-dense AC (doxorubicin/cyclophosphamide) followed or preceded by paclitaxel every 2 weeksb
• Dose-dense AC (doxorubicin/cyclophosphamide) followed or preceded by weekly paclitaxelb
• TC (docetaxel and cyclophosphamide)
• Olaparib, if germline BRCA1/2 mutationsc,d
• High-riske TNBC: Preoperative pembrolizumab + carboplatin + paclitaxel, followed by preoperative pembrolizumab + cyclophosphamide +
doxorubicin or epirubicin, followed by adjuvant pembrolizumab
• TNBC and residual disease after preoperative therapy with taxane-, alkylator-, and anthracycline-based chemotherapyd: Capecitabine
Useful in Certain Circumstances: Other Recommended Regimens:
• Dose-dense AC (doxorubicin/cyclophosphamide) • AC followed by docetaxel every 3 weeksb
• AC (doxorubicin/cyclophosphamide) every 3 weeks (category 2B) • EC (epirubicin/cyclophosphamide)
• CMF (cyclophosphamide/methotrexate/fluorouracil) • TAC (docetaxel/doxorubicin/cyclophosphamide)
• AC followed by weekly paclitaxelb • For TNBC:
• Capecitabine (maintenance therapy for TNBC after adjuvant Paclitaxel + carboplatin (various schedules) (category 2A)
chemotherapy) Docetaxel + carboplatin (category 2A)
Additional Considerations for Those Receiving Preoperative/Adjuvant Therapy (BINV-L, 3)

a Alternative taxanes (ie, docetaxel, paclitaxel, albumin-bound paclitaxel) may be substituted for select patients due to medical necessity (ie, hypersensitivity reaction). If
substituted for weekly paclitaxel or docetaxel, then the weekly dose of albumin-bound paclitaxel should not exceed 125 mg/m2.
b It is acceptable to change the administration sequence to taxane (with or without HER2-targeted therapy) followed by AC.
c Consider
 addition of adjuvant olaparib for 1 y for those with germline BRCA1/2 mutations and:
• TNBC, if 1) ≥pT2 or ≥pN1 disease after adjuvant chemotherapy, or 2) residual disease after preoperative chemotherapy
• HR-positive, HER2-negative tumors, if 1) ≥4 positive lymph nodes after adjuvant chemotherapy (category 2A), or 2) residual disease after preoperative therapy and
a clinical stage, pathologic stage, ER status, and tumor grade (CPS+EG) score ≥3.
Adjuvant olaparib can be used concurrently with endocrine therapy.
d Patients in the OlympiA trial did not receive capecitabine; thus, there are no data on sequencing or to guide selection of one agent over the other.
e High-risk criteria include stage II–III TNBC. The use of adjuvant pembrolizumab (category 2A) may be individualized.

Note: All recommendations are category 2A unless otherwise indicated.

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PREOPERATIVE/ADJUVANT THERAPY REGIMENSa

HER2-Positive
Preferred Regimens:
• Paclitaxel + trastuzumabf
• TCH (docetaxel/carboplatin/trastuzumab)
• TCHP (docetaxel/carboplatin/trastuzumab/pertuzumab)
• If no residual disease after preoperative therapy or no preoperative therapy: Complete up to one year of HER2-targeted therapy with
trastuzumabi (category 1) ± pertuzumab.
• If residual disease after preoperative therapy: Ado-trastuzumab emtansine (category 1) alone. If ado-trastuzumab emtansine discontinued
for toxicity, then trastuzumab (category 1) ± pertuzumab to complete one year of therapy.g,h If node positive at initial staging, trastuzumab
+ pertuzumab (category 1)i
Useful in Certain Circumstances: Other Recommended Regimens:
• Docetaxel + cyclophosphamide + trastuzumab • AC followed by docetaxelb + trastuzumabh (doxorubicin/
b h
• AC followed by T + trastuzumab (doxorubicin/cyclophosphamide cyclophosphamide followed by docetaxel + trastuzumab)
followed by paclitaxel plus trastuzumab, various schedules) • AC followed by docetaxelb + trastuzumab + pertuzumabh
• AC followed by Tb + trastuzumab + pertuzumabh (doxorubicin/ (doxorubicin/cyclophosphamide followed by docetaxel +
cyclophosphamide followed by paclitaxel plus trastuzumab plus trastuzumab + pertuzumab)
pertuzumab, various schedules) • Paclitaxel/carboplatin + trastuzumab + pertuzumab
• Neratinibg (adjuvant setting only)
• Paclitaxel + trastuzumab + pertuzumabh
• Ado-trastuzumab emtansine (TDM-1) (adjuvant setting only)
Additional Considerations for Those Receiving Preoperative/Adjuvant Therapy (BINV-L, 3)

g Consider
 extended adjuvant neratinib following adjuvant trastuzumab-containing
therapy for patients with HR-positive, HER2-positive disease with a perceived
high risk of recurrence. The benefit or toxicities associated with extended neratinib
a Alternative taxanes (ie, docetaxel, paclitaxel, albumin-bound paclitaxel) may in patients who have received pertuzumab or ado-trastuzumab emtansine is
be substituted for select patients due to medical necessity (ie, hypersensitivity unknown.
reaction). If substituted for weekly paclitaxel or docetaxel, then the weekly h Trastuzumab given in combination with an anthracycline is associated with
dose of albumin-bound paclitaxel should not exceed 125 mg/m2. significant cardiac toxicity. Concurrent use of trastuzumab and pertuzumab with an
b It is acceptable to change the administration sequence to taxane (with or anthracycline should be avoided.
without HER2-targeted therapy) followed by AC. i Updated results from the adjuvant APHINITY trial in HER2-positive early breast
f Paclitaxel
 + trastuzumab may be considered for patients with low-risk cancer, with a median follow-up of 8.4 years, have confirmed the benefit of adding
T1,N0,M0, HER2-positive disease, particularly those not eligible for other pertuzumab to trastuzumab plus chemotherapy in preventing recurrences in those
standard adjuvant regimens due to comorbidities. with node positive disease.

Note: All recommendations are category 2A unless otherwise indicated.

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PREOPERATIVE/ADJUVANT THERAPY REGIMENS

Additional Considerations for Those Receiving Preoperative/Adjuvant Therapy
• Consider scalp cooling to reduce incidence of chemotherapy-induced alopecia for patients receiving neoadjuvant/adjuvant chemotherapy.
Results may be less effective with anthracycline-containing regimens.
• Sequence of therapies in the adjuvant setting:
Chemotherapy and endocrine therapy should be given sequentially, with endocrine therapy given after chemotherapy.
Adjuvant olaparib can be given concurrently with endocrine therapy.
For sequencing of RT with systemic therapy, see BINV-I (2).
• Considerations for HER2-positive disease:
An FDA-approved biosimilar is an appropriate substitute for trastuzumab.
Trastuzumab and hyaluronidase-oysk injection for subcutaneous use may be substituted for trastuzumab. It has different dosage and
administration instructions compared to intravenous trastuzumab. Do not substitute trastuzumab and hyaluronidase-oysk for or with ado-
trastuzumab emtansine.
Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use may be substituted anywhere that the combination of
intravenous pertuzumab and intravenous trastuzumab are given as part of systemic therapy. Pertuzumab, trastuzumab, and
hyaluronidase-zzxf injection for subcutaneous use has different dosing and administration instructions compared to the intravenous
products.

Note: All recommendations are category 2A unless otherwise indicated.

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DOSING: PREOPERATIVE/ADJUVANT THERAPY REGIMENS

HER2-Negative
Preferred Regimens
• Dose-dense AC followed by paclitaxel2 • Preoperative pembrolizumab + chemotherapy followed by adjuvant
Doxorubicin 60 mg/m2 IV day 1 pembrolizumab4
Cyclophosphamide 600 mg/m2 IV day 1 Preoperative:
◊ Cycled every 14 days for 4 cyclesl ◊ Pembrolizumab 200 mg IV Day 1
◊ Followed by: ◊ Paclitaxel 80 mg/m2 IV Days 1, 8, 15
Paclitaxel 175 mg/m2 by 3 h IV infusion day 1 ◊ Carboplatin AUC 5 IV Day 1
◊ Cycled every 14 days for 4 cyclesl Or
• Dose-dense AC followed by weekly paclitaxel2 ◊ Carboplatin AUC 1.5 IV Days 1, 8, 15
Doxorubicin 60 mg/m2 IV day 1 – Cycled every 21 days x 4 cycles (cycles 1–4)
Cyclophosphamide 600 mg/m2 IV day 1 Followed by:
◊ Cycled every 14 days for 4 cyclesj ◊ Pembrolizumab 200 mg IV Day 1
◊ Followed by: ◊ Doxorubicin 60 mg/m2 IV Day 1 or Epirubicin 90 mg/m2 IV Day 1
Paclitaxel 80 mg/m2 by 1 h IV infusion weekly for 12 weeks ◊ Cyclophosphamide 600 mg/m2 IV Day 1
• TC3 – Cycled every 21 days x 4 cycles (cycles 5–8)
Docetaxel 75 mg/m2 IV day 1 Followed by:
Cyclophosphamide 600 mg/m2 IV day 1 Adjuvant pembrolizumab 200 mg IV Day 1
◊ Cycled every 21 days for 4–6 cyclesj ◊ Cycled every 21 days x 9 cycles
• Capecitabine5
1000–1250 mg/m2 PO twice daily on days 1–14
◊ Cycled every 21 days for 6–8 cycles
• Olaparib6
300 mg PO twice daily
Cycled every 28 days for 1 y

j All cycles are with myeloid growth factor support. See NCCN Guidelines for Hematopoietic Growth Factors.
The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule and initiation of
supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior treatment, and comorbidity. The optimal delivery of anti-cancer
agents therefore requires a health care delivery team experienced in the use of anti-cancer agents and the management of associated toxicities in patients with cancer.

Note: All recommendations are category 2A unless otherwise indicated.

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DOSING: PREOPERATIVE/ADJUVANT THERAPY REGIMENS

HER2-Negative HER2-Negative
Other Recommended Regimens Useful in Certain Circumstances
• AC followed by docetaxel every 3 weeks7 • Paclitaxel + carboplatin • Dose-dense AC2
Doxorubicin 60 mg/m² IV on day 1 Weekly paclitaxel + carboplatin1,10 Doxorubicin 60 mg/m² IV day 1
Cyclophosphamide 600 mg/m² IV day 1 (preoperative setting only) Cyclophosphamide 600 mg/m² IV day 1
◊ Cycled every 21 days for 4 cycles ◊ Paclitaxel 80 mg/m2 days 1, 8, and 15 ◊ Cycled every 14 days for 4 cyclesj
◊ Followed by: ◊ Carboplatin AUC 5 or 6 day 1; • AC15
Docetaxel 100 mg/m² IV on day 1 – Cycled every 21 days x 4 cycles Doxorubicin 60 mg/m² IV on day 1
◊ Cycled every 21 days for 4 cycles
Weekly paclitaxel + weekly carboplatin11,12 Cyclophosphamide 600 mg/m² IV day 1
• EC chemotherapy8 ◊ Paclitaxel 80 mg/m2 days 1, 8, and 15 ◊ Cycled every 21 days for 4 cycles
Epirubicin 100 mg/m² IV day 1 ◊ Carboplatin AUC 1.5–2 days 1, 8, and 15
Cyclophosphamide 830 mg/m² IV day 1 • CMF chemotherapy16,17
– Cycled every 28 days x 6 cycles
◊ Cycled every 21 days for 8 cycles Cyclophosphamide 100 mg/m² PO days 1–14
• Docetaxel + carboplatin (4–6 cycles)1,13,14,j Methotrexate 40 mg/m² IV days 1 & 8
• TAC chemotherapy9
Docetaxel 75 mg/m² IV day 1 Docetaxel 75 mg/m2 day 1 5-fluorouracil 600 mg/m² IV days 1 & 8
Doxorubicin 50 mg/m² IV day 1 Carboplatin AUC 6 day 1 ◊ Cycled every 28 days for 6 cycles
Cyclophosphamide 500 mg/m² IV day 1 ◊ Cycled every 21 days x 4–6 cycles
Or
◊ Cycled every 21 days for 6 cyclesl Cyclophosphamide 600 mg/m2 IV day 1
Methotrexate 40 mg/ m2 IV day 1
5-fluorouracil 600 mg/m2 IV day 1
◊ Cycled every 21 days for 8 cycles
• AC followed by weekly paclitaxel18
Doxorubicin 60 mg/m² IV day 1
Cyclophosphamide 600 mg/m² IV day 1
◊ Cycled every 21 days for 4 cycles
◊ Followed by
Paclitaxel 80 mg/m² by 1 h IV infusion weekly for
12 weeks

• Capecitabine (maintenance therapy)19

650 mg/m2 PO twice daily on days 1–28
Cycled every 28 days for 1 year

j All cycles are with myeloid growth factor support. See NCCN Guidelines for Hematopoietic Growth Factors.
The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule and initiation of
supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior treatment, and comorbidity. The optimal delivery of anti-cancer
agents therefore requires a health care delivery team experienced in the use of anti-cancer agents and the management of associated toxicities in patients with cancer.

Note: All recommendations are category 2A unless otherwise indicated.

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Table of Contents
Invasive Breast Cancer Discussion

DOSING: PREOPERATIVE/ADJUVANT THERAPY REGIMENS

HER2-Positivek,l,m
Preferred Regimens
Paclitaxel + trastuzumab20 TCH21 TCH + pertuzumab22 TDM-1
Paclitaxel 80 mg/m IV weekly for 12
2
Docetaxel 75 mg/m IV day 1
2
Docetaxel 75 mg/m2 IV day 1 3.6 mg/kg day 1
weeks Carboplatin AUC 6 IV day 1 Carboplatin AUC 6 IV day 1 ◊ Cycled every 21 days for
◊ With: ◊ Cycled every 21 days for 6 cycles ◊ Cycled every 21 days for 6 cycles 14 cycles
Trastuzumab 4 mg/kg IV with first ◊ With: With:
dose of paclitaxel Trastuzumab 4 mg/kg IV wk 1 Trastuzumab 8 mg/kg IV day 1
◊ Followed by: ◊ Followed by: Pertuzumab 840 mg IV day 1
Trastuzumab 2 mg/kg IV weekly to Trastuzumab 2 mg/kg IV for 17 wks ◊ Followed by:
complete 1 y of treatment. As an ◊ Followed by: Trastuzumab 6 mg/kg IV on day 1
alternative, trastuzumab 6 mg/kg IV Trastuzumab 6 mg/kg IV Pertuzumab 420 mg IV day 1
every 21 days may be used following ◊ Cycled every 21 days to complete ◊ Cycled every 21 days to complete 1 y of
the completion of paclitaxel, and 1 y of therapyn therapyn
given to complete 1 y of trastuzumab OR
treatment. Trastuzumab 8 mg/kg IV wk 1
◊ Followed by:
Trastuzumab 6 mg/kg IV
◊ Cycled every 21 days to complete
1 y of therapyn

m Pertuzumab,
trastuzumab, and hyaluronidase-zzxf injection for subcutaneous
use may be substituted anywhere that the combination of intravenous pertuzumab
and intravenous trastuzumab are given as part of systemic therapy. Pertuzumab,
trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use has different
k An FDA-approved biosimilar is an appropriate substitute for trastuzumab. dosing and administration instructions compared to the intravenous products.
l Trastuzumab and hyaluronidase-oysk injection for subcutaneous use may be n Evaluate left ventricular ejection fraction (LVEF) prior to and during treatment.
substituted for trastuzumab. It has different dosage and administration instructions The optimal frequency of LVEF assessment during adjuvant trastuzumab therapy
compared to intravenous trastuzumab. Do not substitute trastuzumab and is not known. The FDA label recommends LVEF measurements prior to initiation
hyaluronidase-oysk for or with ado-trastuzumab emtansine. of trastuzumab and every 3 mo during therapy.
The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule and initiation of
supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior treatment, and comorbidity. The optimal delivery of anti-cancer
agents therefore requires a health care delivery team experienced in the use of anti-cancer agents and the management of associated toxicities in patients with cancer.

Note: All recommendations are category 2A unless otherwise indicated.

BINV-L
Version 4.2024, 07/03/24 © 2024 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
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Table of Contents
Invasive Breast Cancer Discussion

DOSING: PREOPERATIVE/ADJUVANT THERAPY REGIMENS

HER2-Positivek,l,m
Useful in Certain Circumstances
AC followed by T + trastuzumab23 Dose-dense AC followed by AC or Dose-Dense AC followed by Docetaxel/cyclophosphamide +
Doxorubicin 60 mg/m2 IV day 1 paclitaxel + trastuzumab24 T + trastuzumab + pertuzumab25 trastuzumab26
Cyclophosphamide 600 mg/m2 IV Doxorubicin 60 mg/m2 IV day 1 Doxorubicin 60 mg/m2 IV day 1 Docetaxel 75 mg/m2 IV day 1
day 1 Cyclophosphamide 600 mg/m2 IV Cyclophosphamide 600 mg/m2 IV Cyclophosphamide 600 mg/m2 IV
◊ Cycled every 21 days for 4 day 1 day 1 day 1
cycles. ◊ Cycled every 14 days for 4 cycles ◊ Cycled every 21 days for 4 cycles ◊ Cycled every 21 days for 4 cycles
◊ Followed by: ◊ Followed by: or ◊ With:
Paclitaxel 80 mg/m2 by 1 h IV Paclitaxel 175 mg/m2 by 3 h IV For dose-dense: Cycle every 14 Trastuzumab 4 mg/kg IV wk 1
weekly for 12 wks infusion day 1 days for 4 cycles ◊ Followed by
◊ With: ◊ Cycled every 14 days for 4 cyclesj ◊ Followed by: Trastuzumab 2 mg/kg IV weekly for
Trastuzumab 4 mg/kg IV with first ◊ With: Pertuzumab 840 mg IV day 1 11 wks
dose of paclitaxel Trastuzumab 4 mg/kg IV with first followed by 420 mg IV ◊ Followed by
◊ Followed by: dose of paclitaxel Trastuzumab 8 mg/kg IV day 1 Trastuzumab 6 mg/kg IV
Trastuzumab 2 mg/kg IV weekly ◊ Followed by: followed by 6 mg/kg IV ◊ Cycled every 21 days to complete
to complete 1 y of treatment. As Trastuzumab 2 mg/kg IV weekly to Paclitaxel 80 mg/m2 IV days 1, 8, 1 y of therapy of trastuzumab
an alternative, trastuzumab 6 complete 1 y of treatment. As an and 15 therapyn
mg/kg IV every 21 days may be alternative, trastuzumab ◊ Cycled every 21 days for 4 cycles OR
used following the completion of 6 mg/kg IV every 21 days may be ◊ Followed by: Trastuzumab 8 mg/kg IV wk 1
paclitaxel, and given to complete 1 y used following the completion of Trastuzumab 6 mg/kg IV day 1 ◊ Followed by:
of trastuzumab treatment.n paclitaxel, and given to complete 1 y Pertuzumab 420 mg IV day 1 Trastuzumab 6 mg/kg IV every 21
of trastuzumab treatment.n ◊ Cycled every 21 days to complete days to complete 1 y of trastuzumab
1 y of therapyn therapyn

m Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous

use may be substituted anywhere that the combination of intravenous pertuzumab
j Allcycles are with myeloid growth factor support. See NCCN Guidelines for and intravenous trastuzumab are given as part of systemic therapy. Pertuzumab,
Hematopoietic Growth Factors. trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use has different
k An FDA-approved biosimilar is an appropriate substitute for trastuzumab. dosing and administration instructions compared to the intravenous products.
l Trastuzumab and hyaluronidase-oysk injection for subcutaneous use may n Evaluate LVEF prior to and during treatment. The optimal frequency of LVEF
be substituted for trastuzumab. It has different dosage and administration assessment during adjuvant trastuzumab therapy is not known. The FDA label
instructions compared to intravenous trastuzumab. Do not substitute recommends LVEF measurements prior to initiation of trastuzumab and every 3 mo
trastuzumab and hyaluronidase-oysk for or with ado-trastuzumab emtansine. during therapy.
The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule and initiation of
supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior treatment, and comorbidity. The optimal delivery of anti-cancer
agents therefore requires a health care delivery team experienced in the use of anti-cancer agents and the management of associated toxicities in patients with cancer.

Note: All recommendations are category 2A unless otherwise indicated.

BINV-L
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Invasive Breast Cancer Discussion

DOSING: PREOPERATIVE/ADJUVANT THERAPY REGIMENS

HER2-Positivek,l,m
Other Recommended Regimens
AC followed by docetaxel + trastuzumab20,27 Paclitaxel/carboplatin + trastuzumab AC followed by docetaxel + trastuzumab + pertuzumab29
Doxorubicin 60 mg/m2 IV day 1 + pertuzumab28 Doxorubicin 60 mg/m2 IV day 1
Cyclophosphamide 600 mg/m2 IV day 1 Paclitaxel 80 mg/m2 IV day 1 and 8 Cyclophosphamide 600 mg/m2 IV day 1
◊ Cycled every 21 days for 4 cycles Carboplatin AUC 6 IV day 1 ◊ Cycled every 21 days for 4 cycles
◊ Followed by: ◊ Cycled every 21 days for 9 cycles ◊ Followed by:
Docetaxel 100 mg/m2 IV day 1 Traztuzumab 8 mg/kg IV day 1 Pertuzumab 840 mg IV day 1 followed by 420 mg IV
◊ Cycled every 21 days for 4 cycles Pertuzumab 840 mg IV day 1
◊ With: ◊ Followed by: Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV
Trastuzumab Trastuzumab 6 mg/kg IV day 1 Docetaxel 75–100 mg/m2 IV day 1
◊ 4 mg/kg IV wk 1; Followed by: Pertuzumab 420 mg IV day 1 ◊ Cycled every 21 days for 4 cycles
◊ 2 mg/kg IV weekly for 11 wks; Followed by: ◊ Cycled every 21 days to ◊ Followed by:
◊ 6 mg/kg IV complete 1 y of therapy Trastuzumab 6 mg/kg IV
◊ Cycled every 21 days to complete 1 y Pertuzumab 420 mg IV day 1
of trastuzumab therapyn ◊ Cycled every 21 days to complete 1 y of therapyn

HER2-Positivek,l,m
Useful in Certain Circumstances
Neratinib30 Paclitaxel + trastuzumab + pertuzumab31 Ado-trastuzumab emtansine (T-DM1)32
120 mg PO daily on days 1–7; Followed by: Paclitaxel 80 mg/m2 IV day 1 3.6 mg/kg IV day 1
160 mg PO daily on days 8–14; Followed by: ◊ Cycled every 7 days x 12 cycles ◊ Cycled every 21 days for 17 cycles
240 mg PO daily on days 15–28 Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV
◊ Cycled every 28 days x 1 cycle Pertuzumab 840 mg IV day 1 followed by 420 mg IV
◊ Followed by: ◊ Cycled every 21 days x 4 cycles
240 mg PO daily on days 1–28 ◊ Followed by:
◊ Cycled every 28 days x 12 cycles beginning with cycle 2 Trastuzumab 6 mg/kg IV;
Pertuzumab 420 mg IV day 1;
◊ Cycled every 21 days to complete 1 y of therapyn
k An FDA-approved biosimilar is an appropriate substitute for trastuzumab.
l Trastuzumab and hyaluronidase-oysk injection for subcutaneous use may be substituted for trastuzumab. It has different dosage and administration instructions
compared to intravenous trastuzumab. Do not substitute trastuzumab and hyaluronidase-oysk for or with ado-trastuzumab emtansine.
m Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use may be substituted anywhere that the combination of intravenous pertuzumab and
intravenous trastuzumab are given as part of systemic therapy. Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use has different dosing
and administration instructions compared to the intravenous products.
n Evaluate LVEF prior to and during treatment. The optimal frequency of LVEF assessment during adjuvant trastuzumab therapy is not known. The FDA label
recommends LVEF measurements prior to initiation of trastuzumab and every 3 mo during therapy.
The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule and initiation of
supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior treatment, and comorbidity. The optimal delivery of anti-cancer
agents therefore requires a health care delivery team experienced in the use of anti-cancer agents and the management of associated toxicities in patients with cancer.

Note: All recommendations are category 2A unless otherwise indicated.

BINV-L
Version 4.2024, 07/03/24 © 2024 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
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PREOPERATIVE/ADJUVANT THERAPY REGIMENS - REFERENCES

1 Gupta S, Nair NS, Hawaldar RW, et al. Addition of platinum to sequential taxane- 16 Goldhirsch A, Colleoni M, Coates AS, et al: Adding adjuvant CMF chemotherapy to either
anthracycline neoadjuvant chemotherapy in patients with triple-negative breast cancer: radiotherapy or tamoxifen: are all CMFs alike? The International Breast Cancer Study Group
A phase III randomized controlled trial. Presented at: 2022 San Antonio Breast Cancer (IBCSG). Ann Oncol 1998;9:489-493.
Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS5-01. 17 Jakesz R, Hausmaninger H, Kubista E, et al. Austrian Breast and Colorectal Cancer Study
2 Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus
Group Trial 5. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide,
conventionally scheduled and sequential versus concurrent combination chemotherapy methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade
as postoperative adjuvant treatment of node-positive primary breast cancer: First in premenopausal patients with hormone-responsive breast cancer--Austrian Breast and
report of intergroup trial C9741/cancer and leukemia group B trial 9741. J Clin Oncol Colorectal Cancer Study Group Trial 5. J Clin Oncol 2002;20:4621-4627.
2003;21:1431-1439. 18 Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in adjuvant treatment of breast
3 Jones S, Holmes F, O’Shaughnessey J, et al. Docetaxel with cyclophosphamide
cancer. N Engl J Med 2008;258:1663-1671.
is associated with an overall survival benefit compared with doxorubicin and 19 Wang X, Wang SS, Huang H, et al. Effect of capecitabine maintenance therapy using lower
cyclophosphamide: 7-year follow-up of US Oncology Research trial 9735. J Clin Oncol dosage and higher frequency vs observation on disease-free survival among patients with early-
2009;27:1177-1183; Nitz U, Gluz O, Clemens M, et al. West German Study PlanB Trial: stage triple-negative breast cancer who had received standard treatment: The SYSUCC-001
Adjuvant four cycles of epirubicin and cyclophosphamide plus docetaxel versus six randomized clinical trial. JAMA 2021;325:50-58.
cycles of docetaxel and cyclophosphamide in HER2-negative early breast cancer. J 20 Tolaney S, Barry W, Dang C, et al. Adjuvant paclitaxel and trastuzumab for node-negative
Clin Oncol 2019;37:799-808. HER2-positive breast cancer. N Engl J Med 2015;372:134-141.
4 Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast
21 Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer.
cancer. N Engl J Med, 2020;382:810-821. N Engl J Med 2011;365:1273-1283.
5 Masuda N, Lee SJ, Ohtani S, et al. Adjuvant capecitabine for breast cancer after 22 Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with
preoperative chemotherapy. N Engl J Med 2017;376:2147-2159. standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens
6 Tutt ANJ, Garber JE, Kaufman B, et al. Adjuvant Olaparib for Patients with BRCA1- or
in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study
BRCA2-Mutated Breast Cancer. N Engl J Med 2021;384:2394-2405. (TRYPHAENA). Ann Oncol 2013;24:2278-2284.
7 von Minckwitz G1, Raab G, Caputo A, et al. Doxorubicin with cyclophosphamide 23 Romond EH, Perez EZ, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable
followed by docetaxel every 21 days compared with doxorubicin and docetaxel every HER2 positive breast cancer. N Engl J Med 2005;353:1673-1684.
14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of 24 Dang C, Fornier M, Sugarman S, et al: The safety of dose-dense doxorubicin and
the German Breast Group. J Clin Oncol 2005;23:2676-2685. cyclophosphamide followed by paclitaxel with trastuzumab in HER-2/neu over-expressed/
8 Piccart MJ, Di Leo A, Beauduin M, et al. Phase III trial comparing two dose levels of
amplified breast cancer. J Clin Oncol 2008;26:1216-1222.
epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, 25 Swain SM, Ewer MS, Viale G, et al. Pertuzumab, trastuzumab, and standard anthracycline-
and fluorouracil in node-positive breast cancer. J Clin Oncol 2001;19:3103-3110. and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive
9 Martin, Pienkowski T, Mackey J, et al. Adjuvant docetaxel for node-positive breast
localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac
cancer. N Engl J Med 2005;352:22. safety study. Ann Oncol 2018;29:646-653.
10 Sharma P, Kimler BF, O'Dea A, et al. Randomized phase II trial of anthracycline-free 26 Jones SE, Collea R, Paul D, et al. Adjuvant docetaxel and cyclophosphamide plus trastuzumab
and anthracycline-containing neoadjuvant carboplatin chemotherapy regimens in stage in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2
I-III triple-negative breast cancer (NeoSTOP). Clin Cancer Res 2021;27:975-982. study. Lancet Oncol 2013;14:1121-1128.
11 Yu KD, Ye FG, He M, et al. Effect of adjuvant paclitaxel and carboplatin on survival 27 Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or
in women with triple-negative breast cancer: A phase 3 randomized clinical trial. JAMA without trastuzumab for breast cancer. N Engl J Med 2006;354:809-820.
Oncol 2020;6:1390-1396. 28 van Ramshorst MS, van der Voort A, van Werkhoven ED, et al. Neoadjuvant chemotherapy
12 von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients
with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive
with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol
randomised phase 2 trial. Lancet Oncol 2014;15:747-756. 2018;19:1630-1640.
13 Sharma P, Lopez-Tarruella S, Garcia-Saenz J, et al. Efficacy of neoadjuvant 29 Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and
carboplatin plus docetaxel in triple-negative breast cancer: Combined analysis of two trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast
cohorts. Clin Cancer Res 2017;23:649-657. cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol.
14 Zhang L, Wu ZY, Li J, et al. Neoadjuvant docetaxel plus carboplatin versus epirubicin
2012;13:25-32.
plus cyclophosphamide followed by docetaxel in triple-negative, early-stage breast 30 Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in
cancer (NeoCART): Results from a multicenter, randomized controlled, open-label patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind,
phase II trial. Int J Cancer 2022;150:654-662. placebo-controlled, phase 3 trial. Lancet Oncol 2016;17:367-377.
15 Fisher B, Brown AM, Dimitrov NV, et al. Two months of doxorubicin- 31 Nitz UA, Gluz O, Christgen M, et al. De-escalation strategies in HER2-positive early breast
cyclophosphamide with and without interval reinduction therapy compared with 6 cancer (EBC): final analysis of the WSG-ADAPT HER2+/HR- phase II trial: efficacy, safety, and
months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab
cancer patients with tamoxifen-nonresponsive tumors: results from the National ± weekly paclitaxel. Ann Oncol 2017;28:2768-2772.
Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 1990;8:1483-1496. 32 Tolaney SM, Tayob N, Dang C, et al. Adjuvant trastuzumab emtansine versus paclitaxel
in 8combination with trastuzumab for stage I HER2-positive breast cancer (ATEMPT): A
randomized clinical trial. J Clin Oncol 2021;39:2375-2385.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF PREOPERATIVE SYSTEMIC THERAPY

Known Benefits of Preoperative Systemic Therapy Cautions
• Facilitates breast conservation • Possible overtreatment with systemic therapy if clinical stage is
• Can render inoperable tumors operable overestimated
• Treatment response provides important prognostic information at an • Possible undertreatment locoregionally with radiotherapy if
individual patient level, particularly in patients with TNBC or HER2- clinical stage is underestimated
positive breast cancer • Possibility of disease progression during preoperative systemic
• Identifies patients with residual disease at higher risk for relapse to therapy
allow for the addition of supplemental adjuvant regimens, particularly
in patients with TNBC or HER2-positive breast cancer. Candidates for Preoperative Systemic Therapy
• Allows time for genetic testing • Patients with inoperable breast cancer:
• Allows time to plan breast reconstruction in patients electing IBC
mastectomy Bulky or matted cN2 axillary nodes
• Allows time for delayed decision-making for definitive surgery cN3 nodal disease
cT4 tumors
Opportunities • In select patients with operable breast cancer
• May allow SLNB alone if initial cN+ becomes cN0 after preoperative Preoperative systemic therapy is preferred for:
therapy ◊ HER2-positive disease and TNBC, if ≥cT2 or ≥cN1
• May provide an opportunity to modify systemic treatment if no ◊ Large primary tumor relative to breast size in a patient who
preoperative therapy response or progression of disease desires breast conservation
• May allow for more limited radiation fields in patients with cN+ who ◊ cN+ disease likely to become cN0 with preoperative systemic
become cN0/pN0 after preoperative therapy therapy
• Provides excellent research platform to test novel therapies and Preoperative systemic therapy can be considered for cT1c, cN0
predictive biomarkers HER2-positive disease and TNBC
• Patients in whom definitive surgery may be delayed.
Non-candidates for Preoperative Systemic Therapy
• Patients with extensive in situ disease when extent of invasive
carcinoma is not well-defined
• Patients with a poorly delineated extent of tumor
• Patients whose tumors are not palpable or clinically assessable

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF PREOPERATIVE SYSTEMIC THERAPY

• Pathology evaluation of surgical resection specimens following preoperative systemic therapy should include the standardized tissue
sampling and reporting elements of the Residual Cancer Burden (RCB) (category 2B).a
• Randomized trials of chemotherapy demonstrate similar long-term outcomes when patients are given the same treatment preoperatively
compared with postoperatively.b
• Pathologic complete response (pCR) to preoperative systemic therapy is associated with an extremely favorable disease-free and overall
survival (OS), particularly in situations in which all treatment is given preoperatively. The correlation between pathologic response and long-
term outcome is strongest for TNBC, somewhat less so for HER2-positive disease, and least for ER-positive disease.c,d
• A number of chemotherapy regimens have activity in the preoperative setting. In general, those chemotherapy regimens recommended in
the adjuvant setting may be considered in the preoperative setting. See Preoperative/Adjuvant Therapy Regimens (BINV-L).
• Preoperative endocrine therapy alone may be considered for patients with ER-positive disease based on comorbidities or low-risk luminal
biology based on clinical characteristics and/or genomic signatures (until desired effect is achieved). Data shows that optimal duration for
response if achieved between 4–6 months.e
• Patients with HER-2 positive, ≥cT2 and/or cN+ should be considered for HER2-directed therapy preoperatively.f See Preoperative/Adjuvant
Therapy Regimens (BINV-L).
• Some studies suggest an increased risk of locoregional recurrence following use of preoperative chemotherapy.g These trials delivered
chemotherapy regimens that are no longer standard, did not include targeted therapies, did not use modern imaging techniques, and/or
used non-standard locoregional management. Care should be taken to follow the procedures outlined in BINV-12 and BINV-14 to assure
appropriate locoregional management. Not all patients are appropriate candidates for preoperative systemic therapy. Accurate clinical
staging at baseline prior to initiation of preoperative systemic therapy is critical. See Potentially Operable Disease: Breast and Axillary
Evaluation Prior to Preoperative Systemic Therapy (BINV-12).
• Tumor response should be routinely assessed by clinical exam and imaging studies (see footnote uu on BINV-13) during delivery of
preoperative therapy. It is preferred that the standard regimen is completed prior to surgery. If all intended treatment is not completed prior
to surgery, the remainder may be given in the adjuvant setting. Patients with operable breast cancer experiencing progression of disease
during preoperative systemic therapy may be given an alternate systemic regimen or proceed to surgery if deemed resectable. Locoregional
therapy principles should be applied in the same manner as in patients treated with adjuvant systemic therapy.

a Yau C, Osdoit M, van der Noorda M, et al. Residual cancer burden after
neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a
multicentre pooled analysis of 5161 patients. Lancet Oncol 2022;23:149-160. e Hunt KK, Suman VJ, Wingate HF, et al. Local-regional recurrence after
b Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: Updates of neoadjuvant endocrine therapy: Data from ACOSOG Z1031 (Alliance), a
National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Randomized Phase 2 neoadjuvant comparison between letrozole, anastrozole,
Clin Oncol 2008;26:778-785. and exemestane for postmenopausal eomen with estrogen receptor-positive
c von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic clinical stage 2 or 3 breast cancer. Ann Surg Oncol 2023;30:2111-2118.
complete response on prognosis after neoadjuvant chemotherapy in various f An FDA-approved biosimilar is an appropriate substitute for trastuzumab.
intrinsic breast cancer subtypes. J Clin Oncol 2012;30:1796-1804. g Early Breast Cancer Trialists' Collaborative Group (EBTCG). Long-term
d Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long- outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer:
term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet metaanalysis of individual patient data from ten randomised trials. Lancet Oncol
2014;384:164-172. 2018;19:27-39.

Note: All recommendations are category 2A unless otherwise indicated.

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GENE EXPRESSION ASSAYS FOR CONSIDERATION OF ADJUVANT SYSTEMIC THERAPYa,b

NCCN Category Recurrence Risk

NCCN Category
Assay Predictive Prognostic of Evidence and and
of Preference
Consensus Treatment Implications
21-gene (Oncotype Dx)
Yes Yes Preferred 1 BINV-N (2)
(for pN0)
Postmenopausal:
1
Preferred
21-gene (Oncotype Dx)
Yes BINV-N (2)
for pN1 (1–3 positive nodes)c Yes Premenopausal:
2A
Other
70-gene (MammaPrint)
Not determined Yes Other 1 BINV-N (3)
for pN0 and pN1 (1–3 positive nodes)
50-gene (Prosigna)
Not determined Yes Other 2A BINV-N (3)
for pN0 and pN1 (1–3 positive nodes)
12-gene (EndoPredict)
Not determined Yes Other 2A BINV-N (3)
for pN0 and pN1 (1–3 positive nodes)
Predictive
of benefit of
Breast Cancer Index (BCI) Yes Other 2A BINV-N (4)
extended adjuvant
endocrine therapy

a Gene expression assays provide prognostic and therapy-predictive information that complements T,N,M and biomarker information. Use of these assays is not required
for staging. The 21-gene assay (Oncotype Dx) is preferred by the NCCN Breast Cancer Panel for prognosis and prediction of chemotherapy benefit. Other prognostic
gene expression assays can provide prognostic information but the ability to predict chemotherapy benefit is unknown.
b Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J).
c In the overall study population of the RxPONDER trial, 10.3% had high-grade disease and 9.2% had 3 involved nodes.

Note: All recommendations are category 2A unless otherwise indicated.

BINV-N
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GENE EXPRESSION ASSAYS FOR CONSIDERATION OF ADJUVANT SYSTEMIC THERAPYa,b

Assay Recurrence Risk Treatment Implications

21-gene Patients with T1b/c–2, pN0, HR-positive, HER2-negative tumors, with risk scores (RS) between 0–10
(Oncotype Dx) have a risk of distant recurrence of <4% and those with RS 11–25 derived no benefit from the addition of
(for <26 chemotherapy to endocrine therapy in the prospective TAILORx study.1
postmenopausal Postmenopausal patients with pT1–3, pN1, HR-positive, HER2-negative, with RS <26 derived no benefit
patients with pN0 from the addition of chemotherapy to endocrine therapy in the prospective RxPONDER study.2
and pN1 [1–3 In postmenopausal patients with pT1–3, HR-positive, HER2-negative, and pN0 and pN1 (1–3 positive
positive nodes])c ≥26 nodes) tumors and an RS ≥26, the addition of chemotherapy to endocrine therapy is recommended.1,2
Premenopausal patients with T1b/c –2, pN0, HR-positive, HER2-negative tumors with RS <16 derived no
≤15 benefit from the addition of chemotherapy to endocrine therapy in the prospective TAILORx study.1
21-gene In premenopausal patients with RS between 16–25, a small benefit from the addition of chemotherapy
(Oncotype Dx) 16–25 could not be ruled out, but it is unclear if the benefit was due to the ovarian suppression effect promoted by
(for premenopausal chemotherapy in premenopausal patients.1,2 For this group, consider chemotherapy followed by endocrine
patients: pN0) therapy or alternatively, ovarian function suppression combined with either tamoxifen or an AI.
In premenopausal patients with HR-positive, HER2-negative, and pN0 tumors and an RS ≥26, the addition
≥26
of chemotherapy to endocrine therapy is recommended.1
In premenopausal patients with pT1–3 and pN1 (1–3 positive nodes) tumors and an RS <26, the addition
21-gene (Oncotype of chemotherapy to endocrine therapy was associated with a lower rate of distant recurrence compared
Dx) <26 with endocrine monotherapy2 but it is unclear if the benefit was due to the ovarian suppression effects
(for premenopausal promoted by chemotherapy. For this group of patients, consider chemotherapy followed by endocrine
patients with 1–3 therapy or alternatively, ovarian function suppression combined with either tamoxifen or an AI.2
positive nodes)c In premenopausal patients with HR-positive, HER2-negative, pT1–3 and pN1 (1–3 positive nodes) tumors
≥26 and an RS ≥26, the addition of chemotherapy to endocrine therapy is recommended.2

a Gene expression assays provide prognostic and therapy-predictive information that complements T,N,M and biomarker information. Use of these assays is not required
for staging. The 21-gene assay (Oncotype Dx) is preferred by the NCCN Breast Cancer Panel for prognosis and prediction of chemotherapy benefit. Other prognostic
gene expression assays can provide prognostic information but the ability to predict chemotherapy benefit is unknown.
b Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J).
c In the overall study population of the RxPONDER trial, 10.3% had high-grade disease and 9.2% had 3 involved nodes. References on
BINV-N 5 of 5
Note: All recommendations are category 2A unless otherwise indicated.
BINV-N
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GENE EXPRESSION ASSAYS FOR CONSIDERATION OF ADJUVANT SYSTEMIC THERAPYa,b

Assay Recurrence Risk Treatment Implications
Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy
(n = 749) or not (n = 748); this was the intention-to-treat population. The 8-year estimates for distant
High metastasis-free survival in the intention-to-treat population were 92.0% (95% CI, 89.6–93.8) for
chemotherapy versus 89.4% (86.8–91.5) for no chemotherapy (HR, 0.66; 95% CI, 0.48–0.92). An
exploratory analysis confined to the subset of patients with HR-positive, HER2-negative disease (1358
70-gene [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows
(MammaPrint) different effects of chemotherapy administration on 8-year distant metastasis-free survival according to
(for pN0 and age: 93.6% (95% CI, 89.3–96.3) with chemotherapy versus 88.6% (83.5–92.3) without chemotherapy in
1–3 positive 464 patients aged ≤50 years (absolute difference 5.0 percentage points [SE, 2.8; 95% CI, −0.5 to 10.4])
nodes) Lowd and 90.2% (86.8–92.7) versus 90.0% (86.6–92.6) in 894 females >50 years (absolute difference 0.2
percentage points [2.1, −4.0 to 4.4]). The 8-year distant metastasis-free survival in the exploratory analysis
by nodal status in these patients was 91.7% (95% CI, 88.1–94.3) with chemotherapy and 89.2% (85.2–
92.2) without chemotherapy in 699 patients who are node-negative (absolute difference 2.5 percentage
points [SE, 2.3; 95% CI, −2.1 to 7.2]) and 91.2% (87.2–94.0) versus 89.9% (85.8–92.8) for 658 patients with
1–3 positive nodes (absolute difference 1.3 percentage points [2.4, −3.5 to 6.1]).3
Node negative:
Low (0–40),
For patients with T1 and T2 HR-positive, HER2-negative, pN0 tumors, a risk of recurrence score in the low
50-gene Intermediate
(41–60), High range, regardless of T size, places the tumor into the same prognostic category as T1a–T1b,N0,M0.4
(Prosigna)
(for pN0 and (61–100)
1–3 positive Node positive:
nodes) Low (0–40) In patients with HR-positive, HER2-negative, pN+ tumors (1–3 positive lymph nodes) with low risk of
recurrence score, treated with endocrine therapy alone, the distant recurrence risk was less than 3.5% at
Node positive: 10 years and no distant recurrence was seen at 10 years in the TransATAC study in a similar group.5
High (41–100)
12-gene For patients with T1 and T2 HR-positive, HER2-negative, and pN0 tumors, a 12-gene low-risk score, regardless
(EndoPredict) Low (≤3.3) of T size, places the tumor into the same prognostic category as T1a–T1b,N0,M0.6
(pN0 and In ABCSG 6/8, patients in the low-risk group had risk of distant recurrence of 4% at 10 years and in the
1–3 positive High (>3.3) TransATAC study, patients with 1–3 positive nodes in the low-risk group had a 5.6% risk of distant recurrence at
nodes) 10 years.6,7 The assay is prognostic in patients treated with endocrine and chemo-endocrine.7

a Gene expression assays provide prognostic and therapy-predictive information that complements T,N,M and biomarker information. Use of these assays is not required
for staging. The 21-gene assay (Oncotype Dx) is preferred by the NCCN Breast Cancer Panel for prognosis and prediction of chemotherapy benefit. Other prognostic
gene expression assays can provide prognostic information but the ability to predict chemotherapy benefit is unknown.
b Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J).
d Postmenopausal patients with UltraLow risk in the Stockholm Tamoxifen trial had a 20-year breast cancer specific survival of 97% with 2–5 years of Tamoxifen
(Esserman LJ, et al. JAMA Oncology 2017;3:1503-1510). Patients with an ultralow-risk in the MINDACT trial have shown 8-year breast cancer specific survival above
99%. (Lopes Cardozo JMN, et al. J Clin Oncol 2022;40:1335-1345). References on
BINV-N 5 of 5
Note: All recommendations are category 2A unless otherwise indicated.
BINV-N
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GENE EXPRESSION ASSAYS FOR CONSIDERATION OF EXTENDED ADJUVANT SYSTEMIC THERAPYa,b

Assay Recurrence Risk/ Treatment Implications

Predictive Result
• For patients with T1 and T2 HR-positive, HER2-negative, and pN0 tumors, a BCI (H/I) in the low-risk range
(0–5), regardless of T size, places the tumor into the same prognostic category as T1a–T1b, N0, M0.
BCI (H/I) Low • Patients with BCI (H/I) low demonstrated a lower risk of distant recurrence (compared to BCI [H/I] high) and
no significant improvement in disease-free survival (DFS) or OS compared to the control arm in terms of
Breast Cancer extending endocrine therapy duration.8
Index (BCI)e • For patients with T1 HR-positive, HER2-negative, and pN0 tumors, a BCI (H/I) high (5.1–10) demonstrated
significant rates of late distant recurrence.
BCI (H/I) High • In secondary analyses of the MA.17, Trans-aTTom, and IDEAL trials, patients with HR-positive, T1–T3, pN0
or pN+ who had a BCI (H/I) high demonstrated significant improvements in DFS when adjuvant endocrine
therapy was extended, compared to the control arm.8-11

a Gene expression assays provide prognostic and therapy-predictive information that complements T,N,M and biomarker information. Use of these assays is not required
for staging. The 21-gene assay (Oncotype Dx) is preferred by the NCCN Breast Cancer Panel for prognosis and prediction of chemotherapy benefit. Other prognostic
gene expression assays can provide prognostic information but the ability to predict chemotherapy benefit is unknown.
b Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J).
e The benefit of testing BCI (H/I) for extended adjuvant endocrine therapy is unknown in patients who had ovarian function suppression, CDK4/6 inhibitors, or olaparib in
addition to adjuvant endocrine therapy. References on
BINV-N 5 of 5
Note: All recommendations are category 2A unless otherwise indicated.
BINV-N
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GENE EXPRESSION ASSAYS FOR CONSIDERATION OF ADJUVANT SYSTEMIC THERAPY

REFERENCES
1 Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med 2018;379:111-121.
2 Kalinsky K, Barlow WE, Meric-Bernstam F, et al. First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy (ET) +/- chemotherapy
(CT) in patients (pts) with 1-3 positive nodes, hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25:
SWOG S1007 (RxPonder). Cancer Res 2021;81:Abstract GS3-00.
3 Piccart M, van 't Veer LJ, Poncet C, et al. 70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised
MINDACT trial with an exploratory analysis by age. Lancet Oncol 2021;22:476-488.
4 Laenkholm AV, Jensen MB, Eriksen JO, et al. PAM50 risk of recurrence score predicts 10-year distant recurrence in a comprehensive Danish cohort of
postmenopausal women allocated to 5 years of endocrine therapy for hormone receptor-positive early breast cancer. J Clin Oncol 2018;36:735-740.
5 Sestak I, Buus R, Cuzick J, et al. Comparison of the performance of 6 prognostic signatures for estrogen receptor–positive breast cancer: A secondary analysis of a
randomized clinical trial. JAMA Oncol 2018;4:545-553.
6 Filipits M, Rudas M, Jakesz R, et al. A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to
conventional clinical risk factors. Clin Cancer Res 2011;17:6012-6020.
7 Sestak I, Martín M, Dubsky P, et al. Prediction of chemotherapy benefit by EndoPredict in patients with breast cancer who received adjuvant endocrine therapy plus
chemotherapy or endocrine therapy alone. Breast Cancer Res Treat 2019;176:377-386.
8 Noordhoek I, Treuner K, Putter H, et al. Breast cancer index predicts extended endocrine benefit to individualize selection of patients with HR(+) early-stage breast
cancer for 10 years of endocrine Therapy. Clin Cancer Res 2021;27:311-319.
9 Sgroi DC, Carney E, Zarrella E, et al. Prediction of late disease recurrence and extended adjuvant letrozole benefit by the HOXB13/IL17BR biomarker. J Natl Cancer
Inst 2013;105:1036-1042.
10 Blok EJ, Kroep JR, Meershoek-Klein Kranenbarg E, et al. Optimal duration of extended adjuvant endocrine therapy for early breast cancer; Results of the IDEAL
Trial (BOOG 2006-05). J Natl Cancer Inst 2017;110:40-48.
11 Bartlett JMS, Sgroi DC, Treuner K, et al. Breast cancer index and prediction of benefit from extended endocrine therapy in breast cancer patients treated in the
Adjuvant Tamoxifen-To Offer More? (aTTom) trial. Ann Oncol 2019;30:1776-1783.

Note: All recommendations are category 2A unless otherwise indicated.

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DEFINITION OF MENOPAUSE
• Menopause is the permanent cessation of menses and includes a profound and permanent decrease in ovarian estrogen synthesis.
• Determination of menopausal status may be required to guide selection of endocrine therapy for breast cancer.
• Menopause is usually a clinical diagnosis made after ≥12 months of amenorrhea. Natural menopause is experienced between ages 42–58
years.
• Breast cancer treatments may affect ovarian function and menses.
In those who are premenopausal at the beginning of chemotherapy and who develop chemotherapy-induced amenorrhea, ovarian function
may still be intact despite amenorrhea or may resume over time. The likelihood of ovarian function resuming after chemotherapy is higher
among those aged <40 years.
Tamoxifen may cause amenorrhea without inducing menopause in premenopausal individuals.
Ovarian function suppression induces amenorrhea and reduces ovarian estrogen synthesis without causing permanent menopause.
• Twelve months of amenorrhea alone is insufficient to diagnose menopause with chemotherapy-induced amenorrhea or with tamoxifen
± ovarian suppression. FSH and estradiol levels are used to support the diagnosis of menopause; however, clear criteria to guide
interpretation of FSH and estradiol in this population is lacking.
Tamoxifen may alter FSH levels, limiting its utility in determination of menopausal status.
FSH and estradiol should be repeated serially to ensure menopausal status in patients with breast cancer with chemotherapy-induced
amenorrhea.
• Evidence-based criteria for the diagnosis of menopause in patients with breast cancer are lacking. Clinical trials in breast cancer have
utilized a variety of definitions of menopause. Reasonable criteria for determining menopause in patients with breast cancer include any of
the following:
Prior bilateral oophorectomy
Age ≥60 years
Age <60 with amenorrhea for ≥12 months in the absence of prior chemotherapy, receipt of tamoxifen, toremifene, or ovarian suppression
and estradiol and FSH in the post-menopausal range
Age <60 years: chemotherapy-induced amenorrhea for ≥12 months with FSH and estradiol in post-menopausal range on serial
assessments
Age <60 years: on tamoxifen with FSH and estradiol level in post-menopausal range
• Menopausal status cannot be determined in those receiving ovarian function suppression

Note: All recommendations are category 2A unless otherwise indicated.

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SYSTEMIC THERAPY FOR ER- AND/OR PR-POSITIVE

RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASEa
HER2-Negative and Postmenopausal or HER2-Positive and Postmenopausalm,n
Premenopausal Receiving Ovarian Ablation or Suppression or Premenopausal Receiving Ovarian
Preferred Regimens Other Recommended Regimens Ablation or Suppression
First-Line Therapy First- and/or Subsequent-Line Therapy
• Aromatase inhibitor + CDK4/6 inhibitorb • Selective ER down-regulator • Aromatase inhibitor ± trastuzumab
Aromatase inhibitor + ribociclib (category 1)c Fulvestrantk • Aromatase inhibitor ± lapatinib
Aromatase inhibitor + abemaciclib For ESR1 mutated tumors, see BINV-Q (6) • Aromatase inhibitor ± lapatinib + trastuzumab
Aromatase inhibitor + palbociclib • Selective ER down-regulator (fulvestrant) + • Fulvestrant ± trastuzumab
• Fulvestrantd + CDK4/6 inhibitorb non-steroidal aromatase inhibitor (anastrozole, • Tamoxifen ± trastuzumab
Fulvestrant + ribociclib (category 1)e letrozole) (category 1)k
Fulvestrant + abemaciclib (category 1) e • Non-steroidal aromatase inhibitor
Fulvestrant + palbociclib Anastrozole
Letrozole
Second- and Subsequent-Line Therapy • Selective ER modulator
• Fulvestrant + CDK4/6 inhibitor (abemaciclib, Tamoxifen
• Steroidal aromatase inactivator
palbociclib, or ribociclib) if CKD4/6 inhibitor not Exemestane
previously used (category 1)f,g
• For PIK3CA or AKT1 activating mutations or PTEN Useful in Certain Circumstances
alterations, see targeted therapy options, see Subsequent-Line Therapy
BINV-Q (6)h • Megestrol acetate
• Everolimus + endocrine therapy (exemestane, • Estradiol
fulvestrant, tamoxifen)i,j • Abemaciclibl
• Targeted therapy options, see BINV-Q (6)
a Baseline assessment of bone density recommended for patients i If there is disease progression while on an everolimus-containing regimen, there are no data to
receiving an aromatase inhibitor who are at risk of osteoporosis (eg, support an additional line of therapy with another everolimus regimen.
age >65, family history, chronic steroids). j A combination of exemestane with everolimus can be considered for patients who meet the
b There is controversy on the choice of CDK4/6 inhibitor as there are no eligibility criteria for BOLERO-2 (progressed within 12 mo or on non-steroidal aromatase
head to head comparisons between the agents and there are some inhibitor).
differences in the study populations in the phase 3 randomized studies.k A single study (S0226) in patients with HR-positive breast cancer and no prior chemotherapy,
c In phase 3 randomized controlled trials, ribociclib + endocrine therapy biological therapy, or endocrine therapy for metastatic disease demonstrated that the addition
have shown OS benefit in the first-line setting. of fulvestrant to anastrozole resulted in prolongation of time to progression and OS. Subset
d Consider for disease progression on adjuvant endocrine therapy or analysis suggested that patients without prior adjuvant tamoxifen and more than 10 years
with early disease relapse within 12 months of adjuvant endocrine since diagnosis experienced the greatest benefit. Two studies with similar design (FACT and
therapy completion SOFEA) demonstrated no advantage in time to progression with the addition of fulvestrant to
e In phase 3 randomized controlled trials, fulvestrant + ribociclib or anastrozole.
abemaciclib has shown OS benefit in the first-line setting l Indicated after progression on prior endocrine therapy and prior chemotherapy in the
f In phase 3 randomized controlled trials, fulvestrant in combination with metastatic setting.
a CDK4/6 inhibitor (abemaciclib, palbociclib, and ribociclib) has shown m An FDA-approved biosimilar is an appropriate substitute for trastuzumab. Trastuzumab and
OS benefit in the second-line setting. hyaluronidase-oysk injection for subcutaneous use may be substituted for trastuzumab. It has
g If there is disease progression while on palbociclib, there are limited different dosage and administration instructions compared to intravenous trastuzumab. Do not
phase II data to support the use of ribociclib in the second line setting substitute trastuzumab and hyaluronidase-oysk for or with ado-trastuzumab emtansine or fam-
h If there is progression while on a PI3K inhibitor, there are limited trastuzumab deruxtecan-nxki.
data to support another line of therapy with a PI3K-pathway inhibitor- n If treatment was initiated with chemotherapy and trastuzumab + pertuzumab, and the
containing regimen. chemotherapy was stopped, endocrine therapy may be added to trastuzumab + pertuzumab.

Note: All recommendations are category 2A unless otherwise indicated.

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SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASEa

HR-Positive and HER2-Negative with Visceral Crisis† or Endocrine Refractory

Setting Subtype/Biomarker Regimen

First Line No germline BRCA1/2 mutationb Systemic chemotherapy BINV-Q (5)

Germline BRCA1/2 mutationb PARPi (olaparib, talazoparib)c (Category 1, preferred)

Second Line HER2 IHC 1+ or 2+/ISH negatived Fam-trastuzumab deruxtecan-nxkie (Category 1, preferred)
Not a candidate for fam-trastuzumab Sacituzumab govitecanf (Category 1, preferred)
deruxtecan-nxki
Systemic chemotherapy BINV-Q (5)
Third Line and Any Systemic chemotherapy BINV-Q (5)
beyond
Biomarker positive (ie, MSI-H, NTRK, Targeted agents BINV-Q (6)
RET, TMB-H)
† According to the 5th ESO-ESMO international consensus guidelines (Cardoso F, et al. Ann Oncol 2020;31:1623-1649) for advanced breast
cancer visceral crisis is defined as: “severe organ dysfunction, as assessed by signs and symptoms, laboratory studies and rapid progression of
disease. Visceral crisis is not the mere presence of visceral metastases but implies important organ compromise leading to a clinical indication
for the most rapidly efficacious therapy.”

a For treatment of brain metastases, see NCCN Guidelines for Central Nervous System Cancers.
b Assess for germline BRCA1/2 mutations in all patients with recurrent or metastatic breast cancer to identify candidates for PARP inhibitor therapy.
c PARPi can be considered for a later line for those with BRCA1/2 mutation, however available evidence suggests it is more effective if used earlier.
d Principles of HER2 Testing (BINV-A).
e Fam-trastuzumab deruxtecan may be considered in a later line for HER2 IHC 1+ or 2+/ISH negative, if not used in second–line. Fam-trastuzumab deruxtecan-nxki
is associated with interstitial lung disease (ILD)/pneumonitis. Regular monitoring for this serious side effect is recommended. For patients with a history of ILD/
pneumonitis, there are no data on managing safety or toxicity of this drug in a trial.
f Sacituzumab govitecan-hziy may be used for adult patients with HR-positive, HER2-negative metastatic/locally advanced unresectable breast cancer after prior
treatment including endocrine therapy, a CDK4/6 inhibitor, and at least two lines of chemotherapy, one of which was a taxane, and at least one of which was in the
metastatic setting. It may be considered for later line if not used as second line therapy.

Note: All recommendations are category 2A unless otherwise indicated.

BINV-Q
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SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASEa

HR-Negative and HER2-Negative (Triple-Negative Breast Cancer; TNBC)

Setting Subtype/Biomarker Regimen
First Line PD-L1 CPS ≥10g regardless of germline BRCA Pembrolizumab + chemotherapy (albumin-bound paclitaxel,
mutation statusb paclitaxel, or gemcitabine and carboplatin)h (Category 1, preferred)
PD-L1 CPS <10g and no germline BRCA1/2
Systemic chemotherapy BINV-Q (5)
mutationb
• PARPi (olaparib, talazoparib) (Category 1, preferred)
PD-L1 CPS <10g and germline BRCA1/2 mutationb
• Platinum (cisplatin or carboplatin) (Category 1, preferred)
Second Germline BRCA1/2 mutationb PARPi (olaparib, talazoparib) (Category 1, preferred)
Line Sacituzumab govitecani (Category 1, preferred)
Any
Systemic chemotherapy BINV-Q (5)
No germline BRCA1/2 mutationb
Fam-trastuzumab deruxtecan-nxkie (Category 1, preferred)
and HER2 IHC 1+ or 2+/ISH negatived
Third Line
Biomarker positive (ie, MSI-H, NTRK, RET, TMB-H) Targeted agents BINV-Q (6)
and beyond
Any Systemic chemotherapy BINV-Q (5)

a For treatment of brain metastases, see NCCN Guidelines for Central Nervous System Cancers.
b Assess for germline BRCA1/2 mutations in all patients with recurrent or metastatic breast cancer to identify candidates for PARP inhibitor therapy.
d Principles of HER2 Testing (BINV-A).
e Fam-trastuzumab deruxtecan may be considered in a later line for HER2 IHC 1+ or 2+/ISH negative, if not used in second–line. Fam-trastuzumab deruxtecan-
nxki is associated with interstitial lung disease (ILD)/pneumonitis. Regular monitoring for this serious side effect is recommended. For patients with a history of ILD/
pneumonitis, there are no data on managing safety or toxicity of this drug in a trial.
g PD-L1 expression is assessed using 22C3 antibody. Threshold for positivity combined positive score ≥10.
h While available data are in the first-line setting, this regimen can be used for second and subsequent lines of therapy if PD-1/PD-L1 inhibitor therapy has not been
previously used. If there is disease progression while on a PD-1/PD-L1 inhibitor, there are no data to support an additional line of therapy with another PD-1/PD-L1
inhibitor.
i Sacituzumab govitecan-hziy may be used in patients who have received at least 1 prior regimen in the metastatic setting. It may be considered for later line if not used
as second line therapy.

Note: All recommendations are category 2A unless otherwise indicated.

BINV-Q
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SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASEk

HR-Positive or -Negative and HER2-Positivej,k

Setting Regimen
Pertuzumab + trastuzumab + docetaxel (Category 1, preferred)
First Linel
Pertuzumab + trastuzumab + paclitaxel (preferred)
Second Linen Fam-trastuzumab deruxtecan-nxkim (Category 1, preferred)
Tucatinib + trastuzumab + capecitabinen (Category 1, preferred)
Third Line
Ado-trastuzumab emtansine (T-DM1)o
Trastuzumab + docetaxel or vinorelbine
Trastuzumab + paclitaxel ± carboplatin
Fourth Line Capecitabine + trastuzumab or lapatinib
and Beyond Trastuzumab + lapatinib (without cytotoxic therapy)
(optimal
sequence is Trastuzumab + other chemotherapy agentsq,r
not known)p Neratinib + capecitabine
Margetuximab-cmkb + chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine)
Targeted Therapy Options BINV-Q (6)
j Considerations for those receiving systemic HER2-targeted therapy (BINV-Q 4).
k Assess for germline BRCA1/2 mutations in all patients with recurrent or metastatic breast cancer to identify candidates for PARP inhibitor therapy. While olaparib and
talazoparib are FDA-indicated in HER2-negative disease, the panel supports use in any breast cancer subtype associated with a germline mutation. There is lower-level
evidence for HER2-positive tumors, therefore category 2A for this setting.
l Maintenance trastuzumab/pertuzumab after response (with concurrent endocrine therapy if ER+ and HER2+ metastatic breast cancer).
m Fam-trastuzumab deruxtecan-nxki may be considered in the first-line setting as an option for select patients (ie, those with rapid progression within 6 months of
neoadjuvant or adjuvant therapy [12 months for pertuzumab-containing regimens]). Fam-trastuzumab deruxtecan-nxki is associated with interstitial lung disease (ILD)/
pneumonitis. Regular monitoring for this serious side effect is recommended. For patients with a history of ILD/pneumonitis, there are no data on managing safety or
toxicity of this drug in a trial.
n Tucatinib + trastuzumab + capecitabine is preferred in patients with both systemic and CNS progression in the third-line setting and beyond; and it may be given in the
second-line setting.
o May be used as an option for third-line and beyond; the optimal sequence for third-line therapy and beyond is not known. If not a candidate fam-trastuzumab T-DM1
could be considered in the second-line.
p Multiple lines of concurrent chemotherapy with anti-HER2 therapy (trastuzumab or a TKI) offer clinical benefit for recurrent unresectable HER2+ metastatic breast cancer
and have been studied in phase 2 or 3 trials. Clinical experience suggests frequent clinical benefit for such treatment. However, there are no meaningful data for use
of any of these regimens among patients previously treated with pertuzumab-based chemotherapy, ado-trastuzumab emtansine, fam-trastuzumab deruxtecan-nxki, or
trastuzumab/capecitabine/tucatinib regimens. Thus, the optimal sequence or true benefit of therapy is not known.
q Trastuzumab given in combination with an anthracycline is associated with significant cardiac toxicity. Concurrent use of trastuzumab and pertuzumab with an
anthracycline should be avoided.
r Trastuzumab may be safely combined with all non-anthracycline–containing preferred and other single agents listed on (BINV-Q 5) for recurrent or metastatic breast
cancer.

Note: All recommendations are category 2A unless otherwise indicated.

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Additional Considerations for Those Receiving Systemic Therapy for HER2-Positive Disease
• When receiving taxane-containing regimen:
Alternative taxanes (ie, docetaxel, paclitaxel, albumin-bound paclitaxel) may be substituted for select patients due to medical
necessity (ie, hypersensitivity reaction). If substituted for weekly paclitaxel or docetaxel, then the weekly dose of albumin-bound
paclitaxel should not exceed 125 mg/m2.
Consider cryotherapy of hands and feet to decrease the risk of peripheral neuropathy.1,2
• An FDA-approved biosimilar is an appropriate substitute for trastuzumab.
• Trastuzumab and hyaluronidase-oysk injection for subcutaneous use may be substituted for trastuzumab. It has different dosage
and administration instructions compared to intravenous trastuzumab. Do not substitute trastuzumab and hyaluronidase-oysk for or
with ado-trastuzumab emtansine or fam-trastuzumab deruxtecan-nxki.
• Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use may be substituted anywhere that the
combination of intravenous pertuzumab and intravenous trastuzumab are given as part of systemic therapy. Pertuzumab,
trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use has different dosing and administration instructions compared
to the intravenous products.
• Patients previously treated with chemotherapy plus trastuzumab in the absence of pertuzumab in the metastatic setting may be
considered for one line of therapy including both trastuzumab plus pertuzumab in combination with or without cytotoxic therapy
(such as vinorelbine or taxane). Further research is needed to determine the ideal sequencing strategy for anti-HER2 therapy.
• For treatment of brain metastases, see NCCN Guidelines for Central Nervous System Cancers.

1 Sphar BG, Bowe C, Dains JE. The impact of peripheral cooling on chemotherapy-induced peripheral neuropathy: An integrative review. J Adv Pract Oncol
2020;11:845-857.
2 Hanai A, Ishiguro H, Sozu T, et al. Effects of cryotherapy on objective and subjective symptoms of paclitaxel-induced neuropathy: Prospective self-controlled trial. J
Natl Cancer Inst 2018;110:141-148.

Note: All recommendations are category 2A unless otherwise indicated.

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Systemic Chemotherapy for HR-Positive or -Negative and HER2-Negativea,s,t,u,v

Preferred Regimens Other Recommended Regimens Useful in Certain Circumstances
• Anthracyclines • Cyclophosphamide • AC (doxorubicin/cyclophosphamide)
Doxorubicin • Docetaxel • EC (epirubicin/cyclophosphamide)
Liposomal doxorubicin • Albumin-bound paclitaxel • CMF (cyclophosphamide/
• Taxanes • Epirubicin methotrexate/fluorouracil)
Paclitaxel • Ixabepilone • Docetaxel/capecitabine
• GT (gemcitabine/paclitaxel)
• Anti-metabolites • Gemcitabine/carboplatin
Capecitabine • Carboplatin + paclitaxel or albumin-bound paclitaxel
Gemcitabine
• Microtubule inhibitors
Vinorelbine
Eribulin

• For specific lines of systemic therapy options for HR-positive and HER2-negative with visceral crisis or endocrine refractory, see BINV-Q (1).
• For specific lines of systemic therapy options for HR-negative and HER2-negative (TNBC), see BINV-Q (2).
• For specific lines of systemic therapy options for HR-negative or -positive and HER2-positive, see BINV-Q (3).

a For treatment of brain metastases, see NCCN Guidelines for Central Nervous System Cancers.
s Alternative taxanes (ie, docetaxel, paclitaxel, albumin-bound paclitaxel) may be substituted for selectpatients due to medical necessity (ie, hypersensitivity reaction).
If substituted for weekly paclitaxel or docetaxel, then the weekly dose of albumin-bound paclitaxel should not exceed 125 mg/m2.
t Sequential single agents are preferred, but chemotherapy combinations may be used in select patients with high tumor burden, rapidly progressing disease, and
visceral crisis.
u Consider scalp cooling to reduce incidence of chemotherapy-induced alopecia for patients receiving chemotherapy. Results may be less effective with anthracycline
containing regimens.
v Consider cryotherapy of hands and feet to decrease the risk of peripheral neuropathy when receiving taxane therapies.

Note: All recommendations are category 2A unless otherwise indicated.

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TARGETED THERAPIES AND ASSOCIATED BIOMARKER TESTING

FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE
Biomarkers Associated with FDA-Approved Therapies
Breast Cancer Biomarker Detection FDA-Approved Agents NCCN Category NCCN Category
Subtype of Evidence of Preference
Preferred second-
HR-positive/ PIK3CA activating NGS, PCR (Blood or tumor tissue if Alpelisib + fulvestrantx Category 1 or subsequent-line
HER2-negativew mutation blood negative) therapy

PIK3CA or AKT1 Preferred second-

HR-positive/ NGS, (Blood or tumor tissue if or subsequent-line
activating mutations or Capivasertib + fulvestranty Category 1
HER2-negativey blood negative) therapy in select
PTEN alterations patientsy
HR-positive/ Other recommended
ESR1 mutation NGS, PCR (Tumor tissue or blood) Elacestrantz Category 2A
HER2-negativez regimen
Germline BRCA1 or Olaparib
Any Germline sequencing Category 1 Preferred
BRCA2 mutation Talazoparib
Larotrectinibaa
FISH, NGS, PCR (Tumor tissue or
Any NTRK fusion blood) Entrectinibaa Category 2Abb
Repotrectinibbb
Pembrolizumabcc,dd Useful in certain
Any MSI-H/dMMR IHC, NGS, PCR, (Tumor tissue) Category 2A circumstances
Dostarlimab-gxlyee
Any TMB-H (≥10 mut/Mb) NGS (Tumor tissue or blood) Pembrolizumabcc,dd Category 2A
Any RET-fusion NGS (Tumor tissue or blood) Selpercatinibff Category 2A
w For HR-positive/HER2-negative breast cancer, assess for PIK3CA mutations with tumor
or liquid biopsy to identify candidates for alpelisib plus fulvestrant. PIK3CA mutation
testing can be done on tumor tissue or ctDNA in peripheral blood (liquid biopsy). If liquid bb Repotrectinib is indicated for the treatment of solid tumors that have an NTRK gene fusion
biopsy is negative, tumor tissue testing is recommended. and are locally advanced or metastatic or where surgical resection is likely to result in
x The safety of alpelisib in patients with Type 1 or uncontrolled Type 2 diabetes has not severe morbidity and have progressed following treatment or have no satisfactory alternative
been established. therapy. The recommendation in the first-line setting is category 2B.
y In adult patients with PIK3CA or AKT1 activating mutations, or for PTEN alterations after cc NCCN Guidelines for Management of Immunotherapy-Related Toxicities.
disease progression or recurrence after ≥1 prior lines of endocrine therapy, including one dd Pembrolizumab is indicated for the treatment of patients with unresectable or metastatic,
line containing a CDK4/6 inhibitor. microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, or
z For postmenopausal or premenopausal patients receiving ovarian ablation or TMB-H tumors that have progressed following prior treatment and who have no satisfactory
suppression or adult males with ER-positive, HER2-negative, ESR1-mutated disease alternative treatment options.
after progression on one or two prior lines of endocrine therapy, including one line ee Dostarlimab-gxly is indicated for adult patients with MSI-H/dMMR unresectable or
containing a CDK4/6 inhibitor. Assess for ESR1 mutations at progression following prior metastatic tumors that have progressed on or following prior treatment and who have no
lines of endocrine therapy. satisfactory alternative treatment options.
aa Larotrectinib and entrectinib are indicated for the treatment of solid tumors that have ff Selpercatinib is indicated for adult patients with locally advanced or metastatic solid tumors
an NTRK gene fusion without a known acquired resistance mutation and have no with a RET gene fusion that have progressed on or following prior systemic treatment or who
satisfactory alternative treatments or that have progressed following treatment. have no satisfactory alternative treatment options.

Note: All recommendations are category 2A unless otherwise indicated.

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EMERGING BIOMARKERS TO IDENTIFY NOVEL THERAPIES FOR PATIENTS WITH STAGE

IV (M1) DISEASE

Breast Cancer Emerging Detection Potential Targeted NCCN Category NCCN Category of
Subtype Biomarkers Therapyhh of Evidence Preference
ER+/HER2- HER2 activating NGSgg Neratinib ± fulvestrantii Category 2B Useful in certain
ER-/HER2- mutations Neratinib ± trastuzumab/ circumstances
fulvestrantjj • If ER+/HER2-, in
patients who have
already received
CDK4/6 inhibitor
therapy.
Any Somatic BRCA1/2 NGSgg Olaparibkk Category 2B Useful in certain
mutations circumstances
Any Germline PALB2 Germline Olaparibkk Category 2B Useful in certain
sequencing circumstances

gg Tumor tissue or ctDNA.

hh At the present time, the datafor the emerging biomarkers for the potential targeted agents noted in the table are promising but limited.
ii Ma CX, Luo J, Freedman RA, et al. The phase II MutHER study of neratinib alone and in combination with fulvestrant in HER2-mutated, non-amplified metastatic
breast cancer. Clin Cancer Res 2022;28:1258-1267.
jj Jhaveri KL, Goldman JW, Hurvitz SA, et al. Neratinib plus fulvestrant plus trastzuzumab (N+F+T) for hormone receptor-positive (HR+), HER2-negative, HER2-mutant
metastatic breast cancer (MBC): Outcomes and biomarker analysis from the SUMMIT trial. J Clin Oncol 2022;40:1028-1028.
kk Tung NM, Robson ME, Ventz S, et al. TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes.
J Clin Oncol 2020;38:4274-4282.

Note: All recommendations are category 2A unless otherwise indicated.

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DOSING: SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE
HER2-Negative Regimens:
• Anthracyclines: • Cyclophosphamide14 • Fam-trastuzumab deruxtecan-nxki • Gemcitabine/carboplatin30
Doxorubicin 60–75 mg/m2 IV day 1; cycled 50 mg PO daily on days 1–21 (for HER2 IHC 1+ or 2+/ISH Gemcitabine 1000 mg/m2 on days 1 and 8
every 21 days1 Cycled every 28 days negative) 24 Carboplatin AUC 2 IV on days 1 and 8
Doxorubicin 20 mg/m2 IV day 1 weekly2 5.4 mg/kg IV day 1 ◊ Cycled every 21 days
Liposomal doxorubicin3 50 mg/m2 IV day 1; • Docetaxel15,16
Cycled every 21 days
cycled every 28 days 60–100 mg/m2 IV day 1 • Carboplatin/albumin-bound paclitaxel31
• AC25
Cycled every 21 days Carboplatin AUC 2 IV on days 1 and 8
• Taxanes: Doxorubicin 60 mg/m2 IV day 1
Albumin-bound paclitaxel 125 mg/m2 IV on
Paclitaxel 175 mg/m2 IV day 1; cycled every 21 • Docetaxel17 Cyclophosphamide 600 mg/m2 IV day
days 1 and 8
days4 35 mg/m2 IV weekly for 6 weeks 1
Cycled every 21 days
Paclitaxel 80 mg/m2 IV day 1 weekly5 followed by a 2-week rest, then repeat ◊ Cycled every 21 days
• Carboplatin/paclitaxel32,33
• Antimetabolites: • Albumin-bound paclitaxel18,19 • EC26
Paclitaxel 175–200 mg/m2 IV day 1
Capecitabine6 1000–1250 mg/m2 PO twice 100 mg/m2
Epirubicin 75 mg/m2 IV day 1
Carboplatin AUC 6 IV day 1
daily days 1–14; cycled every 21 days Cyclophosphamide 600 mg/m2 IV day
or 125 mg/m2 IV days 1, 8, and 15 Cycled every 21 days
Capecitabine7 1500 mg PO twice daily days 1
or
1–7 and days 15–21 cycled every 28 days Cycled every 28 days ◊ Cycled every 21 days
8 Paclitaxel 100 mg/m2 IV days 1, 8, and 15
Gemcitabine 800–1200 mg/m IV days 1, 8,
2
• Albumin-bound paclitaxel18 • CMF27 Carboplatin AUC 2 IV days 1, 8, and 15
and 15; cycled every 28 days 260 mg/m2 IV Cyclophosphamide 100 mg/m2 PO Cycled every 28 days
• Microtubule inhibitors: Cycled every 21 days days 1–14
Vinorelbine9,10 • Epirubicin20 Methotrexate 40 mg/m2 IV days 1
◊ 25 mg/m2 IV day 1 weekly; or and 8 See dosing for targeted therapies on
60–90 mg/m2 IV day 1 BINV-Q (13)
◊ 20–35 mg/m2 IV days 1 and 8; cycled every 5-fluorouracil 600 mg/m IV days 1
2
Cycled every 21 days
21 days; or and 8
◊ 25–30 mg/m IV days 1, 8, and 15; cycled
2
• Ixabepilone21 ◊ Cycled every 28 days
every 28 days 40 mg/m2 IV day 1 • Docetaxel/capecitabine28
Eribulin11 1.4 mg/m2 IV days 1 and 8; cycled Cycled every 21 days Docetaxel 75 mg/m2 IV day 1
every 21 days Capecitabine 950 mg/m2 PO twice
• Platinum (for TNBC and germline BRCA1/2 • Sacituzumab govitecan-hziy
daily days 1–14
mutation) (for TNBC or HR+/HER2-)22,23
◊ Cycled every 21 days
Carboplatin12 AUC 6 IV on day 1 10 mg/kg IV on days 1 and 8
Cycled every 21 days • GT29
◊ Cycled every 21–28 days
13
Cisplatin 75 mg/m IV on day 1
2 Paclitaxel 175 mg/m2 IV day 1
Gemcitabine 1250 mg/m2 IV days 1
◊ Cycled every 21 days
and 8 (following paclitaxel on day 1)
◊ Cycled every 21 days

The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose References on
and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior BINV-Q 11 of 14
treatment, and comorbidity. The optimal delivery of anti-cancer agents therefore requires a health care delivery team experienced in the use of anti-
cancer agents and the management of associated toxicities in patients with cancer.
Continued
Note: All recommendations are category 2A unless otherwise indicated.
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DOSING: SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE
HER2-Positive Regimens:ll,mm,nn
• Pertuzumab + trastuzumab + docetaxel34 • Tucatinib + trastuzumab + capecitabine37 • Weekly paclitaxel/carboplatin + trastuzumab41
Pertuzumab 840 mg IV day 1 followed by 420 Tucatinib 300 mg orally twice daily on Paclitaxel 80 mg/m2 IV days 1, 8, and 15
mg IV days 1–21 Carboplatin AUC 2 IV days 1, 8, and 15
Trastuzumab 8 mg/kg IV day 1 followed by 6 Trastuzumab 8 mg/kg IV day 1 followed ◊ Cycled every 28 days
mg/kg IV day 1 every 21 days by 6 mg/kg IV day 1 every 21 days Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV
Docetaxel 75–100 mg/m2 IV day 1 Capecitabine 1000 mg/m2 orally twice weekly
◊ Cycled every 21 days daily on days 1–14 or
Cycled every 21 days Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV
• Pertuzumab + trastuzumab + paclitaxel35,36 day 1 every 21 days36
• Ado-trastuzumab emtansine (T-DM1)38
Pertuzumab 840 mg IV day 1 followed by 420 • Trastuzumab + paclitaxel42,43
3.6 mg/kg IV day 1
mg IV Paclitaxel 175 mg/m2 IV day 1 cycled every 21 days42
◊ Cycled every 21 days
◊ Cycled every 21 days or
Trastuzumab 4 mg/kg IV day 1 followed by 2 • Fam-trastuzumab deruxtecan-nxki39
Paclitaxel 80–90 mg/m2 IV day 1 weekly44
mg/kg IV weekly 5.4 mg/kg IV day 1
Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV
or ◊ Cycled every 21 days
weekly
Trastuzumab 8 mg/kg IV day 1 followed by 6 • Paclitaxel/carboplatin + trastuzumab40 or
mg/kg IV day 1 every 21 days37 Carboplatin AUC 6 IV day 1 Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV
Paclitaxel 80 mg/m2 IV day 1 weekly35 or Paclitaxel 175 mg/m2 IV day 1 day 1 every 21 days36
Paclitaxel 175 mg/m2 day 1 ◊ Cycled every 21 days
◊ Cycled every 21 days • Trastuzumab + docetaxel44,45
Trastuzumab 4 mg/kg IV day 1 followed
Docetaxel 80–100 mg/m2 IV day 1 cycled every 21 days44
by 2 mg/kg IV weekly
or
or
Docetaxel 35 mg/m2 IV days 1, 8, and 15 weekly cycled
Trastuzumab 8 mg/kg IV day 1 followed
every 28 days45
by 6 mg/kg IV day 1 every 21 days36
Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV
weekly
ll An FDA-approved biosimilar is an appropriate substitute for trastuzumab.
or
mm Trastuzumab and hyaluronidase-oysk injection for subcutaneous use may be substituted for Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV
trastuzumab. It has different dosage and administration instructions compared to intravenous day 1 every 21 days36
trastuzumab. Do not substitute trastuzumab and hyaluronidase-oysk for or with ado-trastuzumab
emtansine or fam-trastuzumab deruxtecan-nxki. See dosing for targeted therapies on
nn Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use may be substituted
BINV-Q (13)
anywhere that the combination of intravenous pertuzumab and intravenous trastuzumab are given as
part of systemic therapy. Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous
use has different dosing and administration instructions compared to the intravenous products.
The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose References on
and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior BINV-Q 11 of 14
treatment, and comorbidity. The optimal delivery of anti-cancer agents therefore requires a health care delivery team experienced in the use of anti-
cancer agents and the management of associated toxicities in patients with cancer.
Continued
Note: All recommendations are category 2A unless otherwise indicated.
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DOSING: SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE

HER2-Positive Regimens (continued):ll,mm

• Trastuzumab + vinorelbine10,46,47 • Trastuzumab + lapatinib52 • Margetuximab-cmkb + capecitabine54

Vinorelbine Lapatinib 1000 mg PO daily for 21 days Margetuximab 15 mg/kg IV day 1
◊ 25 mg/m2 IV day 1 weekly; or Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV Capecitabine 1000 mg/m2 PO twice daily
◊ 20–35 mg/m2 IV days 1 and 8; cycled every 21 weekly days 1–14
days; or or ◊ Cycled every 21 days
◊ 25–30 mg/m2 IV days 1, 8, and 15; cycled every
28 days
Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV • Margetuximab-cmkb + eribulin54
day 1 every 21 days36 Margetuximab 15 mg/kg IV day 1
Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg
IV weekly • Neratinib + capecitabine53 Eribulin 1.4 mg/m2 IV days 1 and 8
or Neratinib 240 mg PO daily on days 1–21 ◊ Cycled every 21 days
Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg Capecitabine 750 mg/m2 PO twice daily on days 1–14 • Margetuximab-cmkb + gemcitabine54
IV day 1 every 21 days36 ◊ Cycled every 21 days Margetuximab 15 mg/kg IV day 1
or Gemcitabine 1000 mg/m2 IV days 1 and 8
• Trastuzumab + capecitabine48,49,50
Capecitabine 1000–1250 mg/m2 PO twice daily
Neratinib ◊ Cycled every 21 days
◊ 120 mg PO daily on days 1–7; followed by
days 1–14 cycled every 21 days • Margetuximab-cmkb + vinorelbine54
Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg ◊ 160 mg PO daily on days 8–14; followed by
Margetuximab 15 mg/kg IV day 1
IV weekly42,49 ◊ 240 mg PO daily on days 15–21
Vinorelbine 25–30 mg/m2 IV days 1 and 8
or Capecitabine 750 mg/m² PO twice daily on days 1–14
◊ Cycled every 21 days
Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg ◊ Cycled every 21 days x 1 cycle
IV day 1 every 21 days34,36 Followed by
Neratinib 240 mg PO daily on days 1–21 See dosing for targeted therapies on
• Lapatinib + capecitabine51 Capecitabine 750 mg/m² PO twice daily on days 1–14 BINV-Q (13)
Lapatinib 1250 mg PO daily days 1–21 ◊ Cycled every 21 days beginning with cycle 2
Capecitabine 1000 mg/m2 PO twice daily days 1–14
◊ Cycled every 21 days

ll An FDA-approved biosimilar is an appropriate substitute for trastuzumab.

mm Trastuzumab and hyaluronidase-oysk injection for subcutaneous use may be substituted for trastuzumab. It has different dosage and administration instructions
compared to intravenous trastuzumab. Do not substitute trastuzumab and hyaluronidase-oysk for or with ado-trastuzumab emtansine or fam-trastuzumab deruxtecan-nxki.
The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose
and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior
treatment, and comorbidity. The optimal delivery of anti-cancer agents therefore requires a health care delivery team experienced in the use of anti-
cancer agents and the management of associated toxicities in patients with cancer.
References on
BINV-Q 11 of 14
Note: All recommendations are category 2A unless otherwise indicated.
BINV-Q
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Invasive Breast Cancer Discussion

SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE
REFERENCES
1 Chan S, Friedrichs K, Noel D, et al. Prospective randomized trial of docetaxel versus 16 Harvey V, Mouridsen H, Semiglazov V, et al. Phase III trial comparing three doses
doxorubicin in patients with metastatic breast cancer. J Clin Oncol 1999;17:2341-2354. of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol
2 Gasparini G, Dal Fior S, Panizzoni GA, et al. Weekly epirubicin versus doxorubicin as 2006;24:4963-4970.
second line therapy in advanced breast cancer. A randomized clinical trial. Am J Clin Oncol 17 Rivera E, Mejia JA, Arun BJ, et al. Phase 3 study comparing the use of docetaxel on
1991;14:38-44. an every-3-week versus weekly schedule in the treatment of metastatic breast cancer.
3 O'Brien ME, Wigler N, Inbar M, et al. Reduced cardiotoxicity and comparable efficacy in a Cancer 2008;112:1455-1461.
phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional 18 Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-
doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 2004;15:440-449. bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with
4 Seidman AD, Tiersten A, Hudis C, et al. Phase II trial of paclitaxel by 3-hour infusion as breast cancer. J Clin Oncol 2005;23:7794-7803.
initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol 1995;13:2575- 19 Gradishar W, Dimitry K, Sergey C, et al. Significantly longer progression-free survival
2581. with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast
5 Perez EA, Vogel CL, Irwin DH, et al. Multicenter phase II trial of weekly paclitaxel in cancer. J Clin Oncol 2009;27:3611-3619.
women with metastatic breast cancer. J Clin Oncol 2001;19:4216-4223. 20 Bastholt L, Dalmark M, Gjedde SB, et al. Dose-response relationship of epirubicin in
6 Bajetta E, Procopio G, Celio L, et al. Safety and efficacy of two different doses of the treatment of postmenopausal patients with metastatic breast cancer: a randomized
capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol study of epirubicin at four different dose levels performed by the Danish Breast Cancer
2005;23:2155-2161. Cooperative Group. J Clin Oncol 1996;14:1146-1155.
7 Khan QJ, Bohnenkamp C, Monson T, et al. Randomized trial of fixed dose capecitabine 21 Perez E, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a
compared to standard dose capecitabine in metastatic breast cancer: The X-7/7 trial. J Clin phase II study of patients with advanced breast cancer resistant to an anthracycline, a
Oncol 2023;41:1007-1007. taxane, and capecitabine. J Clin Oncol 2007;25:3407-3414.
8 Seidman AD. Gemcitabine as single-agent therapy in the management of advanced breast 22 Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory
cancer. Oncology (Williston Park) 2001;15:11-14. metastatic triple negative breast cancer. N Engl J Med 2019;380:741-751.
9 Zelek L, Barthier S, Riofrio M, et al. Weekly vinorelbine is an effective palliative regimen 23 Rugo HS, Bardia A, Marme F, et al. Primary Results from TROPiCS-02: A randomized
after failure with anthracyclines and taxanes in metastatic breast carcinoma. Cancer phase 3 study of sacituzumab govitecan (SG) versus treatment of physician’s choice
2001;92:2267-2272. (TPC) in patients with hormone receptor-positive/HER2-negative (HR+/HER2-) advanced
10 Esfahani K, Ferrario C, Le P, Panasci L. The trastuzumab and vinorelbine combination: breast cancer [abstract]. J Clin Oncol 2022;40:Abstract LB1001.
an alternative to taxane-based chemotherapy for early-stage and locally advanced her2- 24 Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated
positive breast cancer. Curr Oncol 2014;21:e723-e727. HER2-low advanced breast cancer. N Engl J Med 2022;7;387:9-20.
11 Cortes J, O'Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of 25 Nabholtz JM, Falkson C, Campos D, et al. Docetaxel and doxorubicin compared with
physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open- doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast
label randomised study. Lancet 2011;377:914-923. cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol 2003;21:968-
12 Isakoff SJ, Mayer EL, He L, et al. TBCRC009: A multicenter phase II clinical trial of 975.
platinum monotherapy with biomarker assessment in metastatic triple-negative breast 26 Langley RE, Carmichel J, Jones AL, et al. Phase III trial of epirubicin plus paclitaxel
cancer. J Clin Oncol 2015;33:1902-1909. compared with epirubicin plus cyclophosphamide as first-line chemotherapy for
13 Silver DP, Richardson AL, Eklund AC, et al. Efficacy of neoadjuvant cisplatin in triple- metastatic breast cancer: United Kingdom Cancer Research Institute. J Clin Oncol
negative breast cancer. J Clin Oncol 2010;28:1145-1153. 2005;23:8322-8330.
14 Licchetta A, Correale P, Migali C, et al. Oral metronomic chemo-hormonal-therapy of 27 Bonadonna G, Brusamolino E, Valagussa P, et al. Combination chemotherapy as an
metastatic breast cancer with cyclophosphamide and megestrol acetate. J Chemother adjuvant treatment in operable breast cancer. N Engl J Med 1976;294:405-410.
2010;22:201-204. 28 Mavroudis D, Papakotoulas P, Ardavanis A, et al. Randomized phase III trial comparing
15 Burris HA, 3rd. Single-agent docetaxel (Taxotere) in randomized phase III trials. Semin docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in
Oncol 1999;26:1-6. women with advanced breast cancer. Ann Oncol 2010;21:48-54.

Continued

Note: All recommendations are category 2A unless otherwise indicated.

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SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE
REFERENCES
29 Albain KS, Nag S, Calderillo-Ruiz G, et al. Gemcitabine plus paclitaxel versus 42 Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal
paclitaxel monotherapy in patients with metastatic breast cancer and prior antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med
anthracycline treatment. J Clin Oncol 2008;26:3950-3957. 2001;344:783-792.
30 O’Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase III 43 Seidman A, Berry DA, Cirrincione C, et al. Randomized phase III trial of weekly compared
study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2
metastatic triple-negative breast cancer (TNBC). [abstract]. J Clin Oncol 2011;29 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors:
(Suppl_15):Abstract 1007. final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 2008;26:1642-1649.
31 Yardley DA, Coleman R, Conte P, et al. nab-Paclitaxel plus carboplatin or 44 Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety
gemcitabine versus gemcitabine plus carboplatin as first-line treatment of patients of trastuzumab combined with docetaxel in patients with human epidermal growth factor
with triple-negative metastatic breast cancer: results from the tnAcity trial. Ann Oncol receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001
2018;29:1763-1770. study group. J Clin Oncol 2005;23:4265-4274.
32 Perez EA, Hillman DW, Stella PJ, et al. A phase II study of paclitaxel plus 45 Esteva FJ, Valero V, Booser D, et al. Phase II study of weekly docetaxel and trastuzumab for
carboplatin as first-line chemotherapy for women with metastatic breast carcinoma. patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:1800-1808.
Cancer 2000;88:124-131. 46 Burstein HJ, Keshaviah A, Baron AD, et al. Trastuzumab plus vinorelbine or taxane
33 Loesch D, Robert N, Asmar L, et al. Phase II multicenter trial of a weekly paclitaxel chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and
and carboplatin regimen in patients with advanced breast cancer. J Clin Oncol vinorelbine or taxane study. Cancer 2007;110:965-972.
2002;20:3857-3864. 47 Andersson M, Lidbrink E, Bjerre K, et al. Phase III randomized study comparing docetaxel
34 Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally
for metastatic breast cancer. N Engl J Med 2012;366:109-119. advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA
35 Datko F, D'Andrea G, Dickler M, et al. Phase II study of pertuzumab, trastuzumab, study. J Clin Oncol 2011;29:264-271.
and weekly paclitaxel in patients with metastatic HER2-overexpressing metastatic 48 von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human
breast cancer [abstract]. Cancer Res 2012;72:Abstract P5-18-20. epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/
36 Leyland-Jones B, Gelmon K, Ayoub JP, et al. Pharmacokinetics, safety, and breast international group 03-05 study. J Clin Oncol 2009;27:1999-2006.
efficacy of trastuzumab administered every three weeks in combination with 49 Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety
paclitaxel. J Clin Oncol 2003;21:3965-3971. of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing
37 Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin
HER2-positive metastatic breast cancer. N Engl J Med 2020;382:597-609. Oncol 1999;17:2639-2648.
38 Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive 50 Bartsch
 R, Wenzel C, Altorjai G, et al. Capecitabine and trastuzumab in heavily pretreated
advanced breast cancer [supplementary appendix available online]. N Engl J Med metastatic breast cancer. J Clin Oncol 2007;25:3853-3858.
2012;367:1783-1791. 51 Geyer
 C, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced
39 Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated breast cancer. N Engl J Med 2006;355:2733-2743.
HER2-positive breast cancer. N Engl J Med 2020;382:610-621. 52 Blackwell KL, Burstein H, Storniolo A, et al. Randomized study of lapatinib alone or in
40 Robert N, Leyland-Jones B, Asmar L, et al. Randomized phase III study of combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic
trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel breast cancer. J Clin Oncol 2010;28:1124-1130.
in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 53 Saura C, Oliveira M, Feng YH, et al. Neratinib plus capecitabine versus lapatinib plus
2006;24:2786-2792. capecitabine in patients with HER2-positive metastatic breast cancer previously treated with
41 Perez EA, Suman VJ, Rowland KM, et al. Two concurrent phase II trials of ≥2 HER2-directed regimens: Findings from the multinational, randomized, phase 3 NALA trial.
paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting. May 31-June
therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG 4, 2019; Chicago, IL. J Clin Oncol 2019;37(suppl): abstract 1002.
study 983252. Clin Breast Cancer 2005;6:425-432. 54 Rugo HS, Im S, Cardoso F, et al. Efficacy of margetuximab vs trastuzumab in patients with
pretreated ERBB2-positive advanced breast cancer. JAMA Oncol 2021;573-584.

Note: All recommendations are category 2A unless otherwise indicated.

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DOSING: TARGETED THERAPIES AND ASSOCIATED BIOMARKER TESTING

FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE

• Alpelisib + fulvestrant1 • Olaparib7 tablet

Alpelisib 300 mg PO daily on days 1–28; fulvestrant 500 mg IM on 300 mg PO twice daily
days 1 and 15 Cycled every 28 days
◊ 28-day cycle for 1 cycle
Followed by alpelisib 300 mg PO daily on days 1–28; fulvestrant 500 mg
IM on day 1 • Pembrolizumab8-11
◊ Cycled every 28 days until disease progression or unacceptable toxicity 200 mg IV on day 1, every 21 days until disease progression or
unacceptable toxicity, or up to 24 months
• Capivasertib + fulvestrant2 or
Capivasertib 400 mg PO twice daily on days 1–4, 8–11, 15–18, 22–25 400 mg IV on day 1, every 6 weeks until disease progression or
Fulvestrant 500 mg IM day 1 and day 15 unacceptable toxicity, or up to 24 months
◊ Cycled every 28 days for 1 cycle
Followed by • Pembrolizumab + chemotherapy (albumin-bound paclitaxel, paclitaxel,
Capivasertib 400 mg PO twice daily on days 1–4, 8–11, 15–18, 22–25 or gemcitabine and carboplatin)12
Fulvestrant 500 mg IM day 1 starting with cycle 2
Pembrolizumab 200 mg IV day 1 (given every 21 days)
◊ Cycled every 28 days until disease progression or unacceptable toxicity
Albumin-bound paclitaxel 100 mg/m2 days 1, 8, 15 (given every 28 days)
• Dostarlimab-gxly3 OR
Paclitaxel 90 mg/m2 IV days 1, 8, 15 (given every 28 days)
500 mg IV on day 1
OR
◊ Cycled every 21 days for cycles 1–4
Followed by 1000 mg IV on day 1 of cycle 5 Pembrolizumab 200 mg IV day 1
◊ Cycled every 42 days starting with cycle 5 Gemcitabine 1000 mg/m2 IV days 1 and 8
Carboplatin AUC 2 IV days 1 and 8
• Elacestrant4 ◊ Given every 21 days
345 mg PO daily on days 1-28
Cycled every 28 days until disease progression or unacceptable toxicity • Selpercatinib13
Patients <50 kg: 120 mg PO twice daily until disease progression or
• Entrectinib5 unacceptable toxicity
600 mg PO daily on days 1–28 Patients ≥50 kg: 160 mg PO twice daily until disease progression or
Cycled every 28 days until disease progression or unacceptable toxicity unacceptable toxicity
• Larotrectinib6 • Talazoparib14 tablet
100 mg PO twice daily on days 1–28 1 mg PO daily
Cycled every 28 days until disease progression or unacceptable toxicity Cycled every 28 days

The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule and initiation
of supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior treatment, and comorbidity. The optimal delivery of
anti-cancer agents therefore requires a health care delivery team experienced in the use of anti-cancer agents and the management of associated toxicities in patients with References on
cancer.
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Invasive Breast Cancer Discussion

TARGETED THERAPIES AND ASSOCIATED BIOMARKER TESTING

FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE

REFERENCES

1 Andre F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med 2019;380:1929-1940.
2 Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor–positive advanced breast cancer. N Engl J Med 2023;388:2058-2070.
3 Berton D, Banerjee S, Curigliano G, et al. Antitumor activity of dostarlimab in patients with mismatch repair–deficient (dMMR) tumors: a combined analysis of 2 cohorts
in the GARNET study. Poster presented at American Society for Clinical Oncology (ASCO), Virtual Meeting, June 4–8, 2021. [Abstract ID: 2564].
4 Bidard FC, Kaklamani V, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive,
human epidermal growth factor receptor 2-negative advanced breast cancer: Results from the randomized phase III EMERALD trial. J Clin Oncol 2022;40:3246-3256.
5 Drilon A, Siena S, Ou SI, et al. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: Combined results from two phase I
trials (ALKA-372-001 and STARTRK-1). Cancer Discov 2017;7:400-409.
6 Drilon A, Laetsch TW, Kummar W, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 2018;378:731-739.
7 Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 2017;377:523-533.
8 Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409-413.
9 Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509-2520.
10 Lala M, Li TR, De Alwis DP, et al. A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Eur J
Cancer 2020;131:68-75.
11 Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab:
prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 2020;21:1353-1365.
12 Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or
metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 2020;396:1817-1828.
13 Subbiah V, Wolf J, Konda B, et al. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid
tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol 2022;23:1261-1273.
14 Litton J, Rugo H, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 2018;379:753-763.

Note: All recommendations are category 2A unless otherwise indicated.

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Invasive Breast Cancer Discussion

PRINCIPLES OF MONITORING METASTATIC DISEASE

Monitoring of patient symptoms and cancer burden during treatment of metastatic breast cancer is important to determine whether the
treatment is providing benefit and that the patient does not have toxicity from an ineffective therapy.

Components of Monitoring
Monitoring includes periodic assessment of varied combinations of symptoms, physical examination, routine laboratory tests, imaging
studies, and blood biomarkers where appropriate. Results of monitoring are classified as response/continued response to treatment, stable
disease, uncertainty regarding disease status, or progression of disease. The clinician typically must assess and balance multiple different
forms of information to make a determination regarding whether disease is being controlled and the toxicity of treatment is acceptable.
Sometimes, this information may be contradictory. Clinicians should take into account patient preferences through a shared decision-making
process.

Definition of Disease Progression

Unequivocal evidence of progression of disease by one or more of these factors is required to establish progression of disease, either
because of ineffective therapy or acquired resistance of disease to an applied therapy. Progression of disease may be identified through
evidence of growth or worsening of disease at previously known sites of disease and/or of the occurrence of new sites of metastatic disease.
• Findings concerning for progression of disease include:
Worsening symptoms such as pain or dyspnea
Evidence of worsening or new disease on physical examination
Declining performance status
Unexplained weight loss
Increasing alkaline phosphatase, alanine aminotransferase (ALT), aspartate transaminase (AST), or bilirubin
Hypercalcemia
New radiographic abnormality or increase in the size of pre-existing radiographic abnormality
New areas of abnormality on functional imaging (eg, bone scan, PET/CT)
Increasing tumor markers (eg, carcinoembryonic antigen [CEA], CA 15-3, CA 27.29)a

a Rising tumor markers (eg, CEA, CA 15-3, CA 27.29) are concerning for tumor progression, but may also be seen in the setting of responding disease. An isolated
increase in tumor markers should rarely be used to declare progression of disease. Changes in bone lesions are often difficult to assess on plain or cross-sectional
radiology or on bone scan. For these reasons, patient symptoms and serum tumor markers may be more helpful in patients with bone-dominant metastatic disease.
Continued
Note: All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF MONITORING METASTATIC DISEASE

Use of Objective Criteria for Response/Stability/Progression
• The most accurate assessments of disease activity typically occur when previously abnormal studies are repeated on a serial and regular
basis. Generally, the same method of assessment should be used over time (eg, an abnormality found on chest CT should generally be
monitored with repeat chest CT).
• Some non-clinically important variation in measurement of abnormalities by all serial studies is common and expected. Therefore, the use
of objective and widely accepted criteria for response, stability, and progression of disease are encouraged. Such systems include the
Response Evaluation Criteria In Solid Tumors (RECIST) guidelines (Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation
criteria in solid tumours: revised RECIST guideline [version 1.1]. Eur J Cancer 2009;45:228-247) and the WHO criteria (Miller AB, Hoogstraten
B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207-214).
• Studies of functional imaging, such as radionuclide bone scans and PET imaging, are particularly challenging when used to assess
response. In the case of bone scans, responding disease may result in a flare or increased activity on the scan that may be misinterpreted
as disease progression, especially on the first follow-up bone scan after initiating a new therapy. PET imaging is challenging because of the
absence of a reproducible, validated, and widely accepted set of standards for disease activity assessment.

Continued
Note: All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF MONITORING METASTATIC DISEASE

Frequency of Monitoring
The optimal frequency of repeat testing is uncertain, and is primarily based on the monitoring strategies utilized in breast cancer clinical
trials. The frequency of monitoring must balance the need to detect progressive disease, avoid unnecessary toxicity of any ineffective therapy,
resource utilization, and determine cost. The following table is to provide guidance, and should be modified for the individual patient based
on sites of disease, biology of disease, and treatment regimen. Reassessment of disease activity should be performed in patients with new or
worsening signs or symptoms of disease, regardless of the time interval from previous studies.

Suggested Intervals of Follow-up for Patients with Metastatic Diseaseb

Baseline Prior to New Chemotherapy Endocrine Therapy Restaging if Concern for

Therapy Progression of Disease

Symptom Assessment Yes Prior to each cycle Every 1–3 months Yes

Physical Examination Yes Prior to each cycle Every 1–3 months Yes

Performance Status Yes Prior to each cycle Every 1–3 months Yes

Weight Yes Prior to each cycle Every 1–3 months Yes

LFTs, CBC Yes Prior to each cycle, as Every 1–3 months Yes
indicated

CT Chest/Abdomen/ Yes Every 2–4 cycles Every 2–6 months Yes

Pelvis with Contrast

Bone Scan Yes Every 4–6 cycles Every 2–6 months Yes

PET/CT As clinically indicated As clinically indicated As clinically indicated As clinically indicated

Tumor Markers As clinically indicated As clinically indicated As clinically indicated As clinically indicated

Brain MRI with As clinically indicated As clinically indicated As clinically indicated As clinically indicated
contrast

b In patients who have long-term stable disease, the frequency of monitoring can be reduced.

Note: All recommendations are category 2A unless otherwise indicated.

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Phyllodes Tumor Discussion

CLINICAL WORKUP FINDINGS TREATMENT SURVEILLANCE

PRESENTATION
Fibroadenoma Observe

Phyllodes,b Clinical
Excisional Benign phyllodesb,f follow-up for
indeterminate
biopsyc 3 y (no RT)
or benign

Follow
Clinical suspicion of Phyllodes, borderline
pathway
phyllodes: or malignantb,f
below
• Palpable mass
• Rapid growth
• History and
• Large size (>3 cm) Wide excisiond
physical exam Phyllodes,b Clinical
• Imaging with Core needle without axillary Phyllodes, borderline
• Ultrasound borderline follow-up for
ultrasound biopsya staging or malignantb,f
• Mammogram for or malignant 3 yg
suggestive of + consider RTe
patients ≥30 y
fibroadenoma
except for size
and/or history of
growth
Invasive or See NCCN Guidelines for Noninvasive Breast Cancer
in situ cancer for DCIS (DCIS-1) or Invasive Breast Cancer (BINV-1)

a FNA or core biopsy may not distinguish a fibroadenoma from a phyllodes

tumor in some cases. The sensitivity of core biopsy for the diagnosis
of phyllodes tumor is greater than that of FNA biopsy, but neither core
biopsy nor FNA biopsy can always differentiate phyllodes tumors from e There are no prospective randomized data supporting the use of RT for phyllodes
fibroadenomas. In cases with clinical suspicion for phyllodes tumor, tumors. However, in the setting where additional recurrence would create
excision of the lesion may be needed for definitive pathologic classification. significant morbidity (eg, chest wall recurrence following mastectomy), RT may be
b Genetic counseling and testing if patient is at risk for hereditary cancer considered following the same principles that are applied to the treatment of soft
syndromes, particularly breast, ovarian, and pancreatic cancer. tissue sarcoma.
c Excisional biopsy includes complete mass removal, but without the intent f The panel endorses the College of American Pathologists Protocol for standardized
of obtaining surgical margins. pathology reporting for all phyllodes tumors (https://documents.cap.org/protocols/
d For borderline or malignant phyllodes tumors, wide excision means Breast.Phyllodes_1.1.0.1.REL_CAPCP.pdf).
excision with the intention of obtaining surgical margins ≥1 cm. Narrow g Borderline and malignant phyllodes tumors are high-risk for local recurrence and
surgical margins are associated with heightened local recurrence risk, but heightened imaging should be considered to include ultrasound every 6 mo after
are not an absolute indication for mastectomy when partial mastectomy BCS for 2 y, then annually through 5 y, in addition to annual mammograms (as age
fails to achieve a margin width ≥1 cm. appropriate).

Note: All recommendations are category 2A unless otherwise indicated.

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Phyllodes Tumor Discussion

PHYLLODES TUMOR RECURRENCE

CLINICAL PRESENTATION WORKUP FINDINGS TREATMENT

Re-excision with wide Consider post-

No metastatic margins without axillary operative radiation
• History and physical disease
exam staging (category 2B)e
• Ultrasound
Locally recurrent breast • Mammogram
mass following excision • Tissue samplinga
of phyllodes tumor (histology preferred)
• Consider chest
imaging (x-ray or CT,
CT contrast optional) Metastatic Follow principles of soft tissue sarcoma
disease (See NCCN Guidelines for Soft Tissue Sarcoma)

a FNA or core biopsy may not distinguish a fibroadenoma from a phyllodes tumor in some cases. The sensitivity of core biopsy for the diagnosis of phyllodes tumor is
greater than that of FNA biopsy, but neither core biopsy nor FNA biopsy can always differentiate phyllodes tumors from fibroadenomas. In cases with clinical suspicion
for phyllodes tumor, excision of the lesion may be needed for definitive pathologic classification.
e There are no prospective randomized data supporting the use of RT for phyllodes tumors. However, in the setting where additional recurrence would create significant
morbidity (eg, chest wall recurrence following mastectomy), RT may be considered following the same principles that are applied to the treatment of soft tissue
sarcoma.

Note: All recommendations are category 2A unless otherwise indicated.

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Paget Disease Discussion

CLINICAL WORKUP
PRESENTATION

Examination or imaging
positive for breast lesion

• Clinical breast exam

Clinical suspicion • Diagnostic bilateral mammogram,
of Paget diseasea PAGET-2
ultrasound as necessary

Examination and imaging

negative for breast lesion

a Nipple or areolar eczema, ulceration, bleeding, or itching.

Note: All recommendations are category 2A unless otherwise indicated.

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Paget Disease Discussion

WORKUP TREATMENT
Breast and NAC Clinical follow-up
biopsy negative Re-biopsy if not healing

Breast DCIS See NCCN Guidelines for Noninvasive Breast

and NAC Paget Cancer for DCIS (DCIS-1)
Core biopsy of
Examination
breast lesion and
or imaging
full-thickness skin
positive for
biopsy of involved
breast lesion Appropriate
NAC
systemic
adjuvant therapy
Breast invasive cancer See NCCN Guidelines for Invasive Breast as clinically
and NAC Paget Cancer (BINV-1) indicated

See NCCN
Central lumpectomy including NAC Guidelines for
Breast negative for with WBRT
cancer and positive DCIS or Invasive
Consider or Breast Cancer
NAC Paget breast MRIb Total mastectomyc ± SLNB with or
and tissue without breast reconstruction
sampling or
NAC biopsy positive Central lumpectomy including NAC
for Paget ± SLNB without RT (category 2B)
Examination
Full-thickness
and imaging
skin biopsy of
negative for
involved NAC
breast lesion
NAC biopsy Clinical follow-up
negative for Paget Re-biopsy if not healing

b Principles of Dedicated Breast MRI Testing (BINV-B).

c Mastectomy is always an option with any manifestation of Paget disease (Discussion).

Note: All recommendations are category 2A unless otherwise indicated.

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Breast Cancer During Pregnancy Discussion

WORKUP CLINICAL PRESENTATION PRIMARY TREATMENTa,b ADJUVANT TREATMENTa,d

Begin adjuvant
chemotherapy in second
Discuss trimestera,d
First Continuing Mastectomye +
termination: ± RT postpartuma
trimester pregnancy axillary staginga,b,c
Non-therapeutic ± Adjuvant endocrine
therapy postpartuma
If indicated:
• Chest x-ray Adjuvant chemotherapya,d
(with abdominal ± RT postpartuma
shielding) Mastectomya or BCSe + axillary ± Adjuvant endocrine
If pregnant staginga,b,d
• Abdominal
with therapy postpartuma
ultrasound to
confirmed or
assess liver Second trimester/
breast cancer;
metastases Early third trimester
No distant Preoperative chemotherapy,a,d ± RT postpartuma
• Consider
metastases mastectomy, or BCSe + axillary ± Adjuvant endocrine
non-contrast
on staging staginga,b,d therapy postpartuma
MRI of spine
if indicated to
assess for bone
metastases Adjuvant chemotherapya,d
± RT postpartuma
Late third Mastectomyf or BCSe + axillary
± Adjuvant endocrine
trimester staginga,b
therapy postpartuma
a CT scans and nuclear imaging are contraindicated during pregnancy.
b Considerations and selection of optimal local therapy and systemic therapy are similar to d There are limited data on the use of taxanes during pregnancy. The
that recommended in non–pregnancy-associated breast cancer; see other sections of this optimal schedule is unclear. If used, the NCCN Panel recommends
guideline. However, the selection and timing of chemotherapy, endocrine therapy, and RT weekly administration of paclitaxel after the first trimester if clinically
is different if pregnant. BCS during the first trimester of pregnancy can be considered in indicated by disease status. The use of anti-HER2 therapy is
those who will require adjuvant chemotherapy and can have adjuvant radiation therapy contraindicated during pregnancy.
delayed until after delivery. Chemotherapy should not be administered during the first e Survival outcomes of BCT are equivalent to mastectomy in both
trimester of pregnancy, and RT should not be administered during any trimester of non-pregnancy and pregnancy-associated BCs. Therapeutic RT
pregnancy. Coordination is recommended between the oncology and obstetrics teams is generally avoided during pregnancy due to potential risks to
to plan the optimal timing of systemic therapy administration during pregnancy. Most the fetus. Mastectomy may be preferred, particularly for early (1st
experience with chemotherapy during pregnancy for breast cancer is from regimens trimester) gestational diagnosis, as early BCS may preclude timely
that utilize various combinations of doxorubicin, cyclophosphamide, and fluorouracil. administration of RT. Generally, intervals of 12–16 weeks between
Considerations for postpartum chemotherapy are the same as for non–pregnancy- treatment modalities (surgery, RT, and chemotherapy) are considered
associated breast cancer. acceptable.
c Use of blue dye is contraindicated in pregnancy; radiolabeled sulfur colloid appears to be f If late first trimester, may consider preoperative chemotherapy in the
safe for SLNB in pregnancy. See Considerations for Surgical Axillary Staging (BINV-D). second trimester.

Note: All recommendations are category 2A unless otherwise indicated.

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Inflammatory Breast Cancer Discussion

CLINICAL WORKUP
PRESENTATIONa
• History and physical exam by multidisciplinary team and
obtain medical photography
• CBC
• Comprehensive metabolic panel, including LFTs and
alkaline phosphatase
• Pathology reviewb
• Determination of tumor ER/PR status and
HER2 statusc Preoperative/Adjuvant
Clinical
• Fertility counseling if premenopausald Therapy Regimens
pathologic See IBC-2
• Genetic counseling if patient is at riske for hereditary breast (BINV-L)h
diagnosis of IBC
cancer
• Imaging:
Bilateral diagnostic mammogram, ultrasound as necessary
Chest diagnostic CT ± contrast
Abdomen ± pelvis diagnostic CT with contrast or MRI with
contrast
Bone scan or FDG-PET/CTf,g
Breast MRI (optional)

e For risk criteria, see NCCN Guidelines for Genetic/Familial High-Risk

a IBC is a clinical syndrome in patients with invasive breast cancer that is Assessment: Breast, Ovarian, and Pancreatic.
characterized by erythema and edema (peau d'orange) of a third or more of f If FDG-PET/CT is performed and clearly indicates bone metastasis on both the
the skin of the breast. The differential diagnosis includes cellulitis of the breast PET and CT component, bone scan or sodium fluoride PET/CT may not be
or mastitis. Pathologically, a tumor is typically present in the dermal lymphatics needed.
of the involved skin, but dermal lymphatic involvement is neither required, nor g FDG-PET/CT can be performed at the same time as diagnostic CT. FDG-PET/
sufficient by itself for a diagnosis of IBC. CT is most helpful in situations where standard staging studies are equivocal or
b The panel endorses the College of American Pathologists Protocol for pathology suspicious. FDG-PET/CT may also be helpful in identifying unsuspected regional
reporting for all invasive and noninvasive carcinomas of the breast. nodal disease and/or distant metastases when used in addition to standard
http://www.cap.org. staging studies.
c Principles of Biomarker Testing (BINV-A). h A pertuzumab-containing regimen may be administered preoperatively to patients
d Fertility and Birth Control (BINV-C). with HER2-positive IBC.

Note: All recommendations are category 2A unless otherwise indicated.

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Inflammatory Breast Cancer Discussion

RESPONSE TO TREATMENTj
PREOPERATIVE
THERAPY
• Complete planned chemotherapy regimen course
if not completed preoperatively plus endocrine
Total mastectomy + level l/ll axillary treatment if ER-positive and/or PR-positive (sequential
dissection + RT to chest wall and chemotherapy followed by endocrine therapy).m
Responsei comprehensive RNI with inclusion of • Complete up to one year of HER2-targeted therapy
any portion of the undissected axilla at if HER2-positive (category 1). May be administered
risk ± delayed breast reconstructionk concurrently with RTn and with endocrine therapy if
indicated.

Patients may be candidates

for multiple lines of
systemic therapy to palliate
advanced breast cancer.
At each reassessment Responsei See above pathway
Consider
clinicians should assess
additional systemic
No value of ongoing treatment,
chemotherapyl,m
responsei the risks and benefits
and/or preoperative
of an additional line of
radiation.
systemic therapy, patient No responsei Individualized treatment
performance status,
and patient preferences
through a shared decision-
making process.

i The accurate assessment of in-breast tumor or regional lymph node response to preoperative systemic therapy is difficult, and should include physical examination and
performance of imaging studies (mammogram and/or breast MRI) that were abnormal at the time of initial tumor staging. Selection of imaging methods prior to surgery
should be determined by the multidisciplinary team.
j Patients with recurrent IBC should be treated according to the guideline for recurrence/stage IV (M1) disease (BINV-19).
k Principles of Breast Reconstruction Following Surgery (BINV-H).
l Systemic Therapy Regimens for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-Q).
m Adjuvant Endocrine Therapy (BINV-K).
n Principles of Radiation Therapy (BINV-I).

Note: All recommendations are category 2A unless otherwise indicated.

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Breast Cancer Discussion

American Joint Committee on Cancer (AJCC)

TNM Staging System For Breast Cancer
Primary Tumor (T) The T category of the primary tumor is defined by the same criteria regardless of whether it is based on clinical or pathological criteria, or both. The
T category is based primarily on the size of the invasive component of the cancer. The maximum size of a tumor focus is used as an estimate of disease volume. The
largest contiguous dimension of a tumor focus is used, and small satellite foci of noncontiguous tumor are not added to the size. The cellular fibrous reaction to invasive
tumor cells is generally included in the measurement of a tumor prior to treatment; however, the dense fibrosis observed following neoadjuvant treatment is generally
not included in the pathological measurement because its extent may overestimate the residual tumor volume. The clinical size of a primary tumor (T) can be measured
based on clinical findings (physical examination and imaging modalities, such as mammography, ultrasound, and MR imaging) and pathological findings (gross and
microscopic measurements). Clinical tumor size (cT) should be based on the clinical findings that are judged to be most accurate for a particular case, although it may
still be somewhat inaccurate because the intent of some breast cancers is not always apparent with current imaging techniques and because tumors are composed of
varying proportions of noninvasive and invasive disease, which these techniques are currently unable to distinguish. Size should be measured to the nearest millimeter.
If the tumor size is slightly less than or greater than a cutoff for a given T classification the size should be rounded to the millimeter reading that is closest to the cutoff.
For example, a reported size of 4.9 mm is reported as 5 mm, or a size of 2.04 cm is reported as 2.0 cm (20 mm). The exception to this rounding rule is for a breast
tumor sized between 1.0 and 1.4 mm. These sizes are rounded up to 2 mm, because rounding down would result in the cancer’s being categorized as microinvasive
carcinoma (T1mi) defined as a size of 1.0 mm or less.

Table 1. Definitions for T, N, M T2 Tumor >20 mm but ≤50 mm in greatest dimension

TX Primary tumor cannot be assessed T3 Tumor >50 mm in greatest dimension
T0 No evidence of primary tumor T4 Tumor of any size with direct extension to the chest wall and/
Tis Ductal carcinoma in situ or to the skin (ulceration or macroscopic nodules); invasion
(DCIS)* of the dermis alone does not qualify as T4
Tis  aget disease of the nipple NOT associated with invasive
P T4a Extension to the chest wall; invasion or adherence to
(Paget) carcinoma and/or carcinoma in situ (DCIS) in the underlying pectoralis muscle in the absence of invasion of chest wall
breast parenchyma. Carcinomas in the breast parenchyma structures does not qualify as T4
associated with Paget disease are categorized based on T4b Ulceration and/or ipsilateral macroscopic satellite nodules
the size and characteristics of the parenchymal disease, and/or edema (including peau d’orange) of the skin that does
although the presence of Paget disease should still be noted not meet the criteria for inflammatory carcinoma
T1 Tumor ≤20 mm in greatest dimension T4c Both T4a and T4b are present
T1mi Tumor ≤1 mm in greatest dimension T4d Inflammatory carcinoma
T1a Tumor >1 mm but ≤5 mm in greatest dimension
(round any measurement >1.0–1.9 mm to 2 mm) *Note: Lobular carcinoma in situ (LCIS) is a benign entity and is
T1b Tumor >5 mm but ≤10 mm in greatest dimension removed from TNM staging in the AJCC Cancer Staging Manual, 8th
Edition.
T1c Tumor >10 mm but ≤20 mm in greatest dimension
Continued

Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com.
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Breast Cancer Discussion

Table 1. Definitions for T, N, M (continued) Pathologic (pN)

Regional Lymph Nodes (N) pNX Regional lymph nodes cannot be assessed (e.g., not
Clinical (cN) removed for pathological study or previously removed)
cNX* Regional lymph nodes cannot be assessed (e.g., previously pN0 No regional lymph node metastasis identified or ITCs only
removed)
cN0 No regional lymph node metastases (by imaging or clinical
pN0(i+) ITCs only (malignant cells clusters no larger than 0.2 mm)
examination) in regional lymph node(s)
cN1 Metastases to movable ipsilateral level I, II axillary lymph node(s) pN0(mol+) Positive molecular findings by reverse transcriptase
polymerase chain reaction (RT-PCR); no ITCs detected
cN1mi** Micrometastases (approximately 200 cells, larger than 0.2 mm, but pN1 Micrometastases; or metastases in 1–3 axillary lymph
none larger than 2.0 mm) nodes; and/or in clinically negative internal mammary
nodes with micrometastases or macrometastases by
cN2 Metastases in ipsilateral level I, II axillary lymph nodes that are sentinel lymph node biopsy
clinically fixed or matted;
or in ipsilateral internal mammary nodes in the absence of axillary pN1mi Micrometastases (approximately 200 cells, larger than
lymph node metastases 0.2 mm, but none larger than 2.0 mm)
cN2a Metastases in ipsilateral level I, II axillary lymph nodes fixed to one pN1a Metastases in 1–3 axillary lymph nodes, at least one
another (matted) or to other structures metastasis larger than 2.0 mm
cN2b Metastases only in ipsilateral internal mammary nodes in the pN1b Metastases in ipsilateral internal mammary sentinel
absence of axillary lymph node metastases nodes, excluding ITCs
cN3 Metastases in ipsilateral infraclavicular (level III axillary) lymph
node(s) with or without level I, II axillary lymph node involvement;
pN1c pN1a and pN1b combined.
or in ipsilateral internal mammary lymph node(s) with level I, II pN2 Metastases in 4–9 axillary lymph nodes; or positive
axillary lymph node metastases; ipsilateral internal mammary lymph nodes by imaging in
or metastases in ipsilateral supraclavicular lymph node(s) with or the absence of axillary lymph node metastases
without axillary or internal mammary lymph node involvement
pN2a Metastases in 4–9 axillary lymph nodes (at least one
cN3a Metastases in ipsilateral infraclavicular lymph node(s)
tumor deposit larger than 2.0 mm)
cN3b Metastases in ipsilateral internal mammary lymph node(s) and
axillary lymph node(s) pN2b Metastases in clinically detected internal mammary lymph
nodes with or without microscopic confirmation; with
cN3c Metastases in ipsilateral supraclavicular lymph node(s) pathologically negative axillary nodes
Note: (sn) and (f) suffixes should be added to the N category to denote
confirmation of metastasis by sentinel node biopsy or fine needle aspiration/core
needle biopsy respectively.
*The cNX category is used sparingly in cases where regional lymph nodes have
previously been surgically removed or where there is no documentation of physical
examination of the axilla.
**cN1mi is rarely used but may be appropriate in cases where sentinel node
biopsy is performed before tumor resection, most likely to occur in cases treated Continued
with neoadjuvant therapy.

Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com.
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Breast Cancer Discussion

Table 1. Definitions for T, N, M (continued) Table 2. AJCC Anatomic Stage Groups

Pathologic (pN)
pN3  etastases in 10 or more axillary lymph nodes;
M The Anatomic Stage Group table should only be used in global regions where
or in infraclavicular (level III axillary) lymph nodes; biomarker tests are not routinely available.
or positive ipsilateral internal mammary lymph nodes by Cancer registries in the U.S. must use the Clinical and Pathological Prognostic
imaging in the presence of one or more positive level I, II Stage Group tables for case reporting.
axillary lymph nodes;
or in more than three axillary lymph nodes and Stage 0 Tis N0 M0 Stage IIIA T0 N2 M0
micrometastases or macrometastases by sentinel lymph Stage IA T1 N0 M0 T1 N2 M0
node biopsy in clinically negative ipsilateral internal
mammary lymph nodes; Stage IB T0 N1mi M0 T2 N2 M0
or in ipsilateral supraclavicular lymph nodes T1 N1mi M0 T3 N1 M0
pN3a Metastases in 10 or more axillary lymph nodes (at least Stage IIA T0 N1 M0 T3 N2 M0
one tumor deposit larger than 2.0 mm);
or metastases to the infraclavicular (level III axillary T1 N1 M0 Stage IIIB T4 N0 M0
lymph) nodes T2 N0 M0 T4 N1 M0
pN3b pN1a or pN2a in the presence of cN2b (positive internal Stage IIB T2 N1 M0 T4 N2 M0
mammary nodes by imaging);
or pN2a in the presence of pN1b T3 N0 M0 Stage IIIC Any T N3 M0
pN3c Metastases in ipsilateral supraclavicular lymph nodes Stage IV M1 Any T Any N
Notes:
Note: (sn) and (f) suffixes should be added to the N category to denote 1. T1 includes T1mi.
confirmation of metastasis by sentinel node biopsy or FNA/core needle 2. T0 and T1 tumors with nodal micrometastases (N1mi) are staged as Stage IB.
biopsy respectively, with NO further resection of nodes 3. T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged using
Distant Metastasis (M) the N1 category.
4. M0 includes M0(i+).
M0 No clinical or radiographic evidence of distant 5. The designation pM0 is not valid; any M0 is clinical.
metastases* 6. If a patient presents with M1 disease prior to neoadjuvant systemic therapy, the
cM0(i+) No clinical or radiographic evidence of distant stage is considered Stage IV and remains Stage IV regardless of response to
metastases in the presence of tumor cells or deposits neoadjuvant therapy.
no larger than 0.2 mm detected microscopically or by 7. Stage designation may be changed if postsurgical imaging studies reveal the
molecular techniques in circulating blood, bone marrow, presence of distant metastases, provided the studies are performed within 4
or other nonregional nodal tissue in a patient without months of diagnosis in the absence of disease progression, and provided the
symptoms or signs of metastases patient has not received neoadjuvant therapy.
cM1 Distant metastases detected by clinical and radiographic 8. Staging following neoadjuvant therapy is designated with “yc” or “yp” prefix
means to the T and N classification. There is no anatomic stage group assigned if
pM1 Any histologically proven metastases in distant organs; there is a complete pathological response (pCR) to neoadjuvant therapy, for
or if in non-regional nodes, metastases greater than 0.2 example, ypT0ypN0cM0.
mm Continued

Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com.
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Breast Cancer Discussion

Table 2. AJCC Anatomic Stage Groups (continued)

Histologic Grade (G)

All invasive breast carcinomas should be assigned a histologic grade. The
Nottingham combined histologic grade (Nottingham modification of the SBR
grading system) is recommended and is stipulated for use by the College of
American Pathologists (see www.cap.org). The grade for a tumor is determined
by assessing morphologic features (tubule formation, nuclear pleomorphism, and
calibrated mitotic count), assigning a value from 1 (favorable) to 3 (unfavorable)
for each feature, and totaling the scores for all three categories. A combined score
of 3–5 points is designated as grade 1; a combined score of 6–7 points is grade 2;
a combined score of 8–9 points is grade 3. The use of subjective grading alone is
discouraged.

Invasive Cancer (Scarff-Bloom-Richardson [SBR] Grading System,

Nottingham Modification)
GX Grade cannot be assessed
G1 Low combined histologic grade (favorable);
SBR score of 3–5 points
G2 Intermediate combined histologic grade (moderately favorable); SBR
score of 6–7 points
G3 High combined histologic grade (unfavorable);
SBR score of 8–9 points

Ductal Carcinoma in situ: Nuclear Grade

The grade that should be used for ductal carcinoma in situ is nuclear grade
(www.cap.org)
GX Grade cannot be assessed
G1 Low nuclear grade
G2 Intermediate nuclear grade
G3 High nuclear grade

Continued

Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com.
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Histopathologic Type - WHO Classification 5th Edition (2019)

In situ carcinomas Favorable Histologic Types
Ductal carcinoma in situ (DCIS) (low nuclear grade, intermediate nuclear grade, and Tubular carcinoma
high nuclear grade) Cribriform carcinoma
Insitu papillary neoplasms (papillary DCIS, encapsulated papillary carcinoma, solid Mucinous carcinoma
papillary carcinoma in situ)
Adenoid cystic
Invasive Carcinomas
Low-grade adenosquamous carcinoma metaplastic carcinoma
Invasive breast carcinoma of no special type (ductal and other special patterns)
Low-grade fibromatosis-like metaplastic carcinoma
Microinvasive carcinoma
Invasive lobular carcinoma
Tubular carcinoma
Cribriform carcinoma
Mucinous carcinoma
Mucinous cystadenocarcinoma
Invasive micropapillary carcinoma
Invasive papillary carcinoma
Invasive solid papillary carcinoma
Carcinoma with apocrine differentiation
Metaplastic carcinoma (spindle cell, squamous, with heterologous differentiation,
low-grade adenosquamous carcinoma, low-grade fibromatosis-like and mixed
metaplastic)
Neuroendocrine tumor (NET)
Neuroendocrine carcinoma (NEC)
Salivary gland-type (acinic cell, adenoid cystic, secretory, mucoepidermoid,
polymorphous adenocarcinoma)
Tall cell carcinoma with reversed polarity

Continued

WHO Classification of Tumors Editorial Board, ed. WHO Classification of Tumors, 5th Edition – Breast Tumors. Lyon: International Agency for Research on Cancer 2019.
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Table 3. Clinical Prognostic Stage

Clinical Prognostic Stage applies to ALL patients with breast cancer for clinical classification and staging. It uses clinical tumor (T), node (N) and
metastases (M) information based on history, physical examination, any imaging performed (not necessary for clinical staging) and relevant biopsies.
Genomic profile information is not included in Clinical Prognostic Stage as pathologic information from surgery is necessary to ascertain the prognosis
using these tools.
TNM Grade HER2 ER PR Stage TNM Grade HER2 ER PR Stage
Tis N0 M0 Any Any Any Any 0 T0 N1** M0 Positive IB
T1* N1** M0 Positive
T1* N0 M0 Positive Negative
Positive T2 N0 M0 Positive
T0 N1mi M0 Negative Positive IIA
T1* N1mi M0 Positive Negative
Positive Negative
Negative G1
Negative IA Positive IB
G1 Positive
Positive Negative
Positive Negative
Negative Positive IIA
Negative Negative
Positive Negative
Negative
Negative IB Positive IB
Positive
Positive Negative
Positive Positive
Negative Positive IIA
Positive Negative
Positive Negative
Negative G2
Negative IA Positive IB
G2 Positive
Positive Negative
Positive Negative IIA
Negative Positive
Negative Negative
Positive Negative IIB
Negative
Negative IB Positive IB
Positive
Positive Negative
Positive Positive
Negative Positive
Positive Negative IIA
Positive IA Negative
Negative G3
Negative Positive
G3 Positive
Positive Negative
Positive Negative
Negative Positive IIB
Negative Negative
Positive IB Negative
Negative
Negative Continued
*T1 includes T1mi.
**N1 does not include N1mi. T1 N1mi M0 and T0 N1mi M0 cancers are included for prognostic staging with T1 N0 M0 cancers of the same prognostic factor status.
Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com.
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Table 3. Clinical Prognostic Stage (continued)

TNM Grade HER2 ER PR Stage TNM Grade HER2 ER PR Stage

T2 N1*** M0 Positive IB T0 N2 M0 Positive IIA
T3 N0 M0 Positive T1* N2 M0 Positive
Negative Negative
Positive IIA T2 N2 M0 Positive
Positive T3 N1*** M0 Positive IIIA
Negative T3 N2 M0 Negative
Negative IIB Negative
G1 G1
Positive IIA Positive IIA
Positive Positive
Negative Negative
Negative Negative IIIA
Positive IIB Positive
Negative Negative
Negative Negative IIIB
Positive IB Positive IIA
Positive Positive
Negative Negative
Positive IIA Positive
Positive Positive IIIA
Negative Negative
Negative IIB Negative
G2 G2
Positive IIA Positive IIA
Positive Positive
Negative Negative
Negative IIB Negative IIIA
Positive Positive
Negative Negative
Negative IIIB Negative IIIB
Positive IB Positive IIB
Positive Positive
Negative Negative
Positive Positive
Positive Positive
Negative IIB Negative IIIA
Negative Negative
G3 G3
Positive Positive
Positive Positive
Negative Negative
Negative IIIA Negative IIIB
Positive Positive
Negative Negative
Negative IIIB Negative IIIC
Continued
*T1 includes T1mi.
***N1 includes N1mi. T2, T3, and T4 cancers and N1mi are included for prognostic staging with T2 N1, T3 N1 and T4 N1, respectively.
Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com.
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Table 3. Clinical Prognostic Stage (continued)

Notes:
TNM Grade HER2 ER PR Stage
1. Because N1mi categorization requires evaluation of the entire node, and cannot
T4 N0 M0 Positive IIIA be assigned on the basis of an FNA or core biopsy, N1mi can only be used
T4 N1*** M0 Positive with Clinical Prognostic Staging when clinical staging is based on a resected
Negative
T4 N2 M0 Positive lymph node in the absence of resection of the primary cancer, such as the
Any T N3 M0 Positive situation where sentinel node biopsy is performed prior to receipt of neoadjuvant
Negative
Negative chemotherapy or endocrine therapy.
G1 IIIB 2. For cases with lymph node involvement with no evidence of primary tumor (e.g.
Positive
Positive T0 N1, etc.) or with breast ductal carcinoma in situ (e.g. Tis N1, etc.), the grade,
Negative HER2, ER, and PR information from the tumor in the lymph node should be used
Negative
Positive for assigning stage group.
Negative 3. For cases where HER2 is determined to be “equivocal” by ISH (FISH or CISH)
Negative IIIC testing under the 2013 ASCO/CAP HER2 testing guidelines, the HER2 “negative”
Positive IIIA category should be used for staging in the Clinical Prognostic Stage Group.
Positive 4. The prognostic value of these Prognostic Stage Groups is based on populations
Negative
Positive of persons with breast cancer that have been offered and mostly treated with
Positive appropriate endocrine and/or systemic chemotherapy (including anti-HER2
Negative
Negative therapy).
G2 IIIB
Positive
Positive
Negative
Negative
Positive
Negative
Negative IIIC
Positive
Positive
Negative
Positive
Positive IIIB
Negative
Negative
G3
Positive
Positive
Negative
Negative
Positive IIIC
Negative
Negative
Any T Any N M1 Any Any Any Any IV

Continued
***N1 includes N1mi. T2, T3, and T4 cancers and N1mi are included for prognostic staging with T2 N1, T3 N1 and T4 N1, respectively.

Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com.
Version 4.2024, 07/03/24 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
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Table 4. Pathological Prognostic Stage

Pathological Prognostic Stage applies to patients with breast cancer treated with surgery as the initial treatment. It includes all information used for
clinical staging plus findings at surgery and pathological findings from surgical resection. Pathological Prognostic Stage does not apply to patients treated
with systemic or radiation prior to surgical resection (neoadjuvant therapy).
TNM Grade HER2 ER PR Stage TNM Grade HER2 ER PR Stage
Tis N0 M0 Any Any Any Any 0 T0 N1** M0 Positive IA
T1* N1** M0 Positive
T1* N0 M0 Positive Negative
Positive T2 N0 M0 Positive IB
T0 N1mi M0 Negative Positive
T1* N1mi M0 Positive Negative
Positive Negative IIA
Negative G1
Negative Positive IA
G1 Positive
Positive Negative
Positive Negative IB
Negative Positive
Negative Negative
Positive Negative IIA
Negative
Negative IA Positive IA
Positive
Positive Negative
Positive Positive IB
Negative Positive
Positive Negative
Positive Negative IIA
Negative G2
Negative Positive IA
G2 Positive
Positive Negative
Positive Negative
Negative Positive IIA
Negative Negative
Positive Negative
Negative
Negative IB Positive IA
Positive
Positive Negative
Positive Positive
Negative Positive IIA
Positive Negative
Positive Negative
Negative G3
Negative IA Positive IB
G3 Positive
Positive Negative
Positive Negative
Negative Positive IIA
Negative Negative
Positive Negative
Negative
Negative IB
Continued
*T1 includes T1mi.
**N1 does not include N1mi. T1 N1mi M0 and T0 N1mi M0 cancers are included for prognostic staging with T1 N0 M0 cancers of the same prognostic factor status.
Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com.
Version 4.2024, 07/03/24 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
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Table 4. Pathological Prognostic Stage (continued)

TNM Grade HER2 ER PR Stage TNM Grade HER2 ER PR Stage

T2 N1*** M0 Positive IA T0 N2 M0 Positive IB
T3 N0 M0 Positive T1* N2 M0 Positive
Negative Negative
Positive T2 N2 M0 Positive
Positive IIB T3 N1*** M0 Positive IIIA
Negative T3 N2 M0 Negative
Negative Negative
G1 G1
Positive IA Positive IB
Positive Positive
Negative Negative
Negative Negative
Positive IIB Positive IIIA
Negative Negative
Negative Negative
Positive IB Positive IB
Positive Positive
Negative Negative
Positive Positive
Positive IIB Positive IIIA
Negative Negative
Negative Negative
G2 G2
Positive IB Positive IB
Positive Positive
Negative Negative
Negative Negative IIIA
Positive IIB Positive
Negative Negative
Negative Negative IIIB
Positive IB Positive IIA
Positive Positive
Negative Negative
Positive Positive
Positive IIB Positive IIIA
Negative Negative
Negative Negative
G3 G3
Positive IIA Positive IIB
Positive Positive
Negative Negative
Negative IIB Negative IIIA
Positive Positive
Negative Negative
Negative IIIA Negative IIIC
Continued
*T1 Includes T1mi.
***N1 includes N1mi. T2, T3, and T4 cancers and N1mi are included for prognostic staging with T2 N1, T3 N1 and T4 N1, respectively.
Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com.
Version 4.2024, 07/03/24 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
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Table 4. Pathological Prognostic Stage (continued)

Notes:
TNM Grade HER2 ER PR Stage
1. For cases with lymph node involvement with no evidence of primary tumor (e.g.
T4 N0 M0 Positive IIIA T0 N1, etc.) or with breast ductal carcinoma in situ (e.g. Tis N1, etc.), the grade,
T4 N1*** M0 Positive HER2, ER and PR information from the tumor in the lymph node should be used
Negative
T4 N2 M0 Positive for assigning stage group.
Any T N3 M0 Positive IIIB 2. For cases where HER2 is determined to be “equivocal” by ISH (FISH or CISH)
Negative testing under the 2013 ASCO/CAP HER2 testing guidelines, HER2 “negative”
Negative
G1 category should be used for staging in the Pathological Prognostic Stage Group.
Positive IIIA 3. The prognostic value of these Prognostic Stage Groups is based on populations
Positive of persons with breast cancer that have been offered and mostly treated with
Negative
Negative appropriate endocrine and/or systemic chemotherapy (including anti-HER2
Positive IIIB therapy).
Negative
Negative Table 5. Genomic Profile for Pathologic Prognostic Staging
Positive IIIA When Oncotype DX Score is Less than 11...
Positive
Negative TNM Grade HER2 ER PR Stage
Positive
Positive IIIB T1 N0 M0
Negative Any Negative Positive Any IA
Negative T2 N0 M0
G2 Notes:
Positive IIIA
Positive 1. Obtaining genomic profiles is NOT required for assigning Pathological
Negative Prognostic Stage. However genomic profiles may be performed for use in
Negative IIIB
Positive determining appropriate treatment. If the OncotypeDx® test is performed in cases
Negative with a T1N0M0 or T2N0M0 cancer that is HER2-negative and ER-positive, and
Negative IIIC the recurrence score is less than 11, the case should be assigned Pathological
Positive Prognostic Stage Group IA.
Positive 2. If OncotypeDx® is not performed, or if it is performed and the OncotypeDx®
Negative score is not available, or is 11 or greater for patients with T1–2 N0 M0 HER2–
Positive
Positive IIIB negative, ER-positive cancer, then the Prognostic Stage Group is assigned based
Negative on the anatomic and biomarker categories shown above.
Negative
G3 3. OncotypeDx® is the only multigene panel included to classify Pathologic
Positive Prognostic Stage because prospective Level I data supports this use for patients
Positive with a score less than 11. Future updates to the staging system may include
Negative
Negative results from other multigene panels to assign cohorts of patients to Prognostic
Positive IIIC Stage Groups based on the then available evidence. Inclusion or exclusion in this
Negative staging table of a genomic profile assay is not an endorsement of any specific
Negative
assay and should not limit appropriate clinical use of any genomic profile assay
Any T Any N M1 Any Any Any Any IV based on evidence available at the time of treatment.
***N1 includes N1mi. T2, T3, and T4 cancers and N1mi are included for prognostic staging with T2 N1, T3 N1 and T4 N1, respectively.

Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com.
Version 4.2024, 07/03/24 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
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ABBREVIATIONS

3D three dimensional DVHs dose-volume histograms PBI partial breast irradiation

APBI accelerated partial breast EBRT external beam radiation therapy pCR complete pathological response
irradiation EIC extensive intraductal component PD-1 programmed cell death protein 1
ALND axillary lymph node dissection EPC encapsulated papillary carcinoma
ALT alanine aminotransferase PD-L1 programmed death ligand 1
FDG fluorodeoxyglucose
AST aspartate aminotransferase PMRT postmastectomy radiotherapy
FSH follicle-stimulating hormone
AUC area under the curve FNA fine-needle aspiration PTV planning target volume
BCs breast cancers GnRH gonadotropin-releasing hormone RCB residual cancer burden
BCI breast cancer index H&E hematoxylin and eosin RECIST response evaluation criteria in solid
tumors
BCS breast-conserving surgery IBC inflammatory breast cancer
RNI regional nodal irradiation
BCT breast-conservation therapy IBTR ipsilateral breast tumor recurrence
RS recurrence score
BIA- breast implant-associated IGRT image-guided radiation therapy
RT-PCR reverse transcriptase polymerase
ALCL anaplastic large cell IHC immunohistochemistry chain reaction
lymphoma ILD interstitial lung disease SE standard error
BMI body mass index IMRT intensity modulated radiation therapy SLN sentinel lymph node
CBC complete blood count ISH in situ hybridization SLNB sentinel lymph node biopsy
CEA carcinoembryonic antigen LFTs liver function tests SPC solid papillary carcinoma
CPS combined positive score LH luteinizing hormone SNRI serotonin and norepinephrine
CS Cowden syndrome LVEF left ventricular ejection fraction reuptake inhibitors
LVI lymphovascular invasion SSRI selective serotonin reuptake
ctDNA circulating tumor
inhibitors
deoxyribonucleic acid MSI-H microsatellite instability-high
TMB-H tumor mutational burden-high
DCIS ductal carcinoma in situ NAC nipple-areolar complex
TNBC triple-negative breast cancer
DFS disease-free survival NGS next-generation sequencing
VMAT volumetric modulated arc therapy
NST no special type
DIBH deep-inspiratory breath hold WBRT whole breast radiation therapy
OFS ovarian function suppression
OS overall survival
dMMR mismatch repair deficient

ABBR-1
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NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is
uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the
intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) that the
intervention is appropriate.
Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,
Preferred intervention affordability.
Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
intervention or significantly less affordable for similar outcomes.
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.

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Discussion This Discussion corresponds to the NCCN Guidelines for Breast Cancer. The section for systemic
therapies (preoperative and adjuvant) was updated on June 7th, 2024. The update to the rest of the
Discussion section is in progress.
Table of Contents
Overview ......................................................................................... MS-2
Recurrent/Stage IV Breast Cancer ......................................................................... MS-55
Sensitive/Inclusive Language Usage ............................................... MS-2
Special Situations .................................................................................................. MS-78
Guidelines Update Methodology ...................................................... MS-2
Paget Disease ........................................................................... MS-78
Literature Search Criteria and Guidelines Update Methodology ........ MS-2
Phyllodes Tumors of the Breast ................................................ MS-80
Ductal Carcinoma in Situ (Tis, N0, M0) ............................................ MS-3
Breast Cancer During Pregnancy ............................................ MS-81
Workup for DCIS .......................................................................... MS-3
Inflammatory Breast Cancer ..................................................... MS-83
Primary Treatment for DCIS ......................................................... MS-4
Axillary Breast Cancer ............................................................... MS-86
Management of DCIS After Primary Treatment ............................. MS-8 Summary ............................................................................................................... MS-87

Invasive Breast Cancer ................................................................. MS-10 References ............................................................................................................ MS-88

Workup for Non-metastatic (M0) Invasive Breast Cancer ............ MS-10

Locoregional Treatment of cT1–3, cN0 or cN+, M0 Disease ....... MS-13

Surgery .................................................................................. MS-13

Radiation Therapy .................................................................. MS-18

Adjuvant Radiation Therapy After BCS ................................... MS-21

Adjuvant Radiation Therapy After Mastectomy ........................ MS-23

Breast Reconstruction .................................................................. MS-26

Systemic Therapies (Preoperative and Adjuvant).................................................... MS-30

Post-Therapy Surveillance and Follow-up for T0–3, N1, M0 and T1–3, N0–1, M0 Tumors
............................................................................................................................... MS-52

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Overview If sources do not differentiate gender from sex assigned at birth or organs
Breast cancer is the most common malignancy in females in the United present, the information is presumed to predominantly represent cisgender
States and is second only to lung cancer as a cause of cancer death. The individuals. NCCN encourages researchers to collect more specific data in
American Cancer Society has estimated that 313,510 Americans will be future studies and organizations to use more inclusive and accurate
diagnosed with breast cancer and 42,780 will die of disease in the United language in their future analyses.
States in 2024.1,2 The therapeutic options for patients with noninvasive or
Guidelines Update Methodology
invasive breast cancer are complex and varied. The NCCN Clinical
Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer Literature Search Criteria and Guidelines Update
include guidelines for clinical management of patients with carcinoma in Methodology
situ, invasive breast cancer, Paget disease, Phyllodes tumor, inflammatory Prior to the update of this version of the NCCN Guidelines® for Breast
breast cancer (IBC), male breast cancer, and breast cancer during Cancer, an electronic search of the PubMed database was performed to
obtain key literature using the following search terms: Breast Cancer,
pregnancy. These Guidelines have been developed and are updated
Breast Neoplasms, DCIS, Inflammatory Breast Cancer, OR Phyllodes.
continuously by a multidisciplinary panel of representatives from NCCN
The PubMed database was chosen as it remains the most widely used
Member Institutions with breast cancer-focused expertise in the fields of
resource for medical literature and indexes peer-reviewed biomedical
medical oncology, surgical oncology, radiation oncology, pathology,
literature.3
reconstructive surgery, and patient advocacy.

Sensitive/Inclusive Language Usage The search results were narrowed by selecting studies in humans
published in English. Results were confined to the following article types:
NCCN Guidelines strive to use language that advances the goals of
Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Randomized
equity, inclusion, and representation. NCCN Guidelines endeavor to use
Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation
language that is person-first; not stigmatizing; anti-racist, anti-classist,
Studies.
anti-misogynist, anti-ageist, anti-ableist, and anti-weight-biased; and
inclusive of individuals of all sexual orientations and gender identities.
The potential relevance of the PubMed search was examined. The data
NCCN Guidelines incorporate non-gendered language, instead focusing
from key PubMed articles selected by the Panel for review during the
on organ-specific recommendations. This language is both more accurate
Guidelines update meeting as well as articles from additional sources
and more inclusive and can help fully address the needs of individuals of
deemed as relevant to these Guidelines and discussed by the Panel have
all sexual orientations and gender identities. NCCN Guidelines will
been included in this version of the Discussion section. Recommendations
continue to use the terms men, women, female, and male when citing
for which high-level evidence is lacking are based on the Panel’s review of
statistics, recommendations, or data from organizations or sources that do
lower-level evidence and expert opinion. The complete details of the
not use inclusive terms. Most studies do not report how sex and gender
Development and Update of the NCCN Guidelines are available at
data are collected and use these terms interchangeably or inconsistently.
www.NCCN.org.

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Ductal Carcinoma in Situ (Tis, N0, M0) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and
The diagnosis of ductal carcinoma in situ (DCIS) has increased since the Pancreatic.
introduction and increased utilization of screening mammography.
The role of MRI in management of DCIS remains unclear. MRI has been
According to the American Cancer Society, over 50,000 cases of DCIS of
prospectively shown to have a sensitivity of up to 98% for high-grade
the female breast will be diagnosed in the United States in 2022.1
DCIS.11 In a prospective, observational study of 193 patients with pure
Workup for DCIS DCIS who underwent both mammography and MRI imaging
preoperatively; 93 (56%) patients were diagnosed by mammography and
The recommended workup and staging of DCIS includes history and
153 (92%) were diagnosed by MRI (P < .0001). Of the 89 patients with
physical examination, bilateral diagnostic mammography, pathology
high-grade DCIS, 43 (48%) who were not diagnosed by mammography
review, determination of tumor estrogen receptor (ER) status, and MRI, as
were diagnosed by MRI alone.11 However, other studies suggest that MRI
indicated.
can overestimate the extent of disease.12 Therefore, the surgical decisions
for performing a mastectomy for DCIS should not be solely based on MRI
For pathology reporting, the NCCN Panel endorses the College of
findings alone. If MRI findings suggest more extensive disease than is
American Pathologists (CAP) Protocol for both invasive and noninvasive
seen on mammography such that a markedly larger resection is required
carcinomas of the breast.4
for complete excision, the findings should be verified histologically through
The NCCN Panel recommends testing for ER status in order to determine MRI-guided biopsy of the more extensive enhancement. Studies
the benefit of adjuvant endocrine therapy or risk reduction. This is in performed to determine whether the use of MRI reduces re-excision rates
accordance with the American Society for Clinical Oncology (ASCO)/CAP and decreases local recurrence in patients with DCIS show conflicting
guidelines,5 which recommend that ER testing of newly diagnosed DCIS to results. While several studies suggest no reduction in re-excision rates in
determine potential benefit of endocrine therapies for breast cancer risk patients with pure DCIS undergoing breast-conserving surgery (BCS)
reduction and progesterone receptor (PR) testing be considered optional. following MRI compared with those who did not undergo preoperative
Although the tumor HER2 status is of prognostic significance in invasive MRI,13,14 some have demonstrated a reduction in re-excision rate with use
cancer, its importance in DCIS has not been established. To date, studies of preoperative MRI for DCIS.15,16 One study showed an additional cancer
have either found unclear or weak evidence of HER2 status as a detection rate of 6.2% with preoperative MRI.16 Therefore, the use of
prognostic indicator in DCIS,6-9 and no statistically significant benefit to the preoperative MRI remains controversial. The NCCN Panel recommends
use of trastuzumab concurrently with radiation in HER2-amplified DCIS.10 only performing breast MRI for DCIS in select circumstances where
The NCCN Panel has concluded that HER2 status for DCIS does not alter additional information is warranted during the initial workup, noting that the
the management strategy and therefore is not recommended for DCIS. use of MRI has not been shown to increase likelihood of negative margins
or decrease conversion to mastectomy for DCIS.
Genetic counseling is recommended if the patient is considered to be at
high risk for hereditary breast cancer as defined by the NCCN Guidelines

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Primary Treatment for DCIS In contrast, several population-based studies suggest beneficial effects of
The goal of primary therapy for DCIS is to prevent progression to invasive WBRT for DCIS after BCS; for example, the use of WBRT in patients with
breast carcinoma. Management strategies for DCIS treatment include higher-risk DCIS (eg, higher nuclear grade, younger age, larger tumor
surgery (mastectomy or BCS), and/or radiation therapy (RT), followed by size) was demonstrated to be associated with a modest but statistically
adjuvant endocrine therapy in eligible patients to reduce risk of recurrence. significant improvement in OS.28 In another observational study of the
SEER database including 140,366 patients with DCIS, the 15-year breast
The choice of local treatment does not impact overall disease-related cancer mortality rate was 1.7% for those treated with breast-conserving
survival; therefore, the individual’s preferences for risk reduction must be therapy (BCT) versus 2.3% for patients treated with BCS alone (HR, 0.77;
considered. 95% CI, 0.67–0.88; P < .001), demonstrating a small but significant
reduction in breast cancer mortality with BCS and WBRT compared with
Several prospective randomized trials of pure DCIS have shown that the BCS alone.29
addition of whole breast RT (WBRT) after BCS decreases the rate of
in-breast disease recurrence,17-24 but not distant metastasis-free survival.25 RT Boost: The use of RT boost has been demonstrated to provide a small
A meta-analysis of four large multicenter randomized trials confirmed the but statistically significant reduction in ipsilateral breast tumor recurrence
results of the individual trials, demonstrating that the addition of WBRT (IBTR) risk (4% at 20 years) in all age groups for invasive breast
after BCS for DCIS provides a statistically and clinically significant cancers.30-33
reduction in ipsilateral breast events (hazard ratio [HR], 0.49; 95%
confidence interval [CI]; 0.41–0.58, P < .00001).26 However, these trials A pooled analysis of patient-level data from 10 academic institutions
did not show that the addition of RT has an overall survival (OS) benefit. evaluated outcomes of pure DCIS patients, all treated with BCS and
The long-term follow-up of the NSABP B-17 trial showed that at 15 years, WBRT (n = 4131) who either received RT boost with a median dose of 14
Gy (n = 2661) or received no boost (n = 1470). The median follow-up of
RT resulted in a 52% reduction of ipsilateral invasive recurrence compared
patients was 9 years. A decrease in IBTR was seen in patients who
with excision alone (HR, 0.48; 95% CI, 0.33–0.69, P < .001).23 The OS
received a boost compared with those who did not at 5 years (97.1% vs.
and cumulative all-cause mortality rates through 15 years were similar
96.3%), 10 years (94.1% vs. 92.5%), and 15 years (91.6% vs. 88.0%) (P =
between the two groups (HR for death, 1.08; 95% CI, 0.79–1.48).23 Similar
.0389 for all). The use of RT boost was associated with significantly
findings were reported by a large observational study of the SEER
decreased IBTR across the entire cohort of patients (HR, 0.73; 95% CI,
database that included 108,196 patients with DCIS.27 In a subgroup
0.57–0.94; P = .01).34 In a multivariate analysis that took into account
analysis at 10 years, of 60,000 patients treated with BCS, with or without factors associated with lower IBTR, including grade, ER positive status,
WBRT, a 50% reduction in the risk of ipsilateral recurrence (adjusted HR, use of adjuvant tamoxifen, margin status, and age, the benefit of RT boost
0.47 [95% CI, 0.42–0.53]; P < .001) was associated with the addition of still remained statistically significant (HR, 0.69; 95% CI, 0.53–0.91; P <
WBRT. However, in this study, breast cancer-specific mortality was found .010).34 Even in patients considered very low risk based on negative
to be similar (HR, 0.86 [95% CI, 0.67–1.10]; P = .22).27 margins status (defined as no ink on tumor as per NSABP definition, or
margins >2 mm as per Society of Surgical Oncology [SSO]/American

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Society for Radiation Oncology [ASTRO]/ASCO definition), the RT boost study of 215 patients with DCIS treated with BCS without RT, or systemic
remained statistically significant for decreasing the rate of local relapse. risk reduction therapy, the recurrence rates over 8 years were 0%, 21.5%,
and 32.1% in patients with low-, intermediate-, or high-risk DCIS,
Similar to invasive cancers, though RT boost was beneficial in all age
respectively.38 The stratification for risk of recurrence in this retrospective
groups studied, the magnitude of the absolute benefit of the boost was
study was calculated using the modified Van Nuys Prognostic Index based
greatest in younger patients. Two randomized phase III trials are studying
on tumor grade, size, absence of comedo necrosis, margin width, and age
whether an RT boost reduces recurrence in patients with DCIS
at diagnosis.38
(ClinicalTrials.gov Identifiers: NCT00470236 and NCT00907868).
These trials have completed accrual and are now in active follow-up. A A multi-institutional, non-randomized, prospective study of selected
recent publication on the health-related quality of life (HRQOL) in patients patients with low-risk DCIS treated without radiation has also provided
enrolled in the BIG 3-07/TROG 07.01 phase III trial (NCT00470236) some support for BCS alone without radiation.41 Patients were enrolled
showed that after 2 years, the cosmetic status was impacted negatively onto one of two low-risk cohorts: 1) low- or intermediate-grade DCIS,
with the boost versus no boost, suggesting the importance of informed tumor size ≤2.5 cm (n = 561); or 2) high-grade DCIS, tumor size ≤1 cm (n
shared decision-making regarding addition of boost until data related to = 104). Protocol specifications included excision of the DCIS tumor with a
impact on local recurrence and OS are published.35 According to the 5- minimum negative margin width of ≥3 mm. Only 30% of the patients
year data from this trial, presented at the 2021 annual San Antonio Breast received tamoxifen. Of note, margins were substantially wider than the 3-
Cancer Symposium (SABCS) meeting, 93% of patients in the group who mm protocol requirement in many patients (ie, the low-/intermediate-risk
did not receive a boost were free from local recurrence compared with patient group margins were ≥5 mm in 62% of patients and >10 mm or no
97% in the group who received an RT boost (HR, 0.47; 95% CI, 0.31– tumor on re-excision in 48% of patients).41 Although the rate of IBTR was
0.72; P < .001).36 The peer-reviewed publication of these data is awaited. acceptably low for the low-/intermediate-grade group at 5 years, at a
median follow-up of 12.3 years, the rates of developing an IBTR were
Breast Conserving Surgery Alone Without WBRT: RT adds to treatment 14.4% for low-/intermediate-grade and 24.6% for high-grade DCIS (P =
cost and is accompanied by adverse effects. Therefore, in an attempt to .003). This suggests that IBTR events may be delayed but not prevented
de-escalate treatment and limit morbidity and preserve quality of life in the seemingly low-risk population.
(QOL), several trials have examined omission of RT in carefully selected
The RTOG 9804 trial investigated outcomes of RT omission in the setting
patients at low risk of disease recurrence.
of low-risk DCIS, randomizing 636 patients with low-risk disease to either
There are retrospective series suggesting that selected patients have a RT or observation after surgery.24 In this study, low risk consisted of low-
low risk of in-breast recurrence when treated with excision alone (without to intermediate-grade DCIS measuring <2.5 cm, with negative margins of
WBRT).37-40 For example, in one retrospective review, 10-year ≥3 mm. With a median follow-up of 7 years, a reduced risk of local
disease-free survival (DFS) rates of 186 patients with DCIS treated with recurrence was seen with use of RT compared with observation (0.9% vs.
BCS alone were 94% for patients with low-risk DCIS and 83% for patients 6.7%; HR, 0.11; 95% CI, 0.03–0.47). No difference was seen in either
with both intermediate- and high-risk DCIS.37 In another retrospective DFS or OS. With a follow-up of 15 years, local recurrence rates were

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NCCN Guidelines Version 4.2024

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reduced by 50% with RT versus without RT (7.1% vs. 15.1%; HR, 0.36; did not receive RT (P < .0001), but not in those treated with radiation (P =
95% CI, 0.20–0.66).42 .95).50

The available evidence from four randomized trials (NSABP B-39/RTOG According to the DCIS Consensus Guideline on Margins by
0413,43 OCOG-RAPID,44 University of Florence,45 and GEC-ESTRO46) of SSO/ASTRO/ASCO, the use of at least a 2-mm margin in DCIS treated
patients with breast cancer (tumors ≤3 cm) has shown that accelerated with WBRT is associated with low rates of IBTR.47 Additional factors to
partial breast irradiation (APBI) delivered with multi-catheter brachytherapy consider in assessing adequacy of excision for DCIS include presence of
is noninferior in local control compared with WBRT, with similar toxicity residual calcifications, which margin is close (anterior against skin or
and breast cosmetic outcomes. Patients with DCIS constituted 25%, 18%, posterior against muscle vs. medial, superior, inferior, or lateral), and life
8.8%, and 6% of patients in the NSABP B-39/RTOG 0413, OCOG-RAPID, expectancy of the patient. Notably, in situations where DCIS is admixed
University of Florence, and GEC-ESTRO trials, respectively. Per the with invasive carcinoma, the SSO/ASTRO/ASCO Consensus Guideline on
ASTRO guideline for APBI, patients with screen-detected DCIS measuring Margins for invasive breast cancer should be utilized, which supports “no
<2.5 cm, with grade I or II disease, and with negative margins of 3 mm or tumor on ink” as an adequate margin applying to both the invasive and
more are “suitable” candidates for APBI.47 noninvasive components in this mixed tumor scenario.

Margin Status After Breast-Conserving Therapy: Prospective randomized Mastectomy: Patients with DCIS and evidence of widespread disease (ie,
trials have not been carried out to analyze whether wider margins can disease involving two or more quadrants) on diagnostic mammography or
replace the need for RT for DCIS. Results from a retrospective study of other imaging, physical examination, or biopsy may require mastectomy.
445 patients with pure DCIS treated by excision alone indicated that
margin width was the most important independent predictor of local For DCIS patients undergoing mastectomy, or for local excision in an
recurrence, although the trend for decreasing local recurrence risk with anatomic location that could compromise the lymphatic drainage pattern to
increasing margin width was most apparent with margins <1 mm the axilla (eg, tail of the breast), a sentinel lymph node biopsy (SLNB)
compared to ≥10 mm.48 In a meta-analysis of 4660 patients with DCIS procedure should strongly be considered at the time of definitive surgery
treated with BCS and radiation, a surgical margin of <2 mm was to avoid necessitating a full axillary lymph node dissection (ALND) for
associated with increased rates of IBTR compared with margins of 2 mm, evaluation of the axilla.51-54 Since only a small proportion of patients (about
although no significant differences were observed when margins of >2 mm 25%) with seemingly pure DCIS on initial biopsy will have invasive breast
to 5 mm or >5 mm were compared with 2-mm margins.49 cancer at the time of the definitive surgical procedure55 and will ultimately
require axillary lymph node (ALN) staging, ALND is not recommended
A study retrospectively reviewed a database of 2996 patients with DCIS unless there is pathologically documented invasive cancer or ALN
who underwent BCS to investigate the association between margin width metastatic disease in patients (by either biopsy or SNLB).
and recurrence, controlling all other characteristics.50 Wider margins were
significantly associated with a lower rate of recurrence only in patients who NCCN Recommendations for Primary Treatment of DCI

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Trials are ongoing to determine if there might be a selected favorable Contraindications to BCT are listed in the algorithm (see Special
biology DCIS subgroup where surgical excision is not required. Until such Considerations to Breast Conservation Therapy Requiring RT). Patients
time that definitive evidence regarding the safety of this non-surgical treated with mastectomy are appropriate candidates for breast
approach is demonstrated, the NCCN Panel continues to recommend reconstruction (see Principles of Breast Reconstruction Following Surgery
surgical excision for all DCIS. in the algorithm).

According to the NCCN Panel, primary treatment options for patients with According to the NCCN Panel, complete resection should be documented
DCIS along with their respective categories of consensus are: by analysis of margins and specimen radiography. Post-excision
1) BCS plus WBRT with or without boost (category 1). While considering mammography can be considered for any uncertainty about adequacy of
RT boost for DCIS, the NCCN Panel recommends an individualized the excision remains (eg, the mass and/or microcalcifications are not
approach based on patient preference and other factors such as longevity. clearly within the specimen). Clips may be used to delineate the tumor bed
The NCCN Panel notes that WBRT following BCS reduces IBTR rates in and ensure adequate coverage with radiation, provide design of boost and
DCIS by about 50% to 70%. For DCIS patients treated with BCS alone APBI fields, and provide markers should additional surgery be required
(without radiation), irrespective of margin width, the risk of IBTR is pending the pathologic margin status review.
substantially higher than treatment with excision followed by WBRT (even
For patients with pure DCIS treated by BCS and WBRT, a quantitative
for predefined low-risk subsets of DCIS patients).
description of any tumor close to margin is helpful as a resection width of
2) Total mastectomy, with or without SLNB with optional reconstruction
at least 2 mm is associated with a reduced risk of IBTR relative to
(category 2A).
narrower negative margin widths. The routine practice of obtaining
3) BCS plus APBI in carefully selected patients (category 2A). According
margins >2 mm to further improve outcomes is not supported by the
to the Panel, select patients with low-risk DCIS may be considered
evidence. When there is only minimal or focal DCIS involvement near the
suitable for APBI if they meet all aspects of the definition of RTOG 9804
margin, clinical judgment should be utilized to weigh the risks of re-
low-risk DCIS or ASTRO “suitable” DCIS for APBI.
excision with risk of recurrence for an individual patient.
4) BCS alone (category 2B). The option of BCS alone should be
considered only in cases where the patient and the physician view the For patients with DCIS treated with excision alone (no WBRT), regardless
individual as having a low risk of disease recurrence. For patients with of margin width, there is a substantially higher rate of IBTR than treatment
low-risk disease that has been fully resected with negative margins and with excision and WBRT, even in predefined, low-risk patients. Although
particularly if they are ER-positive and will be receiving endocrine therapy, the optimal margin width for treatment with excision alone is unknown, it
the absolute reduction of in-breast recurrence may not be large enough to should be at least 2 mm, with some evidence suggesting improved IBTR
justify the risks associated with RT. Therefore, according to the NCCN rates with margin widths wider than 2 mm.
Panel, it may be reasonable to omit RT in such cases.
For DCIS with microinvasion (DCIS-M), defined as an invasive focus 1 mm
or smaller in size, the optimal margin width should refer to the DCIS

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margin definition (≥2 mm), given that the majority of DCIS-M is comprised analysis of ER expression in NSABP B-24 suggests that increased levels
of DCIS and the natural history and systemic therapy utilization for DCIS- of ER expression predict for tamoxifen benefit in terms of risk reduction for
M more closely reflect the treatment pattern for pure DCIS than for ipsilateral and contralateral breast cancer development following BCT.60
invasive carcinoma.
A phase III trial randomized patients with excised DCIS to receive WBRT
Management of DCIS After Primary Treatment or no WBRT and tamoxifen versus no tamoxifen.22 The randomization was
Tamoxifen: DCIS falls between atypical ductal hyperplasia (ADH) and independent for each of the two treatments (RT and tamoxifen). With 12.7
invasive ductal carcinoma within the spectrum of breast proliferative years of median follow-up, the use of tamoxifen decreased all new breast
abnormalities. The Breast Cancer Prevention Trial performed by NSABP events (HR, 0.71; 95% CI, 0.58–0.88; P = .002). The use of tamoxifen
showed a 75% reduction in the occurrence of invasive breast cancer in decreased ipsilateral and contralateral breast events in the subjects not
patients with ADH treated with tamoxifen.56,57 These data also showed that given WBRT (ipsilateral HR, 0.77; 95% CI, 0.59–0.98; contralateral HR,
tamoxifen led to a substantial reduction in the risk of developing invasive 0.27; 95% CI, 0.12–0.59), but not in those receiving WBRT (ipsilateral HR,
breast disease.58 The Early Breast Cancer Trialists’ Collaborative Group 0.93; 95% CI, 0.50–1.75; P = .80; contralateral HR, 0.99; 95% CI, 0.39–
(EBCTCG) overview analysis showed that, with 5 years of tamoxifen 2.49; P = 1.0).
therapy, patients with ER-positive or receptor-unknown invasive tumors
The standard dose of tamoxifen is 20 mg/day for 5 years. The phase III
had a 39% reduction in the annual odds of recurrence of invasive breast
TAM-01 trial studied a lower dose of tamoxifen (5 mg for 3 years) in 501
cancer.59
patients with breast intraepithelial neoplasia including DCIS, lobular
Similarly, the NSABP B-24 trial found a benefit from tamoxifen for patients carcinoma in situ (LCIS), and ADH. The rate of recurrence of either
with DCIS after treatment with breast conservation surgery and RT. In that intraepithelial neoplasia or invasive breast cancer was 5.7% among those
study, patients with DCIS who were treated with BCT were randomized to receiving tamoxifen 5 mg daily versus 11.9% for those receiving placebo
receive placebo or tamoxifen. At a median follow-up of 13.6 years, (HR, 0.48; 95% CI, 0.25–0.89) at a median follow-up of 5.1 years.61 The
patients who received tamoxifen had a 3.4% absolute reduction in relative risk (RR) reduction with low-dose tamoxifen seen in the TAM-01
ipsilateral in-breast tumor recurrence risk (HR, 0.30; 95% CI, 0.21–0.42; P trials is consistent with that seen in trials that used a higher dose of
< .001) and a 3.2% absolute reduction in contralateral breast cancers (HR, tamoxifen, but the rate of severe toxicity compared with placebo was less.
0.68; 95% CI, 0.48–0.95; P = .023).23 The patients receiving tamoxifen had
Anastrozole: In patients with ER-positive and/or PR-positive DCIS treated
a 10-year cumulative rate of 4.6% for invasive and 5.6% for noninvasive
by wide local excision with or without RT, a large, randomized,
breast cancers in the ipsilateral breast, compared with 7.3% invasive and
double-blind, placebo-controlled trial (IBIS-II) compared anastrozole (n =
7.2% noninvasive recurrences for those treated with placebo. The
1471) with tamoxifen (n = 1509). The results demonstrated non-inferiority
cumulative 10-year frequency of invasive and noninvasive breast cancer in
of anastrozole to tamoxifen.62 After a median follow-up of 7.2 years, 67
the contralateral breast was 6.9% and 4.7% in the placebo and tamoxifen
recurrences were reported with anastrozole versus 77 for tamoxifen (HR,
groups, respectively. No differences in OS were noted. A retrospective
0.89; 95% CI, 0.64–1.23). A total of 33 deaths were recorded for

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anastrozole and 36 for tamoxifen (HR, 0.9393; 95% CI, 0.58–1.50; P = management of therapy-related complications. The majority of recurrences
.78).62 Although the number of patients reporting any adverse event was of DCIS are in-breast recurrences after BCT, and recurrences mostly
similar between anastrozole (n = 1323, 91%) and tamoxifen (n = 1379, occur in close proximity to the location of the prior disease. Overall,
93%), the side-effect profiles of the two drugs were different. There were approximately one-half of the local recurrences after initial treatment for a
more fractures, musculoskeletal events, hypercholesterolemia, and pure DCIS are invasive in nature, whereas the remainder recur as pure
strokes reported with anastrozole and more muscle spasms, gynecologic DCIS.
cancers and symptoms, vasomotor symptoms, and deep vein thromboses
reported with tamoxifen. The NSABP B-35 study randomly assigned 3104 NCCN Recommendations for Management of DCIS After Primary
Treatment
postmenopausal patients with hormone-positive DCIS treated with
lumpectomy and radiation to either tamoxifen or anastrozole for 5 years. According to the NCCN Panel, in patients with ER-positive DCIS treated
Prior to being randomly assigned, patients were stratified by age—<60 with BCT, endocrine therapy with tamoxifen (for premenopausal and
years or >60 years. The primary endpoint was breast cancer-free postmenopausal patients) or an aromatase inhibitor (AI) (for
interval.63 Anastrozole treatment resulted in an overall statistically postmenopausal patients, especially those <60 years of age or in those
significant decrease in breast cancer-free interval events compared with with concerns of embolism) may be considered as a strategy to reduce the
tamoxifen (HR, 0.73; 95% CI, 0.56–0.96; P = .0234). The significant risk of ipsilateral breast cancer recurrence (category 1 for those
difference in breast cancer-free interval between the two treatments was undergoing BCT followed by RT; category 2A for those undergoing
apparent in the study only after 5 years of follow-up. The estimated excision alone). The benefit of endocrine therapy for ER-negative DCIS is
percentage of patients with a 10-year breast cancer-free interval was not known. Low-dose tamoxifen (5 mg/day for 3 years) is an option only if
89.1% in the tamoxifen group and 93.1% in the anastrozole group.63 In the 20-mg standard-dose of tamoxifen is not tolerated (see DCIS-2 in the
addition, anastrozole resulted in further improvement in breast cancer-free algorithm).
interval in younger postmenopausal patients (<60 years of age). With
Follow-up of patients with DCIS includes interval history and physical
respect to adverse effects, the overall incidence of thrombosis or
examination every 6 to 12 months for 5 years and then annually, as well
embolism was higher in the tamoxifen group while the anastrozole group
as yearly diagnostic mammography. In patients treated with BCT, the first
had slightly more cases of arthralgia and myalgia.63
follow-up mammogram should be performed 6 to 12 months after the
Results of the IBIS-II and the NSABP-B-35 studies indicate that completion of RT (category 2B) (see DCIS-2 in the algorithm). Patients
anastrozole provides at least a comparable benefit as adjuvant treatment receiving endocrine therapy for risk reduction should be monitored as
for postmenopausal patients with hormone receptor (HR)-positive DCIS described in the NCCN Guidelines for Breast Cancer Risk Reduction.
treated with BCS and RT, with a different toxicity profile.

Surveillance after treatment for DCIS helps early recognition of disease

recurrences (either DCIS or invasive disease) and evaluation and

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Invasive Breast Cancer review of the utility of MRI showed conflicting outcome results— one with
Workup for Non-metastatic (M0) Invasive Breast Cancer benefit75 and another without.76 One systematic review67 documented that
breast MRI staging altered surgical treatment in 7.8% to 33.3% of
The recommended workup of localized invasive breast cancer (listed on
patients;67 however, no differences in local recurrence or survival have
BINV-1 in the algorithm) includes a history and physical examination.
been demonstrated. In addition, there is no evidence that use of breast
Complete blood count (CBC) and liver function tests (LFTs) have no
MRI increases rates of margin-negative resection.77,78
added benefit in the detection of underlying metastatic disease in patients
with asymptomatic early-stage breast cancers.64 In addition, monitoring of Breast MRI may assist with identification and management of clinically
disease relapse with any tumor markers is not recommended. occult primary tumors presenting with axillary nodal metastases.79 In
patients with Paget disease not identifiable on mammography, breast MRI
Imaging: Imaging with bilateral diagnostic mammography is
may help determine the extent of disease.80,81 Breast MRI also has utility
recommended; breast ultrasonography is recommended only if necessary.
in screening patients with higher than average risk based on family
The use of MRI in the workup remains controversial. Breast MRI history.82
advocates note its high sensitivity for evaluation of extent of disease,
If breast MRI imaging is performed, a dedicated breast coil, an imaging
particularly for invasive cancer and in dense breasts where
team experienced with reading breast MRI and performing MRI-guided
mammographically occult disease is more likely to elude preoperative
biopsy, and multidisciplinary management are the standard of care.
detection. MRI detractors note that MRI has a high percentage of
false-positive findings, resulting in further diagnostic workup—including According to the NCCN Panel, the use of MRI is optional and is not
MRI-guided biopsy—in many circumstances.65-67 MRI findings tend to universally recommended by experts in the field. Breast MRI may be used
overestimate extent of disease,68 resulting in increased frequency of for staging evaluation to define extent of cancer, in the adjuvant or
mastectomies.69-72 neoadjuvant setting, to detect the presence of multifocal or multicentric
cancer in the ipsilateral breast, or as screening of the contralateral breast
MRI findings alone are not sufficient to determine whether BCT is optimal,
cancer at time of initial diagnosis. Additional indications for breast MRI
as additional tissue sampling is needed to verify true malignant disease
include: clinical axillary metastasis with an occult primary cancer; Paget
warranting excision. MRI use may increase mastectomy rates by
disease of the nipple with breast primary not identified by other breast
identifying areas of mammographically occult disease that may have been
imaging modalities or physical examination; follow-up screening of
adequately treated with radiation after BCS had the disease remained
patients with prior mammographically undetected breast cancers; and
undiscovered without MRI.72
those whose lifetime risk of a second primary breast cancer is >20%
Two prospective randomized studies have examined the utility of (based on models largely dependent on family history).
preoperative MRI in determining disease extent, and neither demonstrated
Pathology Assessment: A central component of the treatment of breast
improvement in rates of re-excision after initial BCS.73,74 Retrospective
cancer is full knowledge of extent of disease and biologic features. Full

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knowledge of extent of disease and biologic features is central to the Genetic Counseling: For patients considered to be at high risk for
treatment of breast cancer. hereditary breast cancer as defined by the NCCN Guidelines for
Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic,
The specimens should be oriented for the pathologist, and specific genetic counseling is recommended.
requests for determination of biomarkers should be stated (eg, ER, PR,
and HER2 status). The Panel also recommends testing for Ki-67 if HR- Distress Assessment: Levels of distress may vary in patients and should
positive, HER2-negative, and considering adjuvant abemaciclib. be addressed individually. Psychological distress can be impacted by body
image and other factors. Younger patients have higher rates of
Accurate pathology reporting requires communication between the psychosocial distress than patients diagnosed at older ages.83-87 The
clinician and the pathologist relating to relevant patient history, prior breast NCCN Breast Cancer Panel recommends assessing for distress in
biopsies, prior irradiation to the chest, pregnancy status, characteristics of patients newly diagnosed with breast cancer using guidance from NCCN
the abnormality biopsied (eg, palpable, mammographically detected Guidelines for Distress Management.
microcalcifications), clinical state of lymph nodes, presence of
inflammatory change or other skin abnormality, and any prior treatment Fertility and Sexual Health: The general considerations for fertility and
administered (eg, chemotherapy, RT). The specimens should be oriented sexual health/function outlined for specific populations in NCCN
for the pathologist, and specific requests for determination of biomarkers Guidelines for Adolescent and Young Adult (AYA) Oncology and NCCN
should be stated. The use of consistent, unambiguous standards for Guidelines for Survivorship are applicable to all patients diagnosed with
reporting is strongly encouraged. Data from both national and local breast cancer. The Panel recommends referring to those guidelines for
surveys show that as many as 50% of pathology reports for breast cancer guidance.
are missing some elements critical to disease management.12,13 Significant
omissions include failure to orient and report surgical margins and failure Numerous epidemiologic studies have demonstrated that childbearing
to report tumor grade consistently. The CAP has developed pathology after treatment for invasive breast cancer does not increase rates of
reporting protocols to promote complete and standardized reporting of recurrence or death from breast cancer.88 The offspring of pregnancies
malignant specimens. CAP provides a protocol for each disease site that after treatment for breast cancer do not have an increased rate of birth
includes cancer case summaries (checklists) along with background defects or other serious childhood illness. However, treatment for breast
documentation. These checklists form the basis for a synoptic, cancer, especially with cytotoxic agents, may impair fertility and fertility
standardized reporting of pathologic findings. The checklists are available may wane during the 5 to 10 years of adjuvant endocrine therapy.
without charge through the CAP website at www.cap.org. Consistent,
unambiguous, and complete pathology reporting is a cornerstone of While the potential to regain menstrual function within 2 years of
quality breast cancer care. The NCCN Breast Cancer Panel endorses the completing chemotherapy is possible, especially for those <35 years of
use of the CAP protocols for reporting the pathologic analysis of all breast age,89 resumption of menses does not correlate with fertility, and
cancer specimens.5 conversely, fertility may be preserved without menses. Therefore, all

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NCCN Guidelines Version 4.2024

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premenopausal patients should be informed about the potential impact of fertility. The fertility specialist should discuss specifics of fertility
chemotherapy on fertility and offered the option of fertility preservation if preservation options including hormonal interventions, ovarian stimulation,
future childbearing is desired. embryo or oocyte cryopreservation, and other investigational options, as
well as the probability of successful gestation and childbirth.104,105
Considerations for fertility preservation should incorporate patient
preference, tumor stage and biology, age of the patient, risk of premature Combining the various modalities for a specific patient may increase the
ovarian failure based on anticipated type and duration of chemotherapy odds of preservation of future fertility. It is important for fetal safety that
and/or endocrine therapy, as well as the timing and duration allowed for patients actively avoid becoming pregnant during breast cancer treatment.
fertility preservation.
Additional Diagnostic Workup
Several studies report lower rates of fertility discussion among female The Panel has reiterated that routine systemic imaging is not indicated for
patients with cancer90-92 despite the updated ASCO guidelines stating that patients with early-stage breast cancer in the absence of signs/symptoms
patients should not be excluded from consideration for discussion of of metastatic disease. Recommendations for additional metastatic workup
fertility preservation for any reason, including parity, prognosis, age, and should be performed for those patients with signs or symptoms suspicious
socioeconomic status.93 The NCCN Panel recommends that all treating for metastatic disease, based on lack of evidence to demonstrate any
physicians should have a discussion with their patients of childbearing benefits with metastatic workup in early-stage disease.106-108 In one study,
potential regarding the options for fertility preservation. Patients who metastases were identified by bone scan in 5.1%, 5.6%, and 14% of
desire to bear children after systemic therapy should be referred to a patients with stage I, II, and III disease, respectively, and no evidence of
fertility specialist prior to initiating systemic (chemotherapy or endocrine) metastasis was detected by liver ultrasonography or chest radiography in
therapy.93-99 patients with stage I or II disease.106 For patients with stage III breast
cancer, the prevalence of a positive liver ultrasound and positive chest
Randomized trials have demonstrated that GnRH agonists (such as
x-ray was 6% and 7%, respectively.106
goserelin) administered prior to initiating chemotherapy and then
administered concurrently with adjuvant chemotherapy protect against CBC, comprehensive metabolic panel, liver function, and alkaline
ovarian failure and reduce the risk of early menopause.100-102 In one trial phosphatase tests should be considered only if the patient is a candidate
goserelin improved the probability of pregnancy from 11% to 21% in for preoperative or adjuvant systemic therapy. A bone scan or sodium
patients with HR-negative early-stage breast cancer.103 Smaller historical fluoride PET/CT is indicated in patients presenting with localized bone
experiences in patients with HR-positive disease have conflicting results pain or elevated alkaline phosphatase. Bone scan or sodium fluoride
with respect to the protective effects of GnRH agonists in fertility PET/CT may not be needed if FDG-PET/CT is performed and clearly
preservation. indicates bone metastasis, on both the PET and CT component.

Patients should be informed of all the various modalities available to A diagnostic chest CT is indicated only if pulmonary symptoms (ie, cough
minimize gonadal damage and preserve ovarian function and future or hemoptysis) are present. Likewise, abdominal and pelvic imaging using

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diagnostic CT or MRI is indicated if the patient has elevated alkaline treatment for the majority of patients with stage I and stage II breast
phosphatase, abnormal results on LFTs, abdominal symptoms, or cancers (category 1).113-117 The optimal choice of surgery is based on a
abnormal physical examination of the abdomen or pelvis. shared decision made by the patient and clinician after discussing benefits
and risks of mastectomy versus BCT in regards to long-term survival, risk
FDG-PET/CT may be performed at the same time as diagnostic CT, and of local recurrence, and the impact on cosmetic outcome and overall QOL.
may be helpful in situations where standard staging studies are equivocal
or suspicious. FDG-PET/CT may also be helpful in identifying Breast Conserving Surgery
unsuspected regional nodal disease and/or distant metastases when used BCS allows patients to preserve their breast without sacrificing oncologic
in addition to standard staging studies. The routine use of FDG-PET/CT outcome. BCS is contraindicated for patients who are pregnant and would
scanning is not recommended in the staging of clinical stage I, II, or require radiation during pregnancy; have diffuse suspicious or
operable III (T3,N1) breast cancer, due to its high false-negative rate for malignant-appearing microcalcifications on mammography; have
the detection of lesions that are small (<1 cm) and/or low-grade disease, widespread disease that cannot be incorporated by local excision of a
the high rate of false-positive scans in patients without locally advanced single region or segment of the breast tissue with a satisfactory cosmetic
disease, the low sensitivity for detection of axillary nodal metastases, and result; have diffusely positive pathologic margins; or have homozygous
the low probability of these patients having detectable metastatic (biallelic) inactivation for ATM mutation (category 2B). Relative
disease.109-112 contraindications to lumpectomy include previous RT to the breast or
chest wall; active connective tissue disease involving the skin (especially
Locoregional Treatment of cT1–3, cN0 or cN+, M0 Disease
scleroderma and lupus); persistently positive pathologic margin; or those
Surgery with a known or suspected genetic predisposition to breast cancer who
Patients with early-stage operable breast cancer initially undergo upfront may have an increased risk of ipsilateral breast recurrence or contralateral
definitive surgery (BCS or mastectomy), and adjuvant systemic therapy if breast cancer with BCT or who may be considered for prophylactic
indicated, based on primary tumor characteristics, such as tumor size, bilateral mastectomy for risk reduction as per the criteria in the NCCN
grade, lymph node involvement, ER/PR status, expression of HER2 Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian,
receptor, and tumor genomics. Some patients with early-stage operable and Pancreatic or may have known or suspected Li-Fraumeni syndrome
HER2-positive or triple-negative disease may be treated with preoperative (category 2B).
systemic therapy first, followed by surgery. For NCCN Panel
recommendations and consideration for preoperative systemic therapy, Several studies of patients with early-stage breast cancer treated with
refer to www.NCCN.org. Radiation is typically sequenced after definitive BCS have identified young age as a significant predictor of an increased
surgery and after systemic chemotherapy (if delivered). likelihood of IBTRs after BCT.118-120 Risk factors, such as a family history
of breast cancer or a genetic predisposition for breast cancer (ie, BRCA1/2
Several randomized trials document that mastectomy is equivalent to
or other cancer-predisposing mutation), are more likely to exist in the
BCT, which includes BCS with WBRT with respect to OS as primary

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population of young patients with breast cancer, thereby confounding the observed in those who received risk-reducing contralateral mastectomy,
independent contributions of age and treatment to clinical outcome.121 although no improvement was seen in OS of these patients.133

With respect to OS outcomes for young patients with breast cancer, BCT The Panel recommends that patients with breast cancer who are ≤35
or mastectomy are similar.115,116,122-124 Some studies have shown improved years or premenopausal and carriers of a known BRCA1/2 mutation
survival125-127 and fewer post-surgical complications128 with BCS. consider additional risk reduction strategies following appropriate risk
assessment and counseling (see NCCN Guidelines for Breast Cancer
Mastectomy Risk Reduction and NCCN Guidelines for Genetic/Familial High-Risk
Mastectomy is indicated for patients who are not candidates for BCS or Assessment: Breast, Ovarian, and Pancreatic). This process should
those who choose to undergo this procedure over BCS. involve multidisciplinary consultations prior to surgery, and should include
a discussion of the risks associated with development of a contralateral
Only limited data are available on the survival impact of risk-reducing
breast cancer as compared with the risks associated with recurrent
contralateral mastectomy in patients with a unilateral breast cancer.129
disease from the primary cancer. Except as specifically outlined in the
Analysis of patients included in the SEER database treated with
NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast,
mastectomy for a unilateral breast cancer from 1998 to 2003 showed that
Ovarian, and Pancreatic, risk reduction mastectomy of the contralateral
contralateral risk-reducing mastectomy performed at the time of treatment
breast to a known unilateral breast cancer treated with mastectomy or
of a unilateral cancer was associated with a reduction in breast
BCT is discouraged by the Panel.
cancer-specific mortality only in the population of young patients (18–49
years of age) with stage I/II, ER-negative breast cancer (HR, 0.68; 95% The NCCN Panel recommends referring to the NCCN Guidelines for Older
CI, 0.53–0.88; P = .004).130 The 5-year breast cancer survival for this Adult Oncology for special considerations for this population.
group was only slightly improved with contralateral risk-reducing
mastectomy versus without (88.5% vs. 83.7%, difference = 4.8%).130 Margin Assessment: After surgical resection, a careful histologic
These differences observed in retrospective analysis could be due to assessment of resection margins is essential. The NCCN Panel notes that
selection bias among patients who chose risk-reducing contralateral benefit of BCS is predicated on achieving pathologically negative margins
mastectomy.131 A statistical simulation of survival outcomes after risk- after resection. The NCCN Panel accepts the most recent definition
reducing contralateral mastectomy among patients with stage I or II breast outlined in the guidelines established by the SSO/ASTRO as the standard
cancer with no BRCA mutation found that the absolute 20-year survival for negative surgical margins for invasive cancer.134
benefit from risk-reducing contralateral mastectomy was <1% among all
For patients with stage I or II invasive cancers after BCS, a positive margin
age, ER status, and cancer stage groups.132 Data from another
is defined as “ink on tumor” (any invasive cancer or DCIS cells on ink).
meta-analysis found no absolute reduction in risk of distant metastases
Patients with positive margins generally require further surgery—either a
with risk-reducing mastectomy.133 Furthermore, among patients with
re-excision to achieve a negative margin or a mastectomy. If re-excision is
unilateral breast cancer who have an increased familial/genetic risk, a
technically feasible to achieve “no ink on tumor,” this can be done with
decrease in metastatic contralateral breast cancer incidence was
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resection of the involved margin guided by the orientation of the initial may have an increased risk of ipsilateral recurrence and therefore may
resection specimen or re-excision of the entire original excision cavity. benefit from re-excision.
There may be select patients with stage III invasive cancers who may be
eligible for BCS. For these patients, the margin status would be assessed Surgical Axillary Staging
with similar definitions. If margins remain positive after further surgical
Axillary status is important for planning systemic adjuvant treatment and
re-excision(s), then mastectomy may be required for optimal local disease
RT. The lymphatic pathways from the breast go to the ALNs, internal
control.
mammary, infraclavicular, and/or supraclavicular lymph nodes.
In order to adequately assess margins following surgery, the Panel
Traditional level I and level II ALNDs require that at least 10 lymph nodes
recommends that the surgical specimens be directionally oriented and that
be provided for pathologic evaluation to accurately stage the axilla.135,136
the pathologist provide descriptions of the gross and microscopic margin
ALND should be extended to include level III nodes only if gross disease is
status and the distance, orientation, and type of tumor (invasive cancer or
apparent in the level II and I nodes. In the absence of gross disease in
pure DCIS) in relation to the closest margin. Marking the tumor bed with
level II nodes, lymph node dissection should include tissue inferior to the
clips facilitates accurate planning of the radiation boost field, where
axillary vein from the latissimus dorsi muscle laterally to the medial border
appropriate.
of the pectoralis minor muscle (levels I and II).
For invasive breast cancers that have a component of DCIS, the negative
Historically, ALND has been the standard of care for axillary staging.137
margin definition of “no ink on tumor” should be utilized based on the
However, ALND is associated with lymphedema and other significant
SSO/ASTRO Consensus Guideline on Margins unless it is DCIS-M, which
morbidities.138-140 This has been largely replaced with SLNB.
behaves more like pure DCIS and 2-mm margins are recommended. In
this setting, “no ink on tumor” is recommended for either DCIS or invasive SLN mapping injections may be peritumoral, subareolar, or subdermal.
cancer cells, primarily because the natural history, treatment, and SLNs can be assessed for the presence of metastases by both
outcomes of these lesions are more similar to invasive cancer than DCIS. hematoxylin and eosin (H&E) staining and cytokeratin
For specifically challenging cases, clinical judgment and discussion with immunohistochemistry (IHC). The clinical significance of a lymph node that
the patient should precede routine re-excision. is negative by H&E staining but positive by cytokeratin IHC is not clear.
Because the historical and clinical trial data on which treatment decisions
The same margin recommendations cannot be applied directly to patients
are based have relied on H&E staining, the Panel does not recommend
undergoing APBI, where data regarding local recurrence are more limited
routine cytokeratin IHC to define node involvement and believes that
than WBRT. Individualized clinical judgment should be utilized on a case-
current treatment decisions should be made based solely on H&E staining.
by-case basis, using postoperative mammography to identify residual
This recommendation is further supported by a randomized clinical trial
calcifications and clinical-pathologic factors such as quantitative extent of
(ACOSOG Z0010) for patients with H&E negative nodes where further
disease near margin, presence of extensive intraductal component (EIC),
examination by cytokeratin IHC was not associated with improved OS over
young age, or multiple close margins to assist in identifying patients who

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a median of 6.3 years.141 In the uncommon situation in which H&E staining positive SLN undergoing a completion ALND versus no ALND. Only
is equivocal, reliance on the results of cytokeratin IHC is appropriate. ER-negative status, age <50 years, and lack of adjuvant systemic therapy
were associated with decreased OS.150 At a median follow-up of 6.3 years,
Two randomized trials compared SLNB alone versus ALND. The Milan locoregional recurrences were noted in 4.1% of patients in the ALND
trial (1998–1999) randomized 516 patients treated with BCS with tumors group and 2.8% of patients in the SLNB group (P = .11). Median OS was
≤2 cm to two arms, one receiving immediate axillary dissection and the approximately 92% in each group.151 Long-term follow-up (median 9.25
other receiving the dissection only if the sentinel node was involved.142 years) results of the ACOSOG Z0011 study showed no statistically
After 79 months of follow-up, there was no difference in OS and DFS.143 significant difference in local recurrence-free survival (RFS) between trial
arms (P = .13).152 The cumulative incidence of ipsilateral axillary
Another similar study, NSABP B-32, conducted between 1999 and 2004,
recurrences at 10 years was 0.5% (2 patients) in those who underwent
randomized 5611 patients with invasive breast cancer ≤2 cm to either
ALND and 1.5% (5 patients) in those who underwent SLNB alone (P =
ALND or SLNB alone with ALND performed only if the SLN was
.28).152 The 10-year cumulative incidence of locoregional recurrences was
positive.144 After 95.6 months of follow-up, OS and DFS were similar in the
6.2% with ALND and 5.3% with SLNB alone (P = .36).152
two groups. Results of a subgroup analysis of this study showed patients
with ALND had significantly higher arm morbidity and significantly more The results of the ACOSOG Z0011 trial demonstrate that there is no
restricted work and social activity and impaired QOL.145,146 benefit to ALND in patients with early-stage breast cancer who have only
one or two SLN metastases (minimal nodal burden) on SLNB after
The ALMANAC trial studied the QOL in patients (n= 1031) with SLNB
receiving WBRT as part of BCT. Mastectomy patients were not enrolled in
versus ALND.147 After 12 months, lymphedema and sensory loss were
the ACOSOG Z0011 trial since these patients do not routinely receive
higher in the ALND group. Operative time, drainage use, hospitalization,
radiation.
and resumption of normal life were much longer in ALND compared to the
SLNB group. The SNAC trial148 and the DBCCG trial149 also showed less Another randomized trial (IBCSG 23-01) was specifically designed to
morbidity with SLNB compared with ALND. compare outcomes in patients with sentinel micrometastases (≤2 mm)
treated with ALND versus no ALND.153 While the ACOSOG Z0011 trial
Based on the results of the above studies, it was clarified that for negative
was limited to those undergoing BCT, this trial included patients
sentinel nodes, ALND is not needed.
undergoing mastectomy (9%).153 Between the group treated with SLNB
The ACOSOG Z0011 trial addressed the role of ALND in those with a plus ALND versus the group that had SLNB alone, there were no
clinically negative axilla but pathologically positive lymph nodes from an differences in 5-year DFS (84.4%; 95% CI, 80.7%–88.1% vs. 87.8%; 95%
SLNB. This trial randomized patients ≥18 years of age with clinical T1/T2 CI, 84.4%–91.2%); cumulative incidence of breast cancer events,
tumors, fewer than 3 positive SLNs, undergoing BCS and WBRT, to SLNB including local, regional, contralateral breast, and distant recurrence
alone (n = 436) or to a completion ALND (n = 420). In this study, there was (10.8%; 95% CI, 7.6–14.0 vs. 10.6%; 95% CI, 7.5–13.8); or OS (97.6%;
no difference in local recurrence, DFS, or OS between patients with 95% CI, 96.0%–99.2% vs. 97.5%; 95% CI, 95.8%–99.1%).153 Regional

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recurrence was <1% for those who underwent ALND and 1% for those In the setting of preoperative chemotherapy, the question that is being
who did not undergo ALND.153 The results of this trial show that in patients explored is whether ALND may be omitted in patients with complete
with micrometastases on SLNB, ALND is not needed. pathologic response after preoperative therapy.

The results of a trial by the European EORTC group (AMAROS) assessed Several prospective studies have evaluated patients with positive lymph
whether axillary RT provides regional control with fewer side effects nodes before preoperative systemic therapy who had clinical complete
compared with ALND.154 This trial included patients (n = 4823) with T1 or response to preoperative therapy and underwent SLNB and ALND. The
T2 breast cancer with positive SLNs randomized to an ALND or axillary results of these studies have shown that in those with node-positive
RT. One thousand four hundred twenty-five patients had positive SLNs disease prior to preoperative systemic therapy, SLNB has a >10% false-
(micrometastatic or macrometastatic), which included a small fraction of negative rate when performed after preoperative systemic therapy. In the
patients (n = 248) treated with mastectomy (17%).154 The results reported SENTINA study,157 the overall false-negative rate was 14.2%. In the
no difference in 5-year OS or DFS for patients randomized to ALND ACOSOG-Z1071 trial,158 the false-negative rate was 12.6% and in the SN
versus axillary radiation.154 The 5-year DFS was 86.9% (95% CI, 84.1– FNAC trial,159 the false-negative rate was 13.3%.
89.3) in the ALND group and 82.7% (79.3–85.5) in the axillary RT group.
The 5-year OS was 93.3% (95% CI, 91.0–95.0) in the ALND group and Subgroup analyses from studies have shown that 1) using dual-agent
92.5% (90.0–94.4) in the axillary RT group.154 At the end of 5 years, lymphatic mapping (radiotracer and blue dye); 2) identifying three or more
lymphedema was less frequent in the group treated with axillary RT versus SLNs; and 3) marking the metastatic lymph node with a clip before
ALND (11% vs. 23%).154 The 10-year follow-up results presented at the neoadjuvant therapy and then resecting it at the time of surgery reduces
2021 SABCS showed no significant differences between the two arms with false-negative rates to <10%.
respect to OS (with ALND, OS was 84.6% vs. 81.4% with axillary RT),
A subgroup analysis of the ACOSOG Z1071 trial showed lower false-
distant metastasis-free survival (with ALND was 81.7% vs. 78.2% with
negative rates in patients who had a clip placed in the positive lymph
axillary RT), or locoregional recurrence rate (3.59% with ALND vs. 4.07%
nodes at the time of initial biopsy followed by removal of the clipped node
with axillary RT). The axillary recurrence with axillary RT was 1.8% versus
during SLN surgery after preoperative systemic therapy.160 A another
0.93% with ALND.155
study of selective localization and removal of clipped nodes with SLNB,
The OTOASAR trial was designed similarly to the AMAROS trial; patients known as targeted axillary dissection (TAD), showed false-negative rates
(n = 2100) with tumors ≤3.0 cm who were clinically node negative were reduced to approximately 2% compared with 4% with removal of the
randomized to receive either ALND or axillary RT if they had 1 to 2 clipped lymph node alone.161
positive SLNs.156 The results showed no difference in axillary recurrence
Several ongoing clinical trials are examining further de-escalation of
with ALND compared with SLNB plus RT to the axilla.156
axillary surgery in those who have positive nodes after preoperative
systemic treatment. The Alliance A011202/MAC19 trial (NCT01901094) is
randomly assigning patients who have sentinel node–positive disease

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after neoadjuvant chemotherapy to ALND versus no further axillary In patients with clinically suspicious (palpable) lymph nodes or 3 or more
surgery. Both arms will receive regional nodal radiation. The SLNB alone suspicious lymph nodes on imaging, or if preoperative systemic therapy is
arm will include axillary RT to the undissected axilla (levels I–III), whereas being considered for patients with suspicious lymph nodes at diagnosis on
the ALND arm will not include RT to levels I or II axillae. examination or imaging, the Panel recommends pathologic confirmation of
malignancy using ultrasound-guided fine-needle aspiration (FNA)163 or
NCCN Recommendations for Surgical Axillary Staging: If ALNs are core biopsy of suspicious nodes with clip placement.
clinically negative (no palpable nodes) at the time of diagnosis, ≤2
suspicious lymph nodes are found on imaging, or ≤2 positive lymph nodes According to the NCCN Panel, the recommendation for ALND of level I
are confirmed by needle biopsy, the Panel recommends SLN mapping. and II nodes is limited to patients with biopsy-proven axillary metastases
(in those who did not receive preoperative systemic therapy) or who have
If SLN is negative, no further surgery is needed in these patients. If SLN is residual disease after preoperative chemotherapy. Highly selected
positive, based on the ACOSOG Z 0011 data, no further surgery is patients with biopsy-proven axillary metastases, who then converted to
recommended only if all of the following criteria are met: the patients have clinically node negative after preoperative systemic therapy, may undergo
cT1–2, N0 tumors, have not received preoperative systemic therapy, only SLNB with removal of the clipped lymph node. This is a currently a
have 1 or 2 positive SLNs, and will undergo BCT (BCS + WBRT). If any of category 2B recommendation as the rate of false negatives is high when
the above criteria are not met, the Panel recommends level I and II axillary SLN is performed after preoperative systemic therapy.
dissection.
According to the NCCN Panel, based on available data, the false-negative
Based on the AMAROS and OTASAR trial data, no further surgery is rate can be reduced by marking biopsied lymph nodes to document their
recommended only if all of the following criteria are met: the patients have removal, using dual tracer, and by removing 3 or more sentinel nodes
cT1–2, N0 tumors, have not received preoperative systemic therapy, have (targeted ALND). When sentinel nodes are not successfully identified, the
1 to 2 positive SLNs, and will undergo lumpectomy or mastectomy along Panel recommends level I and II axillary dissection be performed for
with adjuvant RT with intentional inclusion of undissected axilla at risk. If axillary staging.
any of the above criteria are not met, the Panel recommends level I and II
axillary dissection. In select patients undergoing mastectomy with clinically Radiation Therapy
negative axillae but 1 to 2 positive SLNs, the Panel notes that axillary
Principles of Radiation Therapy
radiation may replace ALND for regional control of disease. Based on the
results of the IBCSG 23-01 trial, the NCCN Panel recommends no ALND It is important to individualize RT planning and delivery. CT-based
for patients with positive SLNs when that disease is limited to only treatment planning is encouraged to delineate target volumes and
micrometastatic. According to the American Joint Committee on Cancer adjacent organs at risk. Greater target dose homogeneity and sparing of
(AJCC) staging, micrometastatic nodal involvement is defined as a normal tissues can be accomplished using compensators such as
metastatic deposit or >0.2 mm but ≤2.0 mm.162 wedges, forward planning using segments, and intensity-modulated RT
(IMRT). Respiratory control techniques including deep inspiration

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breath-hold and prone positioning may be used to try to further reduce Another randomized trial showed similar outcomes among patients
dose to adjacent normal tissues, particularly the heart and lung.164 receiving a hypofractionated schedule (40 Gy in 15 fractions) compared
Verification of treatment setup consistency is done with weekly imaging. with standard fractionation (50 Gy in 25 fractions) in patients (n = 1854)
When using certain techniques (ie, prone breast), more frequent imaging with node-negative breast cancer (n = 1608) or DCIS (n = 246).174 The 9-
may be appropriate. Standard utilization of daily imaging is not year risk of locoregional recurrence was 3.3% in the 50-Gy group and
recommended. Radiation to the breast/chest wall and nodal regions is 3.0% in the 40-Gy group. The 9-year OS was 93.4% in the 50-Gy group
generally delivered with single-energy or mixed-energy photons with or and 93.4% in the 40-Gy group. Radiation-associated cardiac and lung
without electrons. Dose-volume histograms (DVHs) should be used to disease were comparable between the groups.
evaluate dose constraints, evaluate dose to normal tissues (ie, heart,
lung), and ensure adequate coverage to the intended planning target Other shorter schedules of delivering WBRT have also been studied with
volumes (PTVs), including the breast/chest wall, supraclavicular fossa, similar results. The FAST trial compared patients >50 years of age with
axillary levels I–III, and internal mammary nodes. low-risk invasive breast carcinoma (pT1–2, pN0) randomly assigned to the
standard schedule of 50 Gy in 25 fractions over 5 weeks or 30 Gy or 28.5
Whole Breast Radiation Therapy Gy in 5 fractions once weekly. After 10-year follow-up, there were no
WBRT reduces the risk of local recurrence and has shown to have a significant differences reported in normal tissue effects for the standard 50
beneficial effect on survival.114,117 Randomized trials have demonstrated Gy in 25 fractions schedule versus a once-weekly schedule for 5 weeks
decreased in-breast recurrences with an additional boost dose of radiation totaling 28.5 Gy, but normal tissue effects were higher with a weekly
(by photons, brachytherapy, or electron beam) to the tumor bed.165,166 For schedule for 5 weeks totaling 30 Gy.175
greater homogeneity of target dose and to spare normal tissues using
The FAST Forward trial randomized patients with non-metastatic breast
compensators such as tissue wedges, forward planning using segments
cancer (n = 4096) after BCS or mastectomy to one of the following: 40 Gy
and IMRT may be used.167,168
in 15 fractions over 3 weeks; 27 Gy in 5 fractions over 1 week; or 26 Gy in
Four randomized clinical trials have investigated hypofractionated WBRT 5 fractions over 1 week to either whole beast or chest wall.176 The 5-year
schedules (39–42.9 Gy in single fractions of 2.6–3.3 Gy) compared to incidence of ipsilateral breast tumor relapse was 2.1% with the standard
standard 50 Gy in single fractions of 2 Gy.169-172 The 10-year follow-up 40 Gy in 15 fractions over 3 weeks versus 1.7% with 27 Gy in 5 fractions
data from the START trials173 are consistent with the 10-year results of the over 1 week (5.4 Gy per fraction; HR, 0.86; 95% CI, 0.51–1.44) and 1.4%
Canadian trial,172 which reported that local tumor control and breast with 26 Gy in 5 fractions over 1 week (5.2 Gy per fraction; HR, 0.67; 95%
cosmesis were similar with a regimen of 42.5 Gy in 16 fractions over 3.2 CI, 0.38–1.16).176 The moderate or marked tissue effects in the breast or
weeks compared with the standard dose of 50 Gy in 25 fractions over 5 chest wall were 15% with 27 Gy, 12% with 26 Gy, and 10% with 40 Gy,
weeks.172 The START trials reported radiation-related effects to normal but differences between the 40 Gy and 26 Gy groups were not statistically
breast tissue such as breast shrinkage, telangiectasia, and breast edema different.176
as less common with the hypofractionated regimen.173

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NCCN Guidelines Version 4.2024

Breast Cancer

RT Boost to Tumor Bed: In patients with higher risk characteristics (such reconstruction, several techniques using photons and/or electrons are
as age <50 years, high-grade disease, or patients with focally positive appropriate. Chest wall scar boost may be delivered with or without bolus
margins) an RT boost has been shown to reduce local using electrons or photons.
relapse.30,32,166,173,177-179 RT boost treatment in the setting of breast
conservation can be delivered using enface electrons, photons, or NCCN Recommendations for Chest Wall Radiation: The NCCN Panel
brachytherapy.180 recommends a dose of 45 to 50.4 Gy in 25 to 28 fractions to the chest
wall. A boost at the scar of 1.8 to 2 Gy per fraction to a total dose of
NCCN Recommendations for WBRT: The Panel has defined the target as approximately 60 to 66 Gy may be considered in some cases based on
breast tissue at risk. The NCCN Panel recommends a dose of 40 to 42.5 risk. Special consideration should be given to the use of bolus material to
Gy in 15 to 16 fractions for all patients getting whole breast radiation ensure that the skin dose is adequate, particularly in the case of IBC.
without regional nodal radiation, based on its equivalence in efficacy and
Regional Nodal Irradiation
toxicity demonstrated in the moderately hypofractionated trials.173 While
Two studies, MA.20 and EORTC 22922/10925, evaluated the addition of
these abbreviated courses of RT of 40 to 42.5 Gy in 15 to 16 fractions are
regional nodal irradiation (RNI) to the internal mammary nodes and the
the NCCN Panel’s preferred fractionation schema for whole breast
upper axillary nodes including the supraclavicular region, in addition to
radiation, the conventionally fractionated regimen of 46 to 50 Gy in 23 to
WBRT or chest wall irradiation after BCS or mastectomy, respectively. In
25 fractions may be utilized in selected patients. The RT boost doses
MA.20, regional recurrences were reduced from 2.7% with breast
intended to decrease rate of local recurrence are 10 to 16 Gy in 4 to 8 irradiation only to 0.7% with the addition of nodal irradiation.181 The distant
fractions. recurrences were reduced from 17.3% to 13.4%.181 An improvement in
DFS was seen from 77% to 82% at 10 years in those who received RNI
Ultra-hypofractionated WBRT of 28.5 Gy delivered as 5 (once weekly)
compared to those who did not.181 In EORTC 22922/10925, regional RT
fractions may be considered in select patients with pTis/T1/T2/N0 aged
reduced the incidence of regional recurrences from 4.2% to 2.7% and
>50 years after BCS, though the optimal fractionation for the boost
decreased the rate of distant metastases from 19.6% to 15.9% at a
delivery is unknown for this regimen. Alternatively, 26 Gy in 5 daily
median follow-up of 10.9 years.182 Results of 15.7 years follow-up showed
fractions over one week may be considered, though data beyond 5 years that breast cancer mortality (19.8% vs. 16%; 95% CI, 0.70–0.94) and
for local relapse or toxicity are not yet available for this regimen and breast cancer recurrence (27.1% vs. 24.5%; 95% CI, 0.77%–0.98%) were
should be discussed with patients prior to its use. The Panel also notes reduced with internal mammary and medial supraclavicular RT.183
that when using ultra-hypofractionated dosing, it is essential to utilize 3D
planning to minimize inhomogeneity and exposure to heart and lung. The independent contribution of internal mammary nodal RT as a
component of RNI continues to be debated as it is associated with higher
Chest Wall Radiation risk of cardiac and lung toxicity, and data regarding its benefits are
The target includes the ipsilateral chest wall, mastectomy scar, and drain conflicting (discussed in detail below).
sites when indicated. Depending on whether the patient has had breast

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NCCN Guidelines Version 4.2024

Breast Cancer

NCCN Recommendation for RNI: When considering RNI, anatomic rates of fair/poor cosmetic outcome with 3D conformal APBI delivered as
variations across patients result in significant differences in prescription 38.5 Gy in 10 twice-daily fractions.44,190 The majority of APBI patients on
depth and field design. The NCCN Panel therefore NSABP B-39 were treated with the same external beam regimen, and
recommends contouring the individual nodal basins that are at risk using treatment-related toxicities were not different for APBI versus WBRT as
one of the various breast atlases, to ensure adequate RT coverage. 184,185 currently reported.43 Cosmetic outcome analysis, however, is pending.
The recommended dose for RNI is 45 to 50.4 Gy in 25 to 28 fractions to NCCN Recommendation for APBI: The Panel accepts the updated
the regional nodal fields. A supplemental RT boost can be delivered to ASTRO APBI consensus statement for guidance on APBI use.191 The
grossly involved or enlarged lymph nodes (ie, internal mammary or NCCN Panel recommends APBI for any BRCA-negative patient who
clavicular) that have not been surgically addressed. meets the ASTRO 2016 “suitable” criteria defined as age >50 years, ER-
positive invasive ductal carcinoma measuring ≤2 cm (pT1 disease) with
Accelerated Partial Breast Irradiation
negative margin widths of ≥2 mm, and no lymphovascular invasion (LVI),
Several large, randomized trials have been published using various forms
and also permits APBI in patients >50 years of age with screen-detected
of APBI rather than WBRT after BCS. Most of these studies have found
low- or intermediate-grade DCIS measuring ≤2.5 cm, resected with ≥3 mm
that rates of local control in selected patients, with early-stage breast
margins. The Panel prefers the APBI regimen and method followed in the
cancer and low risk of recurrence, are equal to those treated with
trial by University of Florence (30 Gy/5 fractions every other day delivered
WBRT.44,46,186-188 In the NSABP B-39 trial, 10-year cumulative incidence of
using IMRT).187 The Panel encourages participation in clinical trials for
IBTR with APBI was 4.6% compared with 3.9% with WBRT, yielding an
patients who do not meet the above criteria.
absolute difference of 0.7% with an HR of 1.22 (90% CI, 0.94–1.58) that
did not meet the prespecified criteria for equivalence.43 However, given the Adjuvant Radiation Therapy After BCS
small magnitude in IBTR differences between WBRT and APBI, it is not Those who have a positive lymph node have a high risk of recurrence.
likely to be of clinical significance in appropriately selected patients. Therefore, after BCS WBRT is strongly recommended with or without
boost to tumor bed for node-positive disease (category 1 for those with
QOL, toxicity, and cosmetic outcomes have generally been comparable or
positive nodes; category 2A for those with negative axillary nodes). This
slightly favored APBI in randomized trials. For example, the IMPORT-LOW
recommendation is supported by the results of a meta-analysis by the
study compared WBRT with partial breast irradiation delivered as 40 Gy in
EBCTCG showing reduction in 10-year risk of recurrence in those who
15 once-daily fractions using reduced-size breast tangents and found less
received WBRT versus those who did not (19% vs. 35%; RR, 0.52; 95%
breast firmness, less change in breast appearance, and lower average
CI 0.48–0.56).117 In addition, a significant reduction in 15-year risk of
number of adverse events per person with partial breast irradiation.186,189
breast cancer death (21% vs. 25%; RR, 0.82; 95% CI, 0.75–0.90) was
The University of Florence compared WBRT with intensity-modulated
also observed.117
APBI (30 Gy in 5 fractions, delivered every other day), and 10-year results
have shown that APBI produced less acute and late toxicity and better
cosmetic outcomes.187 However, the RAPID trial found significantly higher

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NCCN Guidelines Version 4.2024

Breast Cancer

For patients with a pathologically confirmed, focally positive margin without distant recurrence and breast cancer-specific mortality favoring RT to
EIC, who do not undergo re-excision after BCS, the use of a higher internal mammary nodes.193
radiation boost dose to the tumor bed may be considered, since generally
a boost to the tumor bed is recommended for patients at higher risk of Clinical judgment is needed when determining inclusion of the internal
recurrence. mammary nodes during RNI. Therefore, the NCCN Panel no longer
specifies the fields that should be included for RNI and refers to it as
Regional Nodal Irradiation After BCS comprehensive RNI. According to the Panel, patient selection should
The reduction in the risk of locoregional and distant recurrence and consider risks versus benefits including long-term organ (cardiac and lung)
improvement in DFS seen in the MA.20 and EORTC 22922/10925 toxicities, comorbidities of the patient, age, and life expectancy. In
trials,181,182 and the reduction in breast cancer mortality with 15-year follow- including RT to the internal mammary nodes, meticulous treatment
up of the EORTC 22922 patients,183 support the importance of RNI after planning with normal tissue dose constraints is mandatory.
BCS.
RNI After BCS for Node-Negative Disease: The NCCN Panel
As mentioned previously, routine inclusion of the internal mammary nodes recommends consideration of comprehensive RNI in patients with
as a component of RNI remains somewhat controversial due to the central/medial tumors (in accordance with EORTC 22922 trial criteria) and
associated cardiac and lung toxicities. A Korean trial KROG 08-06 studied in accordance with the MA.20 criteria: 3 tumors, as well as those with T2
independent effect on DFS of RT to internal mammary nodes after BCS or tumors who have undergone limited axillary dissection (<10 lymph nodes)
mastectomy for node-positive disease,192 randomizing patients to RNI with and also have other risk factors, including high-grade histology, ER-
internal mammary RT versus RNI without internal mammary RT. Radiation negative disease, or LVI.181
to the internal mammary nodes did not significantly improve the DFS in
RNI After BCS for Node-Positive Disease: For those with 1 to 3 positive
patients with node-positive breast cancer. However, there was a
nodes, if a patient meets all of the following criteria—has cT1–T2, cN0; did
statistically significant benefit in outcomes with internal mammary nodal
not receive preoperative chemotherapy; and has 1 to 2 positive SLNs—the
RT for patients with medially or centrally located tumors.192 Conflicting
use of comprehensive RNI with or without the intentional inclusion of the
data have arisen from the Danish Breast Cancer Cooperative Group that
recently reported 15-year follow-up of their study on RT to internal axilla is at the discretion of the radiation oncologist. If the patients do not
meet all the criteria listed, the NCCN Panel recommends WBRT with
mammary nodes in patients (n = 3089) with positive nodes and early-
stage breast cancer.193 In this study, RT to the internal mammary nodes inclusion of any portion of the undissected axilla at risk (category 1) with
strong consideration of comprehensive RNI.
was delivered to right-sided patients (n = 1,491), while no RT to internal
mammary nodes was delivered to left-sided patients (n = 1,598). The For those with 4 or more positive nodes, the NCCN Panel recommends
study reported a 15-year improved OS rate of 60.1% with RT to internal comprehensive RNI with inclusion of any portion of the undissected axilla
mammary nodes compared to 55.4% with no RT to internal mammary at risk (category 1).
nodes. Improvements were also seen with respect to risk of developing

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NCCN Guidelines Version 4.2024

Breast Cancer

Radiation Therapy After BCS in Older Adults with ER-Positive Tumors breast cancer mortality in the patients with 1 to 3 positive lymph nodes
WBRT as a component of BCT does not affect breast cancer-specific even when systemic therapy was administered.182,203 According to the
survival in selected patients >70 years of age with more indolent disease. NCCN Panel, post-mastectomy radiation to the chest wall is
In a study of patients with clinical stage I, ER-positive breast cancer who recommended in all of these patients (category 1). Data from the EORTC
were ≥70 years of age at diagnosis, patients were randomized to receive 22922/10925 trial support the inclusion of RNI in patients undergoing post-
BCS with WBRT or BCS alone, both with tamoxifen for 5 years. mastectomy radiation. The trial assessed the independent effects of
Locoregional recurrence rates were 1% in the BCS, radiation, and including RNI versus no RNI when treating the chest wall after
tamoxifen arm and 4% in the BCS plus tamoxifen arm. There were no mastectomy. Based on the benefits demonstrated in this trial, the NCCN
differences in OS, DFS, or need for mastectomy.194 These results were Panel recommends comprehensive RNI to include any undissected axilla
confirmed in an updated analysis of this study with a median follow-up of at risk (category 1 for 1 or more positive nodes).
12.6 years.195 At 10 years, a statistically significant reduction in IBTR was
seen with RT with 90% of patients in the BCS and tamoxifen arm Post-Mastectomy RT for Node-Negative Disease:
compared with 98% in the BCS plus radiation and tamoxifen arm.195 In patients with negative nodes, tumor ≤5 cm, and clear margins (≥1 mm),
Concordant results have been demonstrated in other studies of similar post-mastectomy RT (PMRT) is typically not recommended. However, the
design.196,197 Whether the increase in local relapse without RT is relevant Panel has noted that it may be considered in subsets of these patients
for an individual patient should be individualized after a discussion of the with high-risk features. Based on the inclusion criteria of node-negative
risks and benefits of RT and patient commitment to 5 years of endocrine patients enrolled onto the RNI trials (MA-20 and EORTC 22922), any
therapy if RT omission is being considered. patients with the following high-risk features, including central/medial
tumors, T3 tumors, or tumors ≥2 cm with <10 axillary nodes removed and
The NCCN Guidelines allow for the use of BCS (pathologically negative at least one of the following: grade 3, ER-negative, or LVI, should be
margin required) with 5 years of tamoxifen or an AI, without breast considered for PMRT with RNI to include any undissected axilla at risk.
irradiation, for patients >70 years with clinically negative lymph nodes and Features in node-negative tumors that predict a high rate of local
ER-positive, T1 breast cancers (category 1). recurrence include primary tumors >5 cm or positive pathologic
margins.204
Adjuvant Radiation Therapy After Mastectomy
Post-Mastectomy RT for Node-Positive Disease In patients with positive pathologic margin, if re-resection to negative
Randomized clinical trials have shown that a DFS and OS advantage is margins is not possible, the Panel recommends strongly considering chest
conferred by the irradiation of chest wall and regional lymph nodes in wall irradiation with the addition of comprehensive RNI including any
patients with positive ALNs after mastectomy and ALND.198-202 In these portion of the axilla at risk. Chest wall irradiation should be considered with
trials, the ipsilateral chest wall and the ipsilateral locoregional lymph nodes addition of comprehensive RNI, including any portion of the axilla at risk in
were irradiated. The results of EBCTCG meta-analyses show that RT after those with tumors >5 cm. In patients with tumors ≤5 cm and negative
mastectomy and axillary node dissection reduced both recurrence and margins ≤1 mm, chest wall irradiation should be considered with

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NCCN Guidelines Version 4.2024

Breast Cancer

consideration of comprehensive RNI including any portion of the are candidates for the ALLIANCE 11202 trial assessing whether ALND
undissected axilla at risk only in those with high-risk features. can be safely replaced with axillary RT. ALND is the standard arm of this
trial; however, in the event that a neoadjuvant therapy patient with node-
Considerations for RT in Patients Receiving Preoperative Systemic positive disease (ypN1+) does not undergo a complete axillary dissection,
Therapy all levels of the undissected axilla should be included with the radiation
The Panel recommends that decisions related to administration of treatment.
adjuvant RT for patients receiving preoperative systemic chemotherapy
should be made based on maximal stage (ie, clinical/anatomic stage, RT After Preoperative Therapy and Mastectomy:
Those who have clinically positive nodes at diagnosis that respond to
tumor characteristics) at diagnosis (before preoperative systemic therapy)
preoperative systemic therapy and become node-negative should be
and pathologic stage at definitive surgery (after preoperative systemic
strongly considered to receive RT to the chest wall and comprehensive
therapy). Data from numerous studies in patients with stage III disease
RNI with inclusion of any portion of the undissected axilla at risk based on
suggest that postoperative RT improves local control even for patients
the discussion above.
who have a pathologic complete response (pCR) to neoadjuvant
chemotherapy.205-208
For those with positive nodes (ypN1+) after preoperative systemic therapy,
RT After Preoperative Therapy and BCS:
axillary dissection is the standard treatment arm of the ongoing Alliance
Those who have clinically negative nodes at diagnosis, that remain
11202 trial; however, if RT is indicated it should include chest wall along
pathologically node-negative at definitive surgery (after systemic therapy),
with comprehensive RNI with inclusion of any portion of the undissected
should receive adjuvant RT to the whole breast with the addition of boost
axilla at risk.
to the tumor bed after SLNB.
Those who have node-negative disease at diagnosis and after
Patients who have clinically/radiographically positive nodes at diagnosis
preoperative systemic therapy and whose axilla was assessed by SLNB or
and convert to clinically/radiographically node-negative after preoperative
axillary node dissection may forego RT.
chemotherapy are candidates for the NSABP B-51 trial assessing the
benefit of RNI. Until the results of this trial become available, the existing Two prospective trials are ongoing and will prospectively evaluate the
data suggest that node-positive disease at presentation is at high risk for benefit of RT in patients treated with neoadjuvant therapy (NSABP B-
locoregional recurrence and should be considered to receive 51/RTOG 1304 [NCT01872975] and the Alliance A011202/MAC19 trial
comprehensive RNI with inclusion of any portion of the undissected axilla [NCT01901094]).
at risk.
Sequencing of RT and Systemic Therapy
Patients who have clinically/radiographically positive nodes at diagnosis
who convert to clinically/radiographically negative nodes after preoperative If chemotherapy and radiation are indicated after surgery, adjuvant
chemotherapy, but are found to have persistent nodal disease on SLNB, radiation is typically delivered after the completion of chemotherapy.209,210

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NCCN Guidelines Version 4.2024

Breast Cancer

This recommendation is based on results of the “Upfront-Outback” trial in

which patients who had undergone BCS and axillary dissection were
randomly assigned to receive chemotherapy following RT or RT following
chemotherapy. The initial results showed an increased rate of local
recurrence in the group with delayed RT at a median follow-up of 58
months;210 however, differences in rates of distant or local recurrence were
not statistically significant when the two arms were compared at
135-month follow-up.209 While it is common for RT to follow chemotherapy
when chemotherapy is indicated, based on data from prospective and
retrospective studies, CMF (cyclophosphamide/methotrexate/fluorouracil)
and RT may be given concurrently.

Data from multiple studies of patients treated with endocrine therapy either
before, during, or after RT suggest no difference in outcomes or
toxicity.211-214 Therefore, according to the NCCN Panel, sequential or
concurrent endocrine therapy with RT is acceptable. However, due to
compounding side effects, initiating endocrine therapy at the completion of
RT may be preferred.

When adjuvant capecitabine215 is indicated, since it is a known

radiosensitizing agent with potential to increase toxicity to normal tissue, it
should be given after completion of adjuvant RT.

When adjuvant olaparib is used, the Panel recommends that olaparib be

given after completion of RT. In the OlympiA trial,216 olaparib was not
administered concurrently with RT and there are limited data on safety of
concurrent administration.

Adjuvant HER2-targeted therapy may be delivered concurrently with RT.

Data from clinical trials in the adjuvant setting do not suggest an increased
complication rate with the concurrent administration of HER2-targeted
therapies with adjuvant RT.217

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NCCN Guidelines Version 4.2024

Breast Cancer

Breast Reconstruction Breast Reconstruction After Mastectomy

Breast reconstruction may be an option for anyone receiving surgical Mastectomy results in loss of the breast for breastfeeding, loss of
treatment for breast cancer. Therefore, all patients undergoing breast sensation in the skin of the breast and nipple-areolar complex (NAC), and
cancer treatment should be educated about breast reconstructive options loss of the breast for cosmetic, body image, and psychosocial purposes.
as adapted to their individual clinical situation and be offered an The loss of the breast for cosmetic, body image, and psychosocial issues
opportunity to consult with a reconstructive plastic surgeon. Breast may be partially overcome through the performance of breast
reconstruction should not interfere with the appropriate surgical reconstruction with or without reconstruction of the NAC.
management. This may increase the risk of overall and cancer-related
Those undergoing mastectomy should be offered consultation regarding
death, especially in those with late-stage disease.218 Coordinating
options and timing of breast reconstruction.
consultation and surgical treatment with a reconstructive surgeon should
be executed within a reasonable timeframe. Many factors must be considered in the decision-making about breast
reconstruction. There are several different types of breast reconstruction
Several reconstructive approaches are summarized for these patients in
that include the use of implants, autogenous tissues, or both.224-226
the NCCN Guidelines for Breast Cancer under Principles of Breast
Reconstruction with implants can be performed either by immediate
Reconstruction Following Surgery.
placement of a permanent subpectoral implant or initial placement of a
The decision regarding type of reconstruction includes patient preference, subpectoral expander implant followed by gradual expansion of the
body habitus, smoking history, comorbidities, plans for irradiation, and implant envelope with stretching of the pectoralis major muscle and
expertise and experience of the reconstruction team. Smoking and obesity overlying skin followed by replacement of the expander with a permanent
increase the risk of complications for all types of breast reconstruction implant. A wide variety of implants are available that contain saline,
whether with implant or flap.219-223 Smoking and obesity are therefore silicone gel, or a combination of saline and silicone gel inside a solid
considered a relative contraindication to breast reconstruction by the silicone envelope.
NCCN Panel. Patients should be informed of increased rates of wound
Autogenous tissue methods of reconstruction use various combinations of
healing complications and partial or complete flap failure among patients
fat, muscle, skin, and vasculature from donor sites (ie, abdomen, buttock,
who smoke and have obesity.
back) that may be brought to the chest wall with their original blood supply
Reconstruction is an optional procedure that does not impact the (pedicle flap) or as free flaps with microvascular anastomoses to supply
probability of recurrence or death, but it is associated with an improved blood from the chest wall/thorax.227 Several procedures using autologous
QOL for many patients. It is sometimes necessary to perform surgery on tissue are available including transverse rectus abdominis myocutaneous
the contralateral breast (ie, breast reduction, implantation) to achieve flap, latissimus dorsi flap, and gluteus maximus myocutaneous flap
optimal symmetry between the ipsilateral reconstructed breast and the reconstruction.
contralateral breast.

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NCCN Guidelines Version 4.2024

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Composite reconstruction techniques use implants in combination with placement. Immediate placement of an implant in patients requiring
autogenous tissue reconstruction to provide volume and symmetry. postoperative radiation has an increased rate of capsular contracture,
Patients with underlying diabetes or who smoke tobacco have increased malposition, poor cosmesis, and implant exposure. Surgery to exchange
rates of complications following autogenous tissue breast cancer the tissue expanders with permanent implants can be performed prior to
reconstruction, presumably because of underlying microvascular disease. radiation or after completion of RT.

Reconstruction can be performed either at the time of the mastectomy In a previously radiated patient, the use of tissue expanders/implants is
known as “immediate breast reconstruction” and under the same relatively contraindicated.231 Tissue expansion of irradiated skin can result
anesthetic or in a delayed fashion any time, known as “delayed breast in a significantly increased risk of capsular contracture, malposition, poor
reconstruction.” In many cases, breast reconstruction involves a staged cosmesis, implant exposure, and failed reconstruction.232,233 If a patient
approach requiring more than one procedure such as surgery on the has previously received RT to the breast, autologous tissue reconstruction
contralateral breast to improve symmetry, revision surgery involving the is the preferred method of breast reconstruction.
breast and/or donor site, and/or nipple and areola reconstruction and
tattoo pigmentation. Skin-Sparing Mastectomy
Skin-sparing mastectomy procedures are appropriate for some patients
Plans for post-mastectomy RT can impact decisions related to breast and involve removal of the breast parenchyma including the NAC while
reconstruction since there is a significantly increased risk of implant preserving the majority of the original skin envelope, and are followed by
capsular contracture following irradiation of an implant. Furthermore, post- immediate reconstruction with autogenous tissue, a prosthetic implant, or
mastectomy irradiation may have a negative impact on breast cosmesis a composite of autogenous tissue and an implant. Skin-sparing
when autologous tissue is used in immediate breast reconstruction, and mastectomy involving preservation of the skin of the NAC has become the
may interfere with the targeted delivery of radiation when immediate subject of increased attention. Possible advantages of this procedure
reconstruction is performed using either autologous tissue or breast include improvements in breast cosmesis, body image, and nipple
implants.228,229 Some studies, however, have not found a significant sensation following mastectomy, although the impact of this procedure on
compromise in reconstruction cosmesis after RT.230 The preferred these QOL issues has not been well-studied.234-236 There are limited data
approach to breast reconstruction for irradiated patients was a subject of from surgical series, with short follow-up, that suggest that performance of
controversy among the Panel. While some experienced breast cancer NAC-sparing mastectomy in selected patients is associated with low rates
teams have employed protocols in which immediate tissue reconstructions of occult involvement of the NAC with breast cancer and local disease
are followed by RT, generally RT is preferred to precede autologous recurrence.235,237,238 NAC-sparing procedures may be an option in patients
reconstruction due to the reported loss in reconstruction cosmesis who are carefully selected by experienced multidisciplinary teams.
(category 2B). When implant reconstruction is planned in a post- According to the NCCN Panel, when considering a NAC-sparing
mastectomy patient requiring RT, the NCCN Panel prefers a staged procedure, assessment of nipple margins is mandatory. Retrospective
approach with immediate tissue expander placement followed by implant data support the use of NAC-sparing procedures for patients with breast

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NCCN Guidelines Version 4.2024

Breast Cancer

cancer with low rates of nipple involvement and low rates of local Breast Reconstruction After Lumpectomy
recurrence due to early-stage, biologically favorable (ie, Nottingham grade Issues related to breast reconstruction also pertain to those who undergo
1 or 2, node-negative, HER2-negative, no LVI) invasive cancers and/or or have undergone a lumpectomy, particularly in situations where the
DCIS that are peripherally located in the breast (>2 cm from nipple).239,240 surgical defect is large and/or expected to be cosmetically unsatisfactory.
Contraindications for nipple preservation include evidence of nipple An evaluation of the likely cosmetic outcome of lumpectomy should be
involvement such as Paget disease or other nipple discharge associated performed prior to surgery. Oncoplastic techniques for breast conservation
with malignancy and/or imaging findings suggesting malignant can extend breast-conserving surgical options in situations where the
involvement of nipple and subareolar tissues. Several prospective trials resection by itself would likely yield an unacceptable cosmetic outcome.247
are underway to evaluate NAC-sparing mastectomy in the setting of The evolving field of oncoplastic surgery includes the use of “volume
cancer and enrollment in such trials is encouraged. displacement” techniques performed in conjunction with a large partial
mastectomy.248 Oncoplastic volume displacement procedures combine the
Advantages of a skin-sparing mastectomy procedure include an improved removal of generous regions of breast tissue (typically designed to
cosmetic outcome resulting in a reduction in the size of the mastectomy conform to the segmentally distributed cancer in the breast) with
scar and a more natural breast shape, especially when autologous tissue “mastopexy” techniques in which remaining breast tissues are shifted
is used in reconstruction,241 and the ability to perform immediate together within the breast envelope to fill the resulting surgical defect and
reconstruction. Although no randomized studies have been performed, thereby avoid the creation of significant breast deformity. Volume
results of several mostly retrospective studies have indicated that the risk displacement techniques are generally performed during the same
of local recurrence is not increased when patients receiving skin-sparing operative setting as the breast-conserving lumpectomy by the same
mastectomies are compared with those undergoing non-skin–sparing surgeon who is performing the cancer resection.248,249
procedures. However, strong selection biases almost certainly exist in the
identification of patients appropriate for skin-sparing procedures.242-246 Advantages of oncoplastic volume displacement techniques are that they
Reconstruction of the NAC may also be performed in a delayed fashion if permit the removal of larger regions of breast tissue, thereby achieving
desired by the patient. Reconstructed nipples are devoid of sensation. wider surgical margins around the cancer, and at the same time better
According to the NCCN Panel, skin-sparing mastectomy should be preserve the natural shape and appearance of the breast than do standard
performed by an experienced breast surgery team that works in a breast resections.250
coordinated, multidisciplinary fashion to guide proper patient selection for
skin-sparing mastectomy, determine optimal sequencing of the Limitations of oncoplastic volume displacement techniques include lack of
reconstructive procedure(s) in relation to adjuvant therapies, and perform standardization among centers, performance at only a limited number of
a resection that achieves appropriate surgical margins. Post-mastectomy sites in the United States, and the possible necessity for subsequent
radiation should still be applied for patients treated by skin-sparing mastectomy if pathologic margins are positive when further
mastectomy following the same selection criteria as for standard breast-conserving attempts are deemed impractical or unrealistic.
mastectomy. Nevertheless, the Panel consensus is that these issues should be

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considered prior to surgery for individuals who are likely to have a surgical
defect that is cosmetically unsatisfactory. Those who undergo lumpectomy
and are dissatisfied with the cosmetic outcome after treatment should be
offered a consultation with a plastic surgeon to address the repair of
resulting breast defects. Patients should be informed of the possibility of
positive margins and potential need for secondary surgery, which could
include re-excision segmental resection, or could require mastectomy with
or without loss of the nipple. Oncoplastic procedures can be combined
with surgery on the contralateral unaffected breast to minimize long-term
asymmetry.

Finally, decisions regarding breast reconstruction should primarily focus

on treatment of the tumor, and such treatment should not be
compromised.

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Systemic Therapies (Preoperative and Adjuvant) Other benefits of preoperative systemic therapy include allowing time for
appropriate genetic testing and for planning potential breast reconstruction
This section for systemic therapies (preoperative and adjuvant) was updated on
June 7th, 2024. in patients proceeding with mastectomy. For those with significant residual
disease after standard preoperative systemic therapy, it may provide an
Preoperative Systemic Therapy opportunity to identify patients who may benefit from further adjuvant
The NCCN Panel has outlined the rationale, appropriate patient selection, therapy after surgery. It many allow sentinel lymph node biopsy (SLNB)
and response assessment for preoperative systemic therapy in a new alone or allow for limited radiation fields if clinically node positive disease
section titled, Principles of Preoperative Chemotherapy. becomes clinically node negative after preoperative systemic therapy. In
addition, preoperative systemic therapy also serves as an excellent
Randomized clinical trials have found no significant differences in research platform to test novel therapies and predictive biomarkers by
long-term outcomes when systemic chemotherapy is given before or after providing tumor specimens and blood samples prior to and during
surgery.251,252 Historically, a primary advantage of administering systemic treatment.
preoperative systemic therapy has been to improve surgical outcomes.
Preoperative systemic therapy can convert inoperable tumors to operable Selection of Patients for Preoperative Therapy
and also downstage a significant number of patients with operable breast Not all patients are appropriate candidates for preoperative systemic
cancer to allow for more limited breast conservation procedures. 253 therapy. According to the NCCN Panel, among those with inoperable
Results from large clinical trials and retrospective reviews indicate that breast tumors, preoperative systemic therapy is indicated in patients with
breast conservation rates are improved with preoperative systemic locally advanced or inoperable breast cancer including those with
therapy.252,254 Clinicians need to carefully consider the extent of disease in inflammatory breast cancer; those with bulky or matted cN2 axillary nodes;
the breast, tumor biology and likelihood of adequate tumor response cN3 regional lymph node nodal disease; and cT4 tumors.
before recommending preoperative systemic therapy to improve the
likelihood of successful breast conservation. In patients with operable tumors, preoperative systemic therapy is the
preferred approach for the following scenarios: for patients with TNBC and
In addition, use of preoperative systemic therapy may provide important HER2+ breast cancer that is clinical stage T2N0 and higher or is clinically
prognostic information based on response to therapy. Achieving a node positive; if the patient’s breast cancer subtype is associated with a
pathologic complete response (pCR) to neoadjuvant therapy is associated high likelihood of response; or if a patient desires BCS and the size of the
with favorable disease-free and OS in early-stage breast cancer. The tumor is large relative to that of the breast.
correlation between pathologic response and long-term outcomes in
When preoperative systemic therapy is used to improve the likelihood of
patients with early-stage breast cancer is strongest for patients with
successful breast conservation, the surgical plan should consider the
triple-negative breast cancer, less so for HER2-positive disease, and least
possibility that clear surgical margins may not always be obtained, and a
for hormone-positive disease.255-257
follow-up mastectomy may be required, with or without breast
reconstruction. This consideration is especially important when oncoplastic
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breast reduction techniques or contralateral breast symmetry procedures operable ER-positive, HER2-negative disease, to aid in predicting
are added to the breast-conserving surgery to achieve optimal cosmetic response to preoperative therapy.
outcomes.
Preoperative therapy options:
The NCCN Panel cautions that preoperative systemic therapy is not Chemotherapy: A number of chemotherapy regimens have activity in the
appropriate for certain patients. Preoperative systemic therapy should not preoperative setting. According to the NCCN Panel, those regimens
be offered in patients with extensive in situ disease when the extent of recommended in the adjuvant setting may be considered in the
invasive disease cannot be defined; in patients where the extent of the preoperative setting. In both settings, the underlying aim remains the
tumor is poorly delineated; or in those whose tumors are not clinically same: eradication or control of undiscovered distant metastases.
assessable. The decision to utilize preoperative therapy should be made
in the context of a coordinated and collaborative multi-disciplinary team. Endocrine Therapy: Preoperative endocrine therapy alone may be offered
to those with strongly HR-positive tumors based on comorbidities or low-
For predicting the response of pre-operative endocrine therapy for risk luminal biology based on clinical characteristics and/or genomic
postmenopausal women with ER-positive, HER2-negative, cN0 breast signatures (until desired effect is achieved).260-267 The results of the
cancer, data from the TransNEOS study demonstrate a significant ACOSOG Z1031 trial show that preoperative endocrine therapy is
correlation between 21 gene assay Recurrence Score and clinical effective in reducing residual disease and enabling BCS for many patients
response to preoperative letrozole. Those whose tumors had a with low rates of local-regional recurrence post-surgery. 268
Recurrence Score between 0-17 were significantly more likely to respond
to preoperative letrozole compared with Recurrence Score of 31-100.258 According to the NCCN Panel, the endocrine therapy options include an
aromatase inhibitor (with ovarian function suppression (OFS) for
For predicting the response to pre-operative chemotherapy for post- premenopausal patients) or tamoxifen (with or without OFS for
menopausal, ER-positive, HER2-negative patients with T1/T2, node premenopausal patients). The preferred endocrine therapy option for
negative tumors, another study evaluated the role of the Recurrence postmenopausal patients is an aromatase inhibitor. The panel has added
Score with pathologic response rates after pre-operative systemic therapy. a comment that the optimal response to endocrine therapy, if achieved is
Their findings suggest high Recurrence Scores are associated with a anywhere between 4-6 months based on the above trials.
higher likelihood of pCR after preoperative chemotherapy.259
HER2-Targeted Therapy: For patients with HER2-positive breast cancer,
Based on the above two studies that showed the use of 21-gene that are candidates for preoperative systemic therapy, chemotherapy and
Recurrence Score in predicting response to preoperative chemotherapy, trastuzumab-based therapy is recommended.269 Chemotherapy and dual
258,259 the NCCN panel has added a footnote for considering the use of a
anti-HER2 blockade associated with trastuzumab plus pertuzumab has
gene expression assay during workup when contemplating preoperative shown significant improvements in the pCR rate when compared with
endocrine or systemic therapy for postmenopausal patients with cN0, chemotherapy and trastuzumab in the preoperative setting.

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In the TRYPHAENA trial, preoperative therapy with pertuzumab and chemotherapy.274 There are no data comparing adjuvant pembrolizumab
trastuzumab given along with anthracycline-containing or with other newer adjuvant therapies such as adjuvant capecitabine and/or
anthracycline-free standard chemotherapy regimens to patients with olaparib in patients who meet criteria for treatment with one or more of
operable, locally advanced, or inflammatory HER2-positive breast cancer these agents.
showed pCR rates in all treatment arms ranging from 57% to 66%.270 In
the Neosphere trial, the addition of pertuzumab to trastuzumab and Response Assessment During Preoperative Chemotherapy
docetaxel preoperatively led to a statistically significant increase in pCR in The NCCN panel recommends that tumor response should be routinely
the breast which in turn led to improves outcomes in those with node- assessed by clinical exam during the delivery of preoperative systemic
positive disease.271,272 The NCCN Panel supports the FDA-approved therapy. Patients with operable breast cancer experiencing progression of
indication that a pertuzumab-containing regimen may be administered disease while undergoing preoperative systemic therapy should be taken
preoperatively to patients with greater than or equal to cT2, or greater than promptly to surgery. Imaging during preoperative systemic therapy should
or equal to cN1, HER2-positive, early-stage breast cancer. not be done routinely but may be considered if tumor progression is
suspected. Imaging prior to surgery should be determined by a
Immunotherapy: The randomized phase III multicenter, double-blind, multi-disciplinary team.
placebo-controlled trial (KEYNOTE-522) compared preoperative
carboplatin and paclitaxel followed by doxorubicin or epirubicin and In a multicenter analysis of patients (n=5161), the residual cancer burden
cyclophosphamide in combination with either pembrolizumab (n=784) or (RCB) after preoperative chemotherapy was seen to be prognostic within
placebo (n=390), followed by pembrolizumab or placebo administered each breast cancer subtype.275 Higher RCB scores were significantly
every 3 weeks for up to nine cycles after surgery, in patients with associated with worse event-free survival, with hazard ratios ranging from
previously untreated stage II-III TNBC.273 After a median follow-up of 39.1 1.55 to 2.16 across different breast cancer subtypes.
months, a significant improvement in event-free survival was seen with the
This study highlights RCB as a prognostic factor for outcomes in patients
addition of pembrolizumab compared with placebo plus chemotherapy.
with breast cancer patients undergoing preoperative chemotherapy.275
The 3-year event-free survival rates were 84.5% and 76.8%, respectively
(HR = 0.63, 95% CI = 0.48–0.82; P < .001).273 As noted under the “workup” section, in order to have a standardized
method of pathology reporting, the NCCN endorses the CAP protocol for
The 5-year follow-up of KEYNOTE-522 trial results showed an
pathology reporting for all invasive and noninvasive carcinomas of the
improvement in EFS rate in patients treated with chemotherapy plus
breast. On the Principles of Preoperative Therapy page, the panel
pembrolizumab compared with the placebo arm (81.3% vs. 72.3%), with
encourages that the pathology report from definitive surgery after
reduction in risk for recurrence, progression, complications, or death of
preoperative systemic therapy include the standardized tissue sampling
37% (HR, 0.63; 95% CI, 0.49-0.81).274 Among patients in the trial who had
and reporting elements of the Residual Cancer Burden (RCB). However,
a pCR and received adjuvant pembrolizumab, the 5-year EFS rate was
since RCB reporting is currently not mandatory given its main purpose for
92.2% compared with 88.2% in patients who received only
prognostication only, there is inconsistent reporting of RCB across

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institutions and no uniform agreement among the panel that RCB is efficacy data on the ER-low-positive (1%-10%) group, with ER-low-positive
required in the pathology report, rendering it a category 2B patients reported to be a heterogeneous group with a natural
recommendation. history/biologic behavior often similar to ER-negative cancers,
individualized consideration of risks versus benefits of endocrine therapy
Adjuvant Systemic Therapy
and additional adjuvant therapies should be incorporated into decision-
After surgical treatment, adjuvant systemic therapy should be considered. making. Patients with ER-negative, PR-positive cancers may also be
In patients with early-stage breast cancer, systemic adjuvant therapy is considered for endocrine therapies, however, the efficacy data on this
administered to reduce risk of cancer recurrence. The decision is often group are also limited. The same overall interpretation principles apply but
based on individual risk of relapse and predicted sensitivity to a particular PR should be interpreted as either positive (if 1%–100% of cells have
treatment (eg, ER/PR and HER2 status). The decision to use systemic nuclear staining) or negative (if <1% or 0% of cells have nuclear staining).
adjuvant therapy requires considering and balancing risk for disease For the purposes of this guideline, any ER and/or PR-positive tumors is
recurrence with local therapy alone, the magnitude of benefit from referred to as ‘hormone receptor (HR)-positive’, given that the majority of
applying adjuvant therapy, toxicity of the therapy, and comorbidity. The all breast cancers are ER-positive or ER and PR-positive and the
decision-making process requires collaboration between the health care subgroup of ER negative/PR-positive tumors are relatively uncommon.
team and patient.
The magnitude of risk reduction from adjuvant endocrine therapy is
Stratification for Systemic Adjuvant Therapy dependent on level of ER-expression and on recurrence score (RS) of
gene expression assay test results. Low level of ER expression is less
The NCCN Guidelines stratify, patients with breast cancer based on their likely to benefit from endocrine therapy and a high RS will gain less benefit
HR- status and HER2 expression. Patients are then further stratified with endocrine therapy alone versus those with low RS.
based on risk of disease recurrence based on anatomic and pathologic
characteristics (ie, tumor grade, tumor size, ALN status, angiolymphatic Patients with invasive breast cancers that are HR- positive should be
invasion). considered for adjuvant endocrine therapy regardless of patient age,
lymph node status, or whether adjuvant chemotherapy is to be
Adjuvant Systemic therapy for HR-positive, HER2-negative tumors administered.277 Selected studies suggest that HER2-positive breast
Patients with HR positive, HER2-negative tumors, receive adjuvant cancers may be less sensitive to some endocrine therapies, although
endocrine therapy to reduce the risk of recurrence and those deemed at other studies have failed to confirm this finding.278-286 A retrospective
high risk for distant recurrence despite adjuvant endocrine therapy, analysis of tumor blocks collected in the ATAC trial indicated that HER2
receive adjuvant chemotherapy. The NCCN Guidelines call for the amplification is a marker of relative endocrine resistance independent of
determination of ER and PR content in all primary invasive breast type of endocrine therapy.287 However, given the favorable toxicity profile
cancers276 to determine whether a patient is a candidate for endocrine of the available endocrine therapies, the panel recommends the use of
therapies. Patients with cancers with 1%–100% ER IHC staining are adjuvant endocrine therapy in the majority of patients with HR-positive
considered ER+ and eligible for endocrine therapies. Given the limited
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breast cancer regardless of menopausal status, age, or HER2 status of Aromatase inhibitors: Several studies have evaluated aromatase inhibitors
the tumor. (AI) in the treatment of postmenopausal patients with early-stage breast
cancer. These studies have utilized AI as initial adjuvant therapy, as
Tamoxifen: The most firmly established adjuvant endocrine therapy is sequential therapy following 2 to 3 years of tamoxifen, or as extended
tamoxifen for both premenopausal and postmenopausal patients.59 In therapy following 4.5 to 6 years of tamoxifen. The AIs are not active in the
patients with ER-positive breast cancer, adjuvant tamoxifen decreases the treatment of patients with functioning ovaries and should not be used in
annual odds of recurrence by 41% and the annual odds of death by 31% patients whose ovarian function cannot reliably be assessed owing to
irrespective of the use of chemotherapy, patient age, menopausal status, treatment-induced amenorrhea.
or ALN status.59 In patients receiving both tamoxifen and chemotherapy,
chemotherapy should be given first, followed by sequential tamoxifen.288 The results from two prospective, randomized, clinical trials have provided
Prospective randomized trials have demonstrated that 5 years of evidence of an OS benefit for patients with early-stage breast cancer
tamoxifen is more effective than 1 to 2 years of tamoxifen.289,290 receiving initial endocrine therapy with tamoxifen followed sequentially by
anastrozole (HR, 0.53; 95% CI, 0.28–0.99; P = .045) or exemestane (HR,
The ATLAS trial randomly allocated pre- and postmenopausal patients to 0.83; 95% CI, 0.69–1.00; P = .05 [excluding patients with ER-negative
5 or 10 years (extended therapy) of tamoxifen. The outcome analyses of disease]) when compared with tamoxifen as the only endocrine
6846 patients with ER-positive disease showed that by extending adjuvant therapy.293,294 In addition, the NCIC-CTG MA-17 trial demonstrated a
treatment to 10 years, the risk of relapse and breast cancer-related survival advantage with extended therapy with letrozole compared with
mortality was reduced.291 The risk of recurrence during years 5 to 14 was placebo in patients with ALN-positive (but not lymph node-negative),
21.4% for patients receiving tamoxifen versus 25.1% for controls (absolute ER-positive breast cancer.295 Tamoxifen and aromatase inhibitors have
recurrence reduction 3.7%). Patients who received tamoxifen for 10 years different side effect profiles. Both contribute to hot flashes and night
had a greater reduction in risk of progression, possibly due to a “carryover sweats and may cause vaginal dryness. AIs are more commonly
effect.” The reduction in risk of recurrence was 0.90 (95% CI, 0.79–1.02) associated with musculoskeletal symptoms, osteoporosis, and increased
during 5 to 9 years of tamoxifen treatment and 0.75 (0.62–0.90) after 10 rate of bone fracture, while tamoxifen is associated with an increased risk
years of treatment. There were decreases in the incidence of contralateral for uterine cancer and deep venous thrombosis.
breast cancer as well. Furthermore, reduced mortality was also apparent
after completion of 10 years of treatment with tamoxifen. With regards to Two studies have examined initial adjuvant endocrine treatment with either
toxicity, the most important adverse effects noted in all patients in the tamoxifen or an AI. The ATAC trial demonstrated that anastrozole is
ATLAS trial after with 10 years of tamoxifen treatment were an increased superior to tamoxifen or the combination of tamoxifen and anastrozole in
risk for endometrial cancer and pulmonary embolism.291 The results of the the adjuvant endocrine therapy of postmenopausal patients with
aTTom trial confirm the significant reduction in recurrence and death from HR-positive breast cancer.296,297 With a median of 100 months follow-up,
breast cancer seen in the ATLAS trial with 10 versus 5 years of tamoxifen results in 5216 postmenopausal patients with HR-positive, early-stage
therapy.292 breast cancer enrolled in the ATAC trial demonstrated fewer recurrences

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(HR for DFS, 0.85; 95% CI, 0.76–0.94; P = .003) with anastrozole with those in the tamoxifen arm (9.5% vs. 6.5%).306 After a longer
compared with tamoxifen.298 No difference in survival has been observed follow-up (median 71 months) no significant improvement in DFS was
(HR, 0.90; 95% CI, 0.75–1.07; P = .2). Patients in the combined tamoxifen noted with either tamoxifen followed by letrozole or the reverse sequence
and anastrozole group gained no benefit over those in the tamoxifen as compared with letrozole alone (HR for tamoxifen followed by letrozole,
group, suggesting a possible deleterious effect from the weak estrogenic 1.05; 99% CI, 0.84–1.32; HR for letrozole followed by tamoxifen, 0.96;
effect of tamoxifen in patients with near complete elimination of 99% CI, 0.76–1.21).307
endogenous estrogen levels.297 ATAC trial sub-protocols show a lesser
effect of anastrozole compared with tamoxifen on endometrial tissue;299 Five trials have studied the use of tamoxifen for 2 to 3 years followed
similar effects of anastrozole and tamoxifen on quality of life, with most sequentially by a third-generation AI versus continued tamoxifen in
patients reporting that overall quality of life was not significantly postmenopausal patients. The Italian Tamoxifen Anastrozole (ITA) trial
impaired;300 a greater loss of bone mineral density with anastrozole;301 a randomized 426 postmenopausal patients with breast cancer who had
small pharmacokinetic interference of anastrozole in the presence of completed 2 to 3 years of tamoxifen to either continue tamoxifen or to
tamoxifen of unclear significance;302 and no evidence for an interaction switch to anastrozole to complete a total of 5 years of endocrine
between prior chemotherapy and anastrozole.303 therapy.308 The HR for relapse strongly favored sequential treatment with
anastrozole (HR, 0.35; 95% CI, 0.18–0.68; P = .001) with a trend towards
BIG 1-98 is a randomized trial testing the use of tamoxifen alone for 5 fewer deaths (P = .10).308 Updated results from this study show the HR for
years, letrozole alone for 5 years, or tamoxifen for 2 years followed relapse-free survival as 0.56 (95% CI, 0.35–0.89; P = .01); P value for OS
sequentially by letrozole for 3 years, or letrozole for 2 years followed analysis remained at 0.1.309 The IES trial randomized 4742
sequentially by tamoxifen for 3 years. An early analysis compared postmenopausal patients with breast cancer who had completed a total of
tamoxifen alone versus letrozole alone, including those patients in the 2 to 3 years of tamoxifen to either continue tamoxifen or to switch to
sequential arms during their first 2 years of treatment only.304 With 8010 exemestane to complete a total of 5 years of endocrine therapy.310 The
patients included in the analysis, DFS was superior in the letrozole-treated results at a median of 55.7 months of follow-up demonstrated the
patients (HR, 0.81; 95% CI, 0.70–0.93; log rank P = .003). No interaction superiority of sequential exemestane in DFS (HR, 0.76; 95% CI, 0.66–
between PR expression and benefit was observed. No difference in OS 0.88; P = .0001) with a significant difference in OS in only patients with
was observed. A comparison of the cardiovascular side effects in the ER-positive tumors (HR, 0.83; 95% CI, 0.69–1.00; log rank P = .05). A
tamoxifen and letrozole arms of the BIG 1-98 trial showed that the overall prospectively planned, combined analysis of 3224 patients enrolled in the
incidence of cardiac adverse events was similar (letrozole, 4.8%; ABCSG 8 trial and the ARNO 95 trial has also been reported.311 Patients
tamoxifen, 4.7%). However, the incidence of grade 3 to 5 cardiac adverse in this combined analysis had been randomized following 2 years of
events was significantly higher in the letrozole arm, and both the overall tamoxifen to complete 5 years of adjuvant tamoxifen or 3 years of
incidence and incidence of grade 3 to 5 thromboembolic events was anastrozole. With 28 months of median follow-up available, event-free
significantly higher in the tamoxifen arm.305 In addition, a higher incidence survival was superior with crossover to anastrozole (HR, 0.60; 95% CI,
of bone fracture was observed for patients in the letrozole arm compared 0.44–0.81; P = .0009). No statistically significant difference in survival has

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been observed. An analysis of the ARNO 95 trial alone after 58 months of with OFS is critical, including the potential side effects of premature
median follow-up demonstrated that switching from tamoxifen to menopause.
anastrozole was associated with significant increases in both DFS (HR,
0.66; 95% CI, 0.44–1.00; P = .049) and OS (HR, 0.53; 95% CI, 0.28–0.99; In two randomized trials (TEXT and SOFT), premenopausal patients with
P = .045).294 A meta-analysis of ABCSG 8, ARNO 95, and ITA studies HR-positive early-stage breast cancer were assigned to receive AI
showed significant improvement in OS (HR, 0.71; 95% CI, 0.52-0.98; P = (exemestane) plus OFS or tamoxifen plus OFS for a period of 5 years.314
.04) with a switch to anastrozole.312 Suppression of ovarian estrogen production was achieved with the use of
GnRH agonist triptorelin, oophorectomy, or ovarian irradiation. The DFS
The TEAM trial compared treatment of exemestane alone versus was 92.8% in the exemestane plus OFS as compared with 88.8% in the
sequential therapy of tamoxifen for 2.5 to 3.0 years followed by tamoxifen plus OFS (HR for recurrence, 0.66; 95% CI, 0.55–0.80; P <
exemestane to complete 5 years of hormone therapy.313 At the end of 5 .001).314 The OS did not differ significantly between the two groups (HR for
years, 85% of patients in the sequential group versus 86% in the death in the exemestane plus OFS group, 1.14; 95% CI, 0.86–1.51; P =
exemestane group were disease free (HR, 0.97; 95% CI, 0.88–1.08; P = .37).314
.60). This is consistent with the data from the BIG 1-98 trial,307 in which
tamoxifen followed by letrozole or the reverse sequence of letrozole A 9-year median follow-up analysis of the TEXT-SOFT trials showed
followed by tamoxifen was not associated with significant differences in sustained improvements in DFS with exemestane plus OFS versus
efficacy versus letrozole monotherapy after a median follow-up of 71 tamoxifen plus OFS (HR- 0.77; 95% CI, 0.67 to 0.90) and in distant
months. recurrence-free interval but not OS (HR, 0.98; 95% CI, 0.79 to 1.22).315
Ultimately, with longer follow-up (median = 13 years), an OS was
The NCCN panel finds no meaningful differences in terms of efficacy or
demonstrated for OFS + exemestane in patients with high-risk of
toxicity between the available AIs: anastrozole, letrozole, and exemestane.
recurrence, but not in .exemestane plus OFS in patients with lower risk of
All three have shown similar anti-tumor efficacy and toxicity profiles in
relapse not receiving chemotherapy.316
randomized studies in the adjuvant settings.

Ovarian Function Suppression and Endocrine Therapy: The benefit of OFS in premenopausal patients with high-risk of recurrence
Ovarian function suppression (OFS) is achieved with a was also seen in the results of the ASTRRA trial. This trial studied
gonadotropin-releasing hormone (GnRH) agonist, oophorectomy, or premenopausal patients (n= 1483) with HR-positive breast cancer younger
ovarian irradiation. Available GnRH agonists in the United States include than 45 years treated with surgery and who received chemotherapy (as
goserelin and leuprolide. OFS is generally considered in those who are adjuvant or preoperative therapy) and received 5 years of tamoxifen alone
premenopausal and for tumors with high enough recurrence risk where the or 5 years of tamoxifen with OFS for 2 years. The 8-year DFS with
additional absolute decrease in recurrence compared with tamoxifen alone tamoxifen plus OFS was 85.4% versus 80.2% with tamoxifen alone (HR-
is worth the additional toxicity (young age, high-grade tumor, lymph node 0.67; 95% CI, 0.51 to 0.87).317
involvement). A balanced discussion of the risks and benefits associated

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Breast Cancer

The results of the TEXT-SOFT trials suggest an optimal OFS duration of In a separate cohort analysis of the MA-17 trial, the efficacy of letrozole
5 years and data from the ASTRA trial suggests a benefit with a minimum versus placebo was evaluated after un-blinding of the study in the 1579
of at least 2 years of OFS. The NCCN Panel has included OFS plus patients who had been randomly assigned to placebo after 4.5 to 6 years
endocrine therapy for 5 years as an option for premenopausal patients of tamoxifen.321,322 The median time since completion of tamoxifen was 2.8
with HR–positive breast cancer at higher risk of recurrence (eg, young years. Both DFS and distant DFS were significantly improved in the group
age, high-grade tumor, lymph-node involvement). Premenopausal patients receiving letrozole, thereby providing some evidence for the efficacy of
wishing to continue adjuvant endocrine therapy after ovarian suppression letrozole in patients who had received 4.5 to 6 years of tamoxifen therapy
is stopped should continue with tamoxifen versus AI. followed by no endocrine therapy for an extended period. A formal
quality-of-life analysis demonstrated reasonable preservation of quality of
Duration of Adjuvant Endocrine Therapy life during extended endocrine therapy, although patients may experience
ongoing menopausal symptoms and loss of bone mineral density.323,324 No
Adjuvant endocrine therapy is recommended for a minimum of 5 years. A
data are available regarding use of aromatase inhibitors for more than 5
recent retrospective analysis by the Oxford University studied risk of
years or long-term toxic effects from extended treatment. In addition, the
recurrence for years 5 through 20 after 5 years of endocrine therapy. 318
ATLAS trial data do not provide clear direction for treatment of
These data showed a considerable risk of recurrence between years 5
postmenopausal patients.291 There are no data available to suggest that
and 20 in these patients treated with initial 5 years of endocrine therapy.318
an AI for 5 years is better for long-term benefit than 10 years of tamoxifen.
Data has now emerged showing benefit of extended endocrine therapy in
improving DFS. In the extension study of ABCSG trial 6, HR-positive postmenopausal
patients received 5 years of adjuvant tamoxifen and were randomized to 3
Data from the ATLAS trial (discussed above)291 and the aTTom trial years of anastrozole or no further therapy.325 At a median follow-up of 62.3
confirm greater reduction in recurrence and death from breast cancer with months, patients who received anastrozole (n = 387) were reported to
10 versus 5 years of tamoxifen therapy.292 have a statistically significantly reduced risk of recurrence compared with
patients who received no further treatment (n = 469; HR, 0.62; 95% CI,
For those treated initially with adjuvant tamoxifen, there is evidence for
0.40–0.96; P = .031).325
benefit from extended adjuvant endocrine therapy from several
randomized trials. Results of the MA-17 trial in 5187 patients who had The differences in design and patient populations among the studies of the
completed 4.5 to 6 years of adjuvant tamoxifen demonstrated that aromatase inhibitors do not allow for the direct comparison of the results of
extended therapy with letrozole provides benefit in postmenopausal these studies. A meta-analysis of adjuvant trials of aromatase inhibitors
patients with HR-positive, early-stage breast cancer.295,319 With a median versus tamoxifen alone versus after 2 or 3 years of tamoxifen documented
follow-up of 64 months, letrozole was associated with improved DFS (HR lower recurrence rates with the aromatase inhibitor-containing regimen,
0.52, 95% CI 0.45-0.61) and an improved OS (HR 0.61, 95% CI 0.52-0.71) with no clear impact on OS.326 It is not known whether initial, sequential, or
compared with placebo.320 extended use of adjuvant aromatase inhibitors is the optimal strategy.

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NCCN Guidelines Version 4.2024

Breast Cancer

(category 1) or up to 10 years is limited to those who decline or who have

In patients initially treated with an AI, a randomized phase III trial a contraindication to AIs.
(MA17.R) evaluated the effects of extending adjuvant AI therapy from 5 to
10 years.327 Postmenopausal patients who had completed 4.5 to 6 years Adjuvant Endocrine Therapy for Premenopausal Patients: If
of therapy with an AI (with a median duration of prior tamoxifen of 5 premenopausal at diagnosis, the NCCN Panel recommend 5 years of
years), were randomized to letrozole or placebo for an additional 5 tamoxifen alone (category 1) or tamoxifen with OFS (category 1) or OFS
years.327 Improvement was seen in five-year DFS in those receiving plus AI for 5 years (category 1). Patients who are premenopausal at
letrozole compared to those who received placebo (95% [95% CI diagnosis and who become amenorrheic with chemotherapy may have
93 - 96%] vs. 91% [95% CI 89 -93%]). The annual rate of contralateral continued estrogen production from the ovaries without menses.
breast cancer reported was lower with letrozole (0.49% vs. 0.21%; HR Menopausal status cannot be determined while receiving OFS. AI can
0.42, 95% CI 0.22-0.81%). However, longer duration of AI resulted in more stimulate ovarian function. To assure a true postmenopausal status, serial
frequent bone-related adverse effects compared with those who received assessment of circulating LH, FSH, and estradiol is mandatory when
placebo and no improvement was observed with respect to OS. considering this subset for AI therapy.330,331 Frequency of testing of
Bone-related adverse effects included bone pain (18% vs. 14%), fractures estradiol and FSH/LH levels should be individualized.
(14% vs. 9%), and new-onset osteoporosis (11% vs. 6%).327 Patients with
After 5 years of initial endocrine therapy, for patients who are
high-risk of recurrence (eg. those with lymph node involvement) may
postmenopausal at that time (including those who have become
benefit from extended AI duration (7.5–10 years total).328,329
postmenopausal during the 5 years of tamoxifen therapy), the NCCN
NCCN Recommendations: The decision of whether or not to extend Panel recommends considering extended therapy with an AI for up to 5
adjuvant treatment based on the evidence available should be years (category 1) or based on the data from the ATLAS trial considering
individualized. When considering endocrine therapy, the Panel tamoxifen for an additional 5 years. For those who remain premenopausal
recommends the following adjuvant endocrine therapy options for patients after the initial 5 years of tamoxifen, the panel recommends considering
with early-stage breast cancer. continuing up to 10 years of tamoxifen therapy.

Adjuvant Endocrine Therapy for Postmenopausal Patients: The NCCN Additional considerations during Adjuvant Endocrine Therapy: Symptom
Panel recommends AI as initial adjuvant therapy for 5 years (category 1); management for patients on adjuvant endocrine therapies often requires
and tamoxifen for 2 to 3 years followed by one of the following options: an treatment of hot flashes and the treatment of concurrent depression.
AI to complete 5 years of adjuvant endocrine therapy (category 1) or 5
Venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI) has
years of AI therapy (category 2B); or tamoxifen for 4.5 to 6 years followed
been studied and is an effective intervention in decreasing hot flashes.332-
by 5 years of AI (category 1) or consideration of tamoxifen for up to 10 335 There is evidence suggesting that concomitant use of tamoxifen with
years. In postmenopausal patients, the use of tamoxifen alone for 5 years
certain SSRIs (eg, paroxetine, fluoxetine) may decrease plasma levels of
endoxifen, an active metabolite of tamoxifen.336,337 These SSRIs/SNRIs

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NCCN Guidelines Version 4.2024

Breast Cancer

may interfere with the enzymatic conversion of tamoxifen to endoxifen by osteopenia in patients with breast cancer. The use of a bisphosphonate
inhibiting a particular isoform of cytochrome P-450 (CYP450) enzyme. (oral/IV) or denosumab is recommended to maintain or to improve bone
Individuals with wild-type CYP2D6 alleles are classified as extensive mineral density and reduce risk of fractures in postmenopausal (natural or
metabolizers of tamoxifen. Those with one or two variant alleles with induced) patients receiving adjuvant AI therapy. Optimal duration of either
either reduced or no activity are designated as intermediate therapy has not been established. The optimal duration and benefits
metabolizers and poor metabolizers, respectively. The mild CYP2D6 beyond 3 years is not known. Factors to consider for duration of anti-
inhibitors such as citalopram, escitalopram, sertraline, and venlafaxine osteoporosis therapy include bone mineral density, response to therapy,
appear to have no or only minimal effect on tamoxifen metabolism.330,338,339 and risk factors for continued bone loss or fracture. There are case reports
of spontaneous fractures after denosumab discontinuation. Patients
With respect to CYP2D6 mutation status, a large retrospective study of treated with bisphosphonates or denosumab should undergo a dental
1325 patients found that time to disease recurrence was significantly examination with preventive dentistry prior to the initiation of therapy, and
shortened in poor metabolizers of tamoxifen.340 However, the BIG 1-98 should take supplemental calcium and vitamin D.
trial reported on the outcome based on CYP2D6 genotype in a subset of
postmenopausal patients with endocrine-responsive, early invasive breast The incremental benefit of adding adjuvant chemotherapy to endocrine
cancer. The study found no correlation between CYP2D6 allelic status and therapy in patients with low clinical risk of recurrence such as those with
disease outcome or between CYP2D6 allelic status and tamoxifen-related very small, low grade, lymph node-negative tumors is relatively small.346
adverse effects.341 A genetic analysis of the ATAC trial found no The decision whether or not to administer adjuvant chemotherapy in
association between CYP2D6 genotype and clinical outcomes.342,343 patients with HR-positive, HER2-negative tumors is based on many
Given the limited and conflicting evidence at this time,344 the NCCN Breast factors including lymph node status, size, grade, lymphovascular invasion,
Cancer Panel does not recommend CYP2D6 testing as a tool to determine age, comorbid conditions and/or the results of a gene expression profile
the optimal adjuvant endocrine strategy. This recommendation is test using multigene assays.
consistent with the ASCO Guidelines.345 When prescribing a selective
serotonin reuptake inhibitor (SSRI), it is reasonable to avoid potent and Several commercially-available gene-based assays are useful in
intermediate CYP2D6 inhibiting agents, particularly paroxetine and determining prognosis by predicting distant recurrence, local recurrence,
fluoxetine, if an appropriate alternative exists. or survival. Of these, only one, the 21-gene assay (Oncotype Dx) has
been clinically validated for predicting the benefit of adding adjuvant
For those on tamoxifen, while age-appropriate gynecologic screening is chemotherapy to further reduce the risk of recurrence.
recommended, the use of routine annual pelvic ultrasound is not
recommended. For those receiving AI or who experience ovarian failure 21-gene assay (Oncotype DX) in Node-negative, HR-positive,
secondary to treatment should have monitoring of bone health with a bone HER2-negative disease: The 21-gene recurrence score (RS) is one of the
mineral density determination at baseline and periodically thereafter. .The most validated multigene assays. The RS is helpful in determining the
panel discourages the selective ER modulators to treat osteoporosis or prognosis in patients with HR-positive, HER2-negative tumors treated with

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NCCN Guidelines Version 4.2024

Breast Cancer

endocrine therapy alone by predicting locoregional and distant when treated with endocrine therapy alone.354 In a secondary analysis of
recurrence.347-349 This assay has also been validated to predict the benefit a prospective registry of patients with HR-positive, HER2-negative,
from adding adjuvant chemotherapy to adjuvant endocrine therapy for lymph node-positive tumors, the 5-year risk of distant recurrence in
patients with HR-positive, HER2-negative, node-negative breast patients with a RS of <18, treated with endocrine therapy alone was
cancer.286,350,351 2.7%.355 These results suggest that in patients with limited nodal disease
(1-3 positive lymph nodes) and a low RS, the absolute benefit from
Among patients with T1b/c and T2, lymph node-negative, HR-positive, chemotherapy is likely to be very small.355,356
HER2-negative tumors with RS between 0-10, the risk of distant
recurrence is low and these patients derive no incremental benefit from There is a clear benefit from adjuvant chemotherapy in patients with node
the addition of adjuvant chemotherapy to endocrine therapy.286,352 At the positive, HR-positive, HER2-negative tumors, if the RS is high (≥ 31). In a
other end of the spectrum, patients with lymph node-negative, secondary analysis of the SWOG 8814 trial of patients with HR-positive,
HR-positive, HER2-negative cancers with high RS (≥ 31) have a higher lymph node-positive tumors, high RS (≥31) was predictive of
risk of distant recurrence and secondary analyses of prospective studies chemotherapy benefit. This study evaluated breast cancer specimens from
demonstrate a clear benefit from adjuvant chemotherapy.286,353 node-positive, HR-positive postmenopausal patients (n= 367) randomized
to endocrine therapy with tamoxifen alone or chemotherapy with CAF
For those with intermediate RS (11-25), the TAILORx trial of followed by tamoxifen.350 Compared with tamoxifen alone, treatment with
postmenopausal patients (n= 6711) with lymph node-negative, CAF among patients with a high RS (≥31) resulted in improved 10-year
HR-positive, HER-2 negative breast cancer, showed similar disease-free DFS (55% vs. 43%; HR 0.59, 95% CI 0.35-1.01) and OS (73% vs. 54%;
survival rates at 9-years in those who received adjuvant chemotherapy HR 0.56, 95% CI 0.31-1.02).350
followed by endocrine therapy compared with endocrine therapy alone.353
However, in a subset analysis, patients 50 years of age or younger with The Southwest Oncology Group (SWOG) S1007 RxPONDER trial,357
RS 16-25 had lower rates of distance recurrence with the addition of assigned patients with 1-3 lymph node-positive nodes, HR-positive,
adjuvant chemotherapy to endocrine therapy.353 The cutoff for low, HER2-negative breast cancer and a RS ≤ 25 to standard endocrine
intermediate, and high RS was different in TAILORx versus NSABP B-20. therapy with or without adjuvant chemotherapy. The results showed that
The NSABP-B20 was the first trial to validate the 21-gene assay both as a the addition of adjuvant chemotherapy to endocrine therapy improved
prognostic as well as a predictive tool and identified RS cut-offs to predict invasive disease–free survival among premenopausal—but not
the magnitude of chemotherapy benefit in patients with node-negative, postmenopausal—women with hormone receptor–positive, HER2-
HR-positive breast cancer.7 negative, node-positive breast cancer and a 21-gene assay recurrence
score up to 25.358
21-gene assay (Oncotype DX) in Node- positive, HR-positive,
HER2-negative disease: In the West German Plan B study, patients (n = 70-gene assay (MammaPrint): Results from the randomized MINDACT
110) with lymph node-positive, HR-positive, HER2-negative tumors, and trial,359 demonstrated that the 70-gene assay can identify a subset of
a RS of ≤11, were found to have a 5-year disease-free survival of94.4% patients who have a low likelihood of distant recurrence despite high-risk

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Breast Cancer

clinical features (based on tumor size, grade, nodal status). In this trial, In a subgroup analysis by nodal status, among node-negative patients
79% had lymph node-negative disease and 21% had 1-3 positive lymph with high clinical risk/low genomic risk, the 5-year rate of survival with no
nodes and all patients underwent risk assessment by clinical criteria (using distant metastasis was 95.7% (95% CI, 93.0 to 97.4) in those who
Adjuvant! Online) and genomic risk assessment by the 70-gene assay. received adjuvant chemotherapy compared with 93.2% (95% CI, 90.1 to
95.4) in those who did not receive chemotherapy.359 Among patients with
Patients with low-risk disease according to both clinical criteria and 1-3 positive lymph nodes, the rates of survival without distant metastases
genomic assay results did not receive adjuvant chemotherapy, whereas were 96.3% (95% CI, 93.1 to 98.1) in those who received adjuvant
patients categorized as high-risk by both assessments received chemotherapy versus 95.6 (95% CI, 92.7 to 97.4) in those who did not
chemotherapy. Patients with discordant results (i.e., either high clinical receive adjuvant chemotherapy.359 These data suggest that the additional
risk/low genomic risk or low clinical risk/high genomic risk) were benefit of adjuvant chemotherapy in patients with high-clinical risk/low
randomized to the chemotherapy group or the no-chemotherapy group on genomic risk is likely to be small.
the basis of either the clinical result or the genomic result. The primary
outcome of the study was met with the demonstration that among those 50-gene assay (PAM50): The 50-gene assay (PAM-50) risk of recurrence
with high clinical risk/low genomic risk, the 5-year rate of survival without (ROR) score stratifies patients with HR-positive disease into high,
distant metastasis in those did not receive adjuvant chemotherapy was medium, and low risk groups. Several studies have demonstrated the
94.7% (95% CI, 92.5 to 96.2).359 prognostic value of ROR score in estimating risk of disease recurrence.360-
362

In the intention-to-treat population, among patients at high clinical risk/low

genomic risk by the 70-gene assay, the 5-year rate of survival with no In a study from the Danish Breast Cancer Cooperative Group database,
distant metastasis in those who received chemotherapy was 95.9% (95% patients with lymph node node-negative tumors and low ROR had a
CI, 94.0 to 97.2) versus 94.4% (95% CI, 92.3 to 95.9) in those who did not distant recurrence risk of 5.0% (95% CI, 2.9% to 8.0%) whereas tumors
receive chemotherapy (adjusted HR for distant metastasis or death with with high ROR had a distant recurrence risk of 17.8% (95% CI, 14.0% to
chemotherapy vs.no chemotherapy 0.78; 95% CI, 0.50 to 1.21).359 Among 22.0%).361 Based on these analyses, patients with T1 and T2,
patients at low clinical risk/ high genomic risk, 5-year survival with no HR-positive, HER2- negative, lymph node-negative tumors, a ROR score
distant metastasis was 95.8% with chemotherapy (95% CI, 92.9 to 97.6), in the low range, regardless of tumor size, places the individual into the
compared with a rate of 95.0% (95% CI, 91.8 to 97.0%) without same prognostic category as those with T1a–T1b, N0, M0 tumors.361
chemotherapy (adjusted HR for distant metastasis or death with
chemotherapy vs. no chemotherapy,1.17; 95% CI, 0.59 to 2.28). These In patients with 1-3 lymph-node positive, HR-positive, HER2-negative
data suggest that the results of the 70-gene signature do not provide disease with low-risk of recurrence score, the distant recurrence risk was
evidence for making recommendations regarding chemotherapy for less than 3.5% at 10 years with endocrine therapy alone.361 In TransATAC
patients at low clinical risk.359 study, no distant recurrence was seen at 10 years in a similar group.362

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12-gene assay (EndoPredict): This assay utilizes 12-genes to calculate a trials showed that in patients with HR-positive T1–T3 tumors that are
prognostic score. This assay appears to be useful in identifying a lymph-node negative or positive, those that had a high BCI (H/I)
subgroup of patients with ER-positive, HER2-negative tumors with very demonstrated significant improvements in DFS when adjuvant endocrine
low risk of recurrence without adjuvant chemotherapy and helpful in therapy was extended, compared to the control arm.366-368 Considering the
identifying patients at low risk for a late recurrence.363 Based on results of ability of the multigene assays to predict benefit of adjuvant systemic
two Austrian Breast Cancer Study Group trials- ABCSG-6 and ABCSG-8, chemotherapy and ability to determine prognosis by predicting risk of
patients with HR-positive, HER-2 negative, and lymph-node node-negative distant recurrence, the NCCN Panel has summarized the treatment
disease with a low-risk score by the 12-gene assay had risk of distant implications based on risk scores and nodal status.
recurrence of 4% at 10 years.363 The prognostic value of the risk score
from the 12-gene assay was found to be independent of conventional Multigene Assays for Axillary Lymph Node-Negative HR-Positive,
clinicopathological factors. Patients with T1 and T2 HR-positive, HER2-Negative Tumors
HER2-negative, and lymph node-negative tumors, a 12-gene low-risk
score, regardless of T size, places the tumor into the same prognostic Small tumors (up to 0.5 cm in greatest diameter) that do not involve the
category as T1a–T1b, N0, M0. lymph nodes have a favorable prognosis so adjuvant chemotherapy is not
recommended. According to the NCCN Panel, adjuvant endocrine therapy
In TransATAC study, patients with 1-3 positive nodes in the low-risk group may be considered in this group of patients to reduce the risk for a second
had a 5.6% risk of distant recurrence at 10 years,362 suggesting that contralateral breast cancer, as well as the small benefit in reducing the risk
chemotherapy would be of limited benefit in these patients. of local/regional and distant recurrence.(Category 2B).

Breast Cancer Index: The Breast Cancer Index (BCI) is a combination of For patients with invasive ductal or lobular tumors greater than 0.5 cm in
two profiles, the HOXB13-to-IL17BR expression ratio (H:I ratio) and the diameter and no lymph node involvement (lymph node node-negative), the
Molecular Grade Index (MGI). Compared with clinical prognostic factors NCCN panel recommends strongly considering the 21-gene RT-PCR
(eg, age, tumor size, tumor grade, and lymph node status), the H:I ratio assay to help estimate likelihood of recurrence and benefit from
has been shown to be prognostic in the setting of adjuvant tamoxifen chemotherapy (category 1). The panel has noted that on an exploratory
monotherapy.362,364 The addition of MGI to H:I was determined to provide analysis from the TAILORx study,353 adjuvant chemotherapy may be
additional prognostic discrimination, leading to the BCI assay.364 In a considered in patients 50 years of age or younger with a 21-gene RS of
secondary analysis of the ATAC trial, BCI was prognostic in node negative 16-25. Also, patients with T1b tumors with low grade histology should be
breast cancer for both early (years 0-5) and late (years 5-10) distant considered for endocrine monotherapy, as the TAILORx study353 did not
recurrence.365 For patients with T1 and T2 HR-positive, HER2-negative, include patients with such tumors.
and lymph node-negative tumors, a BCI in the low-risk range, regardless
of T size, places the tumor into the same prognostic category as T1a-T1b, The panel notes that other prognostic multigene assays may be
N0, M0. Secondary analyses of the MA.17, Trans-aTTom, and IDEAL considered to help estimate risk of recurrence, but these assays have not
been validated to predict the benefit of systemic chemotherapy. Also,

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NCCN Guidelines Version 4.2024

Breast Cancer

amongst the other assays, the panel has listed the 70-gene assay as a For those who are candidates for systemic adjuvant chemotherapy based
category 1 option based on the results of the prospective MINDACT359 trial on clinical characteristics, tumor stage, and pathology, the panel
demonstrating the ability of the 70-gene assay to identify a good genomic recommends consideration of multigene assays to assess prognosis as a
risk population despite a high clinical risk, in whom chemotherapy may be tool to assist with treatment decision making. The panel notes in those
omitted without a detrimental effect. High clinical risk in the MINDACT trial with N1mi and N1 tumors, while multigene assays have yet to be proven
was defined for grade 1 tumors as >3 cm N0 or T2N1, for grade 2 tumors to be predictive for adjuvant chemotherapy benefit, they are prognostic
T2N0-1, and for grade 3 tumors T1c-2N0-1. and can be used to identify low-risk patients who are likely to derive little
or no absolute benefit from addition of adjuvant chemotherapy to adjuvant
Furthermore, given no difference in outcomes with or without endocrine therapy. A secondary analysis of the prospective SWOG 8814
chemotherapy in the discordant low clinical risk/high genomic risk group, trial using the 21-gene assay demonstrated no benefit for chemotherapy
the MINDACT study suggests that the 70-gene panel is not useful guiding for patients with 1-3 involved axillary lymph nodes and a low RS, and a
systemic chemotherapy decisions in this subgroup of patients. significant benefit for the addition of adjuvant chemotherapy in those with
high-RS (≥ 31).350 The phase III RxPONDER trial prospectively
Since results of different assays may not be concordant with each other
demonstrated that for premenopausal patients with hormone receptor–
and these assays have not been compared head-to-head prospectively,
positive, HER2-negative, node-positive breast cancer , a 21-gene assay
clinicians should only order one of the available assays for a specific
Recurrence Scores up to 25 had an addition benefit of adjuvant
patient and tumor.
chemotherapy to endocrine therapy for improving invasive disease–free
Multigene Assays for Axillary Lymph Node-Positive HR- Positive, survival .358 In the MINDACT trial, among patients with 1-3 positive nodes
HER2-Negative Tumors who had a high clinical risk of recurrence but low risk by the 70-gene
assay, the rates of survival were similar between those who received
For patients with four or more involved nodes the panel recommends adjuvant chemotherapy in addition to adjuvant endocrine therapy versus
systemic adjuvant chemotherapy followed by endocrine therapy (category those received adjuvant endocrine therapy alone, suggesting that
1). chemotherapy could be omitted in this group.359 Other multigene assays
have not proven to be predictive of benefit from chemotherapy.
Patients with less than four involved nodes or with pN1mi and less than or
equal to 2 mm axillary node metastasis, are most often candidates for For those who are candidates for systemic adjuvant chemotherapy based
chemotherapy in addition to endocrine therapy. The panel recommends on clinical characteristics, tumor stage, and pathology, if multigene assay
that clinical decision making for adjuvant chemotherapy be based on is not available, the panel recommends systemic adjuvant chemotherapy
elements of clinical risk stratification such as clinical characteristics, tumor followed by endocrine therapy (category 1).
stage, pathology and comorbid conditions. If the patient is not a candidate
for chemotherapy, the panel recommends adjuvant endocrine therapy Adjuvant Targeted therapies for HR-positive, HER2-negative tumors
alone (category 2A).

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NCCN Guidelines Version 4.2024

Breast Cancer

Adjuvant therapies are rapidly evolving and CDK 4/6 inhibitors and PARP year invasive DFS for the olaparib group versus placebo group was 82.7%
inhibitors are now indicated in this setting. versus 75.4% (95% CI 3.0% - 11.5%) and 4-year distant DFS was 86.5%
versus 79.1% (95% CI 3.6% -11.3%).373
Adjuvant CDK 4/6 inhibitors: In the MonarchE study, the addition of 2
years of abemaciclib to endocrine therapy reduced the absolute risk of According to the NCCN panel, addition of adjuvant olaparib for 1 year may
recurrence at 4 years by 6.4% (HR 0.664, 95% CI 0.578-0.762, P < be considered for those with germline BRCA 1/2 mutations in patients with
.0001) in patients with HR-positive/HER2-negative, high-risk breast HR-positive, HER2-negative tumors with ≥4 positive lymph nodes after
cancer, defined as 4 or more pathologically involved lymph nodes adjuvant chemotherapy or residual disease after preoperative therapy and
confirmed preoperatively and/or at surgery, or 1–3 pathologically involved a clinical stage, pathologic stage, ER status, and tumor grade (CPS+EG)
lymph nodes with additional high risk features (grade 3 or size ≥5 cm score ≥3 (category 2A).
based on pre-operative imaging and/or pathologically at surgery).369
Adjuvant olaparib may be used concurrently with endocrine therapy.
Two trials of palbociclib as adjuvant therapy in HR-positive, HER2– In patients eligible for both adjuvant olaparib and abemaciclib, the optimal
negative early breast cancer did not show benefit of adding palbociclib to sequencing is not known. (For sequencing of olaparib and/or abemaciclib
adjuvant endocrine therapy in terms of invasive disease-free survival.370,371 with RT, see BINV-I on nccn.org)
The results from the NATALEE trial reported after a median follow-up of Adjuvant bisphosphonate therapy
34 months, showed a statistically significant improvement (3.3%) in
Antiresorptive agents (bisphosphonates and denosumab) have an
invasive disease-free survival with the addition of ribociclib to adjuvant
established role as preventative and therapeutic agents for the
endocrine therapy (HR-0.75, 95% CI 0.62-0.91, P = .003).) for stage II and
management of osteoporosis, hypercalcemia of malignancy, and bone
stage III HR-positive, HER2-negative breast cancer.372 Additional follow-up
metastases.
is needed to characterize the long-term efficacy of ribociclib in this setting.
Bisphosphonates: In the Austrian Breast and Colorectal Cancer Study
According to the current guidelines, 2 years of adjuvant CDK 4/6 therapy
Group trial-12 (ABCSG-12) trial, for patients over 40 years, zoledronic acid
with abemaciclib should be considered in combination with endocrine
significantly reduced the risk of recurrence by 34% (HR, 0.66; P=.014) and
therapy in patients with HR-positive/HER2-negative, high-risk breast
the risk of death by 49% (HR, 0.51; P=.020). However, no improvement
cancer (as detailed above). This is a category 1, preferred option for this
was seen in either DFS or OS in this post hoc analysis among patients
setting.
under 40 years.374 In a planned subgroup analysis of the AZURE trial,
Adjuvant Olaparib: In patients with germline BRCA 1/2 mutations and zoledronic acid improved DFS in patients who were more than 5 years
high-risk HER2-negative tumors, the results of the OlympiA trial showed since menopause at trial entry.375 A meta-analysis of data from seven
that the 4-year OS in the group that received 1 year of adjuvant olaparib adjuvant bisphosphonate trials (AZURE, ABCSG-12, ZO-FAST, Z-FAST,
was 89.8% and 86.4% in the placebo group (95% CI -0.1% -6.8%). The 4- EZO-FAST, NSABP-B34, GAIN), including only those known to be over 50
years, postmenopausal, or with ovarian suppression, showed a significant
© ©
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NCCN Guidelines Version 4.2024

Breast Cancer

benefit for the use of adjuvant bisphosphonates in patients with a Adjuvant Therapy for HER2-negative tumors
low-estrogen state and early-stage breast cancer.376 More recently, the Several combination chemotherapy regimens are appropriate to consider
Early Breast Cancer Trialists' Collaborative Group (EBTCG) conducted a for HR-positive or negative and HER2-negative tumors. All adjuvant
meta-analysis of all randomized adjuvant bisphosphonate studies (26 chemotherapy regimens listed in the NCCN Guidelines have been
studies) and reported convincing evidence that adjuvant bisphosphonates evaluated in phase III clinical trials and are category 1 unless otherwise
provide benefits to postmenopausal (natural or induced) patients with noted.
breast cancer.377 With bisphosphonate therapy, the greatest improvement
was seen in bone recurrence (RR=0.83, P = .004) and bone fractures Preferred Regimens
(RR=0.85, P = .02). No effect was seen on distant recurrence outside
Regimens listed as preferred include dose-dense doxorubicin and
bone (RR =0.98, P =0.69).377 In premenopausal patients, bisphosphonate
cyclophosphamide (AC) followed or preceded by paclitaxel either weekly
therapy did not seem to have a significant effect on bone recurrence.
or biweekly; docetaxel plus cyclophosphamide (TC); olaparib for germline
However, in postmenopausal patients, zoledronic acid significantly
BRCA 1/2 mutations; pembrolizumab for high-risk ER- disease; and
reduced bone recurrence (3.4% vs. 4.5%, RR=0.73, 99% CI 0.53 to 1.00);
capecitabine for residual ER- disease after preoperative chemotherapy.
the difference in breast cancer mortality was not statistically significant
(7.1% vs. 7.9%, RR=0.88, 99% CI 0.69 to 1.11).377 Meta-analysis from Early Breast Cancer Trialists’ Collaborative Group
(EBCTCG) has shown that anthracycline and taxane-based combination
Denosumab: In the adjuvant setting, the ABCSG-18 trial studied the effect
chemotherapy reduces the risk of breast cancer mortality compared with
of denosumab in postmenopausal patients treated with adjuvant AIs and
no chemotherapy. The use of dose-dense schedules has shown to further
showed a reduction in clinical fractures (HR 0.5, P < .0001), which was the
reduce the risk of breast cancer recurrence or death without increasing
primary endpoint of this study.378 The final analysis after a median follow-
mortality. 381
up of 8 years continued to show a benefit with denosumab. Adjuvant
denosumab improved bone metastasis-free survival (88.9 vs. 86.4%; HR, The results of two randomized trials comparing AC chemotherapy with or
0.81; 95% CI, 0.65 to 1.00) and OS (90.9 vs. 89.9%; HR, 0.80; 95% CI, without sequential paclitaxel chemotherapy in patients with axillary
0.64 to 1.01).379 In contrast, results of the phase III trial (D-Care) trial failed node-positive breast cancer suggest improved disease-free rates and
to demonstrate a difference in bone metastasis-free survival in those results from one of the trials showed an improvement in OS, with the
receiving denosumab versus placebo.380 addition of paclitaxel.382,383 On retrospective analysis, the apparent
advantage of the paclitaxel-containing regimen appears greater in patients
Due to these conflicting results from phase III trials, denosumab is
with ER-negative breast cancers.
currently not recommended in the adjuvant setting.379 The panel
recommends considering adjuvant bisphosphonate therapy for risk A randomized trial evaluated the use of concurrent versus sequential
reduction of distant metastasis for 3–5 years in patients with high-risk chemotherapy (doxorubicin followed by paclitaxel followed by
node negative or node-positive tumors. cyclophosphamide vs. doxorubicin plus cyclophosphamide followed by

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NCCN Guidelines Version 4.2024

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paclitaxel) given either every 2 weeks with filgrastim support or every 3 and/or taxane-based) preoperative chemotherapy. The results showed
weeks. The results show no significant difference between the two improved DFS (HR 0.70, 95% CI 0.53-0.92, P = .01) and OS (HR for
chemotherapy regimens but demonstrate a 26% reduction in hazard of death 0.59, 95% CI 0.39-0.90, P = .01) with adjuvant capecitabine. The
recurrence (P = .01) and a 31% reduction in the hazard of death (P = .013) OS was higher in those with TNBC (HR for death, 0.52). Results of two
for the dose-dense regimens.384 other similar trials with adjuvant capecitabine have showed a similar
impact with adjuvant capecitabine in patients with TNBC with no significant
The ECOG E1199 study was a four-arm trial that randomized 4950 impact in those with HR-positive disease.388,389 Based on the above trial
patients to receive AC chemotherapy followed by either paclitaxel or results, the NCCN panel has included adjuvant capecitabine an adjuvant
docetaxel given by either an every-3-week schedule or a weekly therapy option for those with TNBC and residual disease after
schedule.385 In a secondary series of comparisons, weekly paclitaxel was preoperative therapy. For those with germline BRCA 1/2 mutations and
superior to every-3-week paclitaxel in DFS (HR, 1.27; 95% CI, 1.03–1.57; TNBC, according to the NCCN panel, based on the results of OlympiA trial
P = .006) and OS (HR, 1.32; 95% CI, 1.02–1.72; P = .01), and (discussed in section adjuvant therapy for HR-positive, HER2-negative
every-3-week docetaxel was superior to every-3-week paclitaxel in DFS disease) adjuvant olaparib for 1 y may be considered if tumors ≥ pT2 or ≥
(HR, 1.23; 95% CI, 1.00–1.52; P = .02) but not in OS.385 Based on these pN1 disease after adjuvant chemotherapy or in those with residual disease
results, as well as the findings from the CALGB trial 9741 that showed after preoperative chemotherapy (catgeory1). Patients in the OlympiA trial
dose-dense AC followed by paclitaxel every 2 weeks to have a survival did not receive capecitabine; thus, there are no data on sequencing or to
benefit when compared with the regimen of AC followed by every-3-week guide selection of one agent over the other. (For sequencing of
paclitaxel,384 the every-3-week paclitaxel regimen has been removed from capecitabine or Olaparib with RT, see BINV-I on nccn.org)
the guidelines.
If pembrolizumab was given in combination with chemotherapy in the
Combination TC was compared with AC chemotherapy in a trial that preoperative setting, based on the KEYNOTE-522 trial data, the panel
randomized 1016 patients with stage I to III breast cancer.386 At a median recommends adjuvant pembrolizumab.274
follow-up of 7 years, overall DFS (81% vs. 75%; HR, 0.74; 95% CI, 0.56–
0.98; P = .033) and OS (87% vs. 82%; HR, 0.69; 95% CI, 0.50–0.97; P = Other Recommended Regimens
.032) were significantly improved with TC compared with AC. Non-
anthracycline, taxane-based regimen, such as TC may be preferred Other recommended regimens included in the guidelines include: AC;
options in patients for whom anthracyclines are contraindicated. epirubicin and cyclophosphamide (EC); docetaxel, doxorubicin, and
cyclophosphamide (TAC); paclitaxel + carboplatin (various schedules);
Residual disease after preoperative systemic therapy indicates higher risk and docetaxel + carboplatin.
(20% to 30%) of disease relapse.256,387 CREATE-X, a multicenter, open-
label, randomized, phase 3 trial evaluated the efficacy and safety of A trial compared 2 dose levels of EC chemotherapy with CMF
adjuvant capecitabine in patients with HER2-negative primary breast chemotherapy in patients with node-positive breast cancer.390 This study
cancer who had residual invasive disease after standard (anthracycline showed that higher-dose EC chemotherapy was equivalent to CMF

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NCCN Guidelines Version 4.2024

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chemotherapy and superior to moderate-dose EC in event-free survival triple-negative disease, the10-year DFS rate with weekly paclitaxel was
and OS. 69% and the 10-year OS rate was 75%.393

Final results from a randomized trial of TAC versus FAC chemotherapy in The AC regimen for four cycles has been studied in randomized trials,
node-positive breast cancer demonstrated that TAC is superior to FAC.391 resulting in relapse-free survival and OS equivalent to CMF
Estimated 5-year DFS was 75% with TAC and 68% with FAC (HR, 0.72; chemotherapy.394,395 No benefit from dose escalation of either doxorubicin
95% CI, 0.59–0.88; P =.001); survival was 87% with TAC and 81% with or cyclophosphamide was shown.382,396 Studies of CMF chemotherapy
FAC (HR, 0.70; 95% CI, 0.53–0.91; P = .008). DFS favored TAC in both versus no chemotherapy have shown DFS and OS advantages with CMF
ER-positive and ER-negative tumors. At a median follow-up of 73 months, chemotherapy.59,397
results from the 3-arm randomized NSABP B-30 trial comparing TAC
versus AT versus AC followed by docetaxel (AC followed by T) Results of a randomized trial in patients with TNBC (n=434) who received
demonstrated that AC followed by T had a significant advantage in DFS standard adjuvant chemotherapy demonstrated that maintenance therapy
(HR, 0.83; P = .006) but not in OS (HR, 0.86; P = .086) when compared with low-dose capecitabine (dose of 650 mg/m2 twice a day by mouth for 1
with TAC. In addition, both DFS (HR, 0.080; P = .001) and OS (HR, 0.83; year) improved 5-year DFS and OS. The invasive DFS in those who
P = .034) were significantly increased when AC followed by T was receive adjuvant low-dose capecitabine was 85.8% compared with 75.8%
compared with AT, with AT demonstrating non-inferiority compared with in those who did not (HR for risk of distant metastasis or death, 0.60 [95%
TAC.392 CI, 0.38-0.92]; P = .02), the estimated 5-year OS with maintenance
capecitabine was 85.5% versus 81.3% (HR for risk of death, 0.75 [95% CI,
Useful in Certain Circumstances: 0.47-1.19]; P = .22).398

Regimens included in this category include dose dense AC; AC every 3 Adjuvant Therapy for HER2-positive tumors
weeks (Category 2B); CMF; AC followed by weekly paclitaxel; and Trastuzumab containing chemotherapy regimens followed by one year of
capecitabine as maintenance therapy for TNBC after adjuvant HER2-targeted therapy are a backbone of adjuvant therapy patients with
chemotherapy. HER2-positive disease.

The phase III E1199 trial compared patients with node-positive or high-risk
The panel recommends HER2-targeted therapy in patients with
node-negative breast cancer who received 4 cycles of AC every 3 weeks,
HER2-positive tumors (see Principles of HER2 Testing in the NCCN
followed by either paclitaxel or docetaxel, either weekly or every 3 weeks.
Guidelines for Breast Cancer). Pre-operative systemic therapy
The 10-year updated results of this trial showed that incorporation of
incorporating HER-2 targeted agent(s) should be considered for HER-2
weekly paclitaxel and docetaxel every 3 weeks was associated with
positive patients presenting with clinical node-positive tumors or those
significant improvements in DFS, and marginal improvements in OS,
measuring >2 cm (cT2) at presentation.)
compared with paclitaxel given every 3 weeks. Among patients with

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The NCCN Panel suggests trastuzumab and chemotherapy be used for heart failure reported was 0.5%).404 The long-term follow-up data reported
patients with HER2-positive, node-negative tumors measuring 0.6 to 1.0 10-year invasive DFS of 91.3%, breast cancer-specific survival of 98.8%
cm (T1b) and for smaller tumors that have less than or equal to 2 mm and OS rates of 94.3%.405 Accordingly, NCCN panel has listed paclitaxel
axillary node metastases (pN1mi). Some support for this recommendation and trastuzumab as a less intensive therapeutic option, preferred for
comes from studies showing a higher risk of recurrence for patients with patients with low-risk T1,N0,M0, HER2-positive disease, particularly those
HER2-positive, node-negative tumors less than or equal to 1 cm not eligible for other standard adjuvant regimens due to comorbidities.405
compared to those with HER2-negative tumors of the same size.399
The BCIRG 006 study randomized 3222 patients with HER2-positive,
Ten-year breast cancer-specific survival and 10-year recurrence-free node-positive, or high-risk node-negative breast cancer to AC followed by
survival were 85% and 75%, respectively, in patients with tumors docetaxel; AC followed by docetaxel plus trastuzumab for one year; or
characterized as HER2-positive, ER-positive tumors, and 70% and 61%, carboplatin, docetaxel, and trastuzumab for one year.403 At 65-month
respectively, in patients with HER2-positive, ER-negative tumors. Two follow-up, patients receiving AC followed by docetaxel with trastuzumab
additional retrospective series report recurrence-free survival in this (AC-TH) had an HR for DFS of 0.64 (P < .001) when compared with the
subpopulation of HER-2 positive, node-negative tumors measuring 0.6 to group of patients in the control arm receiving the same chemotherapy
1.0 cm (T1b) and/or pN1mi. all treated without trastuzumab. In the first regimen without trastuzumab (AC-T). The HR for DFS was 0.75 (P = .04)
study, 5-year recurrence-free survival rates of 77.1% and 93.7% (P < when patients in the carboplatin/docetaxel/ trastuzumab (TCH)-containing
.001) were observed for patients with HER2-positive and HER2-negative arm were compared to patients in the control arm. No statistically
T1a-bN0M0 breast tumors, respectively, with no recurrence-free survival significant difference in the HR for DFS was observed between the two
differences seen in the HER2-positive group when hormonal receptor trastuzumab-containing arms. An OS advantage was reported for patients
status was considered.400 In the other retrospective study of patients with in both trastuzumab-containing arms relative to the control arm (HR for
small HER2-positive tumors, the risk of recurrence at 5 years was low AC-TH vs. AC-T = 0.63; P = .001; HR for TCH vs. AC-T = 0.77; P = .04).
(99% [95% CI; 96%–100%] for HER2-negative disease and 92% [95% CI; Cardiac toxicity was significantly lower in the TCH arm (9.4% patients with
86%–99%] for HER2-positive disease).401 Subgroup analyses from several >10% relative decline in left ventricular ejection fraction) compared with
of the randomized trials have shown consistent benefit of trastuzumab the AC-TH arm (18.6%; P < .0001). CHF was also more frequent with
irrespective of tumor size or nodal status.402,403 AC-TH than TCH (2% vs. 0.4%; P < .001). Analysis of this trial by critical
clinical event revealed more distant breast cancer recurrences with TCH
Preferred Regimens: (144 vs. 124) but fewer cardiac events with TCH compared with AC-TH (4
The NCCN Panel has included paclitaxel and trastuzumab as an option for vs. 21).403 In the FinHer trial, 1010 patients were randomized to 9 weeks of
patients with low-risk, HER2-positive, stage 1 tumors, based on a trial of vinorelbine followed by 3 cycles of FEC chemotherapy versus docetaxel
406 patients with small, node-negative, HER2-positive tumors treated with for 3 cycles followed by 3 cycles of FEC chemotherapy.406 Patients (n =
this combination. The 3-year rate of DFS was 98.7% (95% CI, 97.6–99.8) 232) with HER2-positive cancers that were either node-positive or
and the risk of serious toxic effects with this regimen was low (incidence of node-negative and greater than or equal to 2 cm and PR-negative were

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further randomized to receive or not receive trastuzumab for 9 weeks The data from the phase III KATHERINE trial reported improved outcomes
during the vinorelbine or docetaxel portions of the chemotherapy only. in patients who had residual invasive cancer and received adjuvant
With a median follow-up of 3 years, the addition of trastuzumab was trastuzumab emtansine (T-DM1). Invasive DFS at 3 years was 88.3% with
associated with a reduction in risk of recurrence (HR, 0.42; 95% CI, 0.21– T-DM1 versus 77.0% with trastuzumab.410 T-DM1 significantly decreased
0.83; P = .01). No statistically significant differences in OS (HR, 0.41; 95% the invasive breast cancer recurrence risk or death (HR 0.50, 95% CI
CI, 0.16–1.08; P = .07) or cardiac toxicity were observed with the addition 0.39-0.64, P < .001).410
of trastuzumab.406 At 5-year follow-up, a comparison of the two arms (ie,
chemotherapy with and without trastuzumab) demonstrated that the HRs The ATEMPT trial was designed to determine whether T-DM1 was more
for distant DFS (HR, 0.65; 95% CI, 0.38–1.12; P = .12) and OS (HR, 0.55; toxic than paclitaxel/Trastuzumab. The long-term followup data of patients
95% CI, 0.27–1.11; P = .094) were higher relative to those reported at 3 who received 1 year of adjuvant T-DM1 (n = 383) or
years.407 The TCH regimen is a preferred regimen, especially for those trastuzumab/paclitaxel (n = 114) reported the 5-year invasive disease free
with risk factors for cardiac toxicity, based on the results of the BCIRG 006 survival rate with T-DM1 of 97.0% (95% CI, 95.2%-98.7%), the 5-year
study. recurrence-free interval of 98.3% (95% CI, 96.3%-99.0%), and the 5-year
OS rate of 97.8% (95% CI, 96.3%-99.3%).411 The study was not powered
The APHINITY trial compared adjuvant trastuzumab plus pertuzumab with to evaluate the efficacy of paclitaxel/trastuzumab, among those who
trastuzumab–placebo, both in combination with standard adjuvant received it, the reported 5-year invasive disease-free survival with this
chemotherapy in patients with node-positive or high-risk node-negative combination was 91.3% (95% CI: 86.0-96.9%), 5-year recurrence free
HER2-positive, operable tumors. The study demonstrated that interval was 93.3% (95% CI: 88.6-98.2%) and 5-year OS was 97.9% (95%
trastuzumab plus pertuzumab significantly improved 3-year iDFS (HR CI: 95.2-100%).411 Based on these data, T-DM1 may be considered an
0.81, 95% CI 0.66-1.00, P =.045).408 With long-term (8-year) follow-up, the alternative for these patients ineligible for paclitaxel/Trastuzumab.
node positive subgroup maintained a clear invasive DFS benefit favoring
the dual HER-2 agent arm demonstrating 8-year invasive DFS of 86% Other recommended regimens:
versus 81% (HR; 0.72, 95% CI 0.60-0.87) with no OS difference; no Anthracycline followed by taxane-containing chemotherapy regimens were
benefit was seen in the node-negative subgroup.409 These updated results used in the NSABP trial B-31,412 NCCTG trial,413 and BCIRG 006 trial.403
from the adjuvant APHINITY trial confirm the long-term benefit of adding
In the NOAH trial, patients were given concurrent taxane and
pertuzumab to trastuzumab plus chemotherapy for node positive disease.
anthracycline, then taxane alone followed by cyclophosphamide–
The panel has designated use of trastuzumab with chemotherapy as a
methotrexate–fluorouracil.414 In the FinHER patients were randomized to
category 1 recommendation for all HER2-positive tumors >1 cm, and
docetaxel or vinorelbine before anthracyclines,406 and PACS 04
based on the data above, chemotherapy plus trastuzumab and
randomized patients to fluorouracil/epirubicin/cyclophosphamide or to
pertuzumab as a category 1, preferred regimen for all HER-2 positive,
epirubicin plus docetaxel.415 The HERA trial did not mandate the choice of
node-positive disease.
chemotherapy, 94% receiving anthracyclines and 26% receiving a taxane
in addition to an anthracycline.

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All of the above adjuvant trials of trastuzumab have demonstrated trastuzumab + pertuzumab and paclitaxel/carboplatin + trastuzumab +
clinically significant improvements in DFS. Furthermore, the HERA trial416 pertuzumab.
and the combined analysis of the NSABP B31 and NCCTG N9831 trials417
showed significant improvement in OS with the use of trastuzumab. A Regimens Useful in Certain Circumstances:
more recent meta-analysis of all the above (excluding the BCIRG 006 One year of extended therapy with neratinib after completion of 1 year of
Trial) showed that addition of trastuzumab resulted in an average absolute adjuvant trastuzumab without pertuzumab was evaluated in the phase III
reduction in 10-year risk of recurrence of 9.0% (95% CI 7.4 to 10.7; P < . ExteNET trial. Neratinib improved invasive DFS (HR 0.73, 95% CI 0.57-
0001), a reduction in 10-year breast cancer mortality by 6.4% (4.9 to 7.8; 0.92, P = .0083) primarily in the subgroup of HR-positive tumors (HR 0.60,
P < .0001), and a reduction in mortality (all causes) by 6.5% (5.0 to 8.0; P 95% CI 0.43-0.83, P = .063). Neratinib is associated with moderate to
<.0001).418 The benefits of trastuzumab are independent of ER severe diarrhea.
status.412,419
Based on the trials listed in the section for “other recommended regimen
The NCCN Panel considers it reasonable to incorporate pertuzumab into and the above data from ExteNET, the NCCN panel has included following
the above adjuvant regimens272,420,421 regimens have been included as useful in certain circumstances:
Docetaxel + cyclophosphamide + trastuzumab; AC followed by paclitaxel
The results of theTRAIN-2 trial showed high pCR rates after treatment + trastuzumab followed by paclitaxel plus trastuzumab, various
regimen with anthracycline plus trastuzumab and pertuzumab (67%) and schedules); AC followed by paclitaxel + trastuzumab + pertuzumab,
also without anthracycline plus trastuzumab and pertuzumab (68%).420 various schedules); Paclitaxel + trastuzumab + pertuzumab; adjuvant
Patients who received anthracycline-containing regimen experienced more neratinib and adjuvant T-DM1.
febrile neutropenia, hypokalemia, and left ventricular ejection fraction
(LVEF) decline to grade 2 or worse (≥10% or to <50%).420 Therapeutic duration and Other Considerations in those receiving HER2-
targeted therapy
A follow-up analysis of the TRAIN-2 study showed similar 3-year EFS and
The length of trastuzumab administration in the adjuvant setting trials
OS with or without anthracyclines in patients with stage II and III HER2-
listed above is 12 months. The HERA trial demonstrated no additional
positive breast cancer. Based on these results, considering the added
benefit extending trastuzumab to 2 years compared with 1 year.
toxicity of anthracycline containing regimens the panel has added non-
anthracycline containing regimens with trastuzumab and pertuzumab as With respect to a duration less than 12 months, the results of the
treatment options.422 PERSEPHONE trial showed non-inferiority for 6 months versus 12 months
of trastuzumab treatment,423 However, the PHARE study observed more
The NCCN panel has included the following regimen as other
events in the 6 month cohort compared to the 12 month cohort, and non-
recommended regimens for HER2-positive disease:
inferiority was not established.424 Furthermore, adverse events over time
doxorubicin/cyclophosphamide (AC) followed by docetaxel + trastuzumab
(followed by docetaxel + trastuzumab); AC followed by docetaxel +

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NCCN Guidelines Version 4.2024

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remained similar in both arms, and comparable to data reported in other status. If used, the treatment options for endocrine therapy,
trials. chemotherapy, and sequencing of treatment with other modalities are
similar to those of the usual histology of breast cancers. There are rare
Considering the conflicting results between PERSEPHONE and PHARE, subtypes of metaplastic carcinoma (eg, low-grade adenosquamous and
in addition to the protocol design of the majority of the randomized trials low-grade fibromatosis-like carcinoma) that have a favorable prognosis
establishing the benefits of trastuzumab which utilized 12 months of even without administration of adjuvant systemic therapies.
therapy, the NCCN panel recommends up to one year of HER2-targeted
therapy with trastuzumab. Based on the updated APHINITY trial data, the The vast majority of pure tubular, pure mucinous, and pure cribriform
addition of pertuzumab may be considered with trastuzumab in those with breast cancers are both ER-positive and HER2-negative. To be
node-positive disease. associated with favorable prognosis, the favorable histologic type should
not be high grade, should be pure (>90% as classified on the surgical
Increased cardiac toxicity has been observed in patients treated with excision, not core biopsy alone), and should be HER-2 negative. If atypical
trastuzumab.412,425,426 In addition, anthracycline and taxane-based pathologic or clinical features are present, consider treating as ductal/NST.
regimens in combination with HER2-targeted agents are associated with
further increased risk of cardiac toxicity.427 The panel recommends The pathology evaluation and accuracy of the ER and/or HER2
evaluation of left ventricular ejection fraction (LVEF) prior to and during determination should be reviewed if these are ER-negative and/or
treatment. The optimal frequency of LVEF assessment during adjuvant HER2-positive, or if a tumor with an ER- and PR-negative status is grade
trastuzumab therapy is not known. The FDA label recommends LVEF 1.276 Should a breast cancer be histologically identified as a pure tubular or
measurements prior to initiation of trastuzumab and every 3 months during mucinous breast cancer and be confirmed as ER-negative, then the tumor
therapy. should be treated according to the guideline for the usual histology,
ER-negative breast cancers. The panel acknowledges that prospective
According to the panel, use of a FDA-approved biosimilar is an data regarding systemic adjuvant therapy of pure tubular and mucinous
appropriate substitute for trastuzumab. Trastuzumab and hyaluronidase- histologies are lack
oysk injection approved for subcutaneous use may be substituted for
intravenous trastuzumab. It is important to note that it has a different
dosage and administration compared to intravenous trastuzumab.

Adjuvant Therapy for Tumors of Favorable Histologies

The guidelines provide systemic treatment recommendations for the
favorable histology of invasive breast cancers (including pure tubular and
pure mucinous cancers, pure cribriform, adenoid cystic secretory
carcinoma and other salivary carcinoma, rare low-grade forms of
metaplastic carcinoma) based on ER/PR status, tumor size and ALN

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Post-Therapy Surveillance and Follow-up for T0–3, N1, developing a second primary breast cancer. Rates of contralateral breast
M0 and T1–3, N0–1, M0 Tumors cancer after either breast-conserving therapy or mastectomy have been
Post-therapy follow-up is optimally performed by members of the reported to be increased in patients with BRCA1/2 mutations when
treatment team and includes the performance of regular history/physical compared with patients with sporadic breast cancer.433-435
examinations every 4 to 6 months for the first 5 years after primary therapy
The Panel recommends that patients with intact uteri who are taking
and annually thereafter. Mammography should be performed annually.
adjuvant tamoxifen should have yearly gynecologic assessments and
Regarding frequency of mammograms after BCS followed by radiation, the rapid evaluation of any vaginal spotting that might occur because of the
NCCN Panel agrees with ASTRO’s “Choosing Wisely” list of risk of tamoxifen-associated endometrial carcinoma in postmenopausal
recommendations released in 2014.428 The recommendations state that patients.436 The performance of routine endometrial biopsy or
“annual mammograms are the appropriate frequency for surveillance of ultrasonography in the asymptomatic woman is not recommended. Neither
breast cancer patients who have had BCS and RT with no clear test has demonstrated utility as a screening test in any population of
advantage to shorter interval imaging. Patients should wait 6 to 12 months patients. The vast majority of patients with tamoxifen-associated uterine
after the completion of RT to begin their annual mammogram surveillance. carcinoma have early vaginal spotting.
Suspicious findings on physical examination or surveillance imaging might
If an adjuvant AI is considered in patients with amenorrhea following
warrant a shorter interval between mammograms.”
treatment, baseline levels of estradiol and gonadotropin followed by serial
The NCCN Panel notes that any imaging of reconstructed breast is not monitoring of these hormones should be performed if endocrine therapy
indicated. with an AI is initiated.330 Bilateral oophorectomy assures postmenopausal
status in young patients with therapy-induced amenorrhea and may be
According to the NCCN Panel, in the absence of clinical signs and considered prior to initiating therapy with an AI in a young woman.
symptoms suggestive of recurrent disease, laboratory or imaging studies
to screen for metastasis are not necessary. The routine performance of Symptom management for patients on adjuvant endocrine therapies often
alkaline phosphatase tests and LFTs are not included in the guidelines.429- requires treatment of hot flashes and the treatment of concurrent
431 In addition, the Panel notes no evidence to support the use of “tumor depression. Venlafaxine, a serotonin-norepinephrine reuptake inhibitor
markers” for breast cancer, and routine bone scans, CT scans, MRI scans, (SNRI), has been studied and is an effective intervention in decreasing hot
PET scans, or ultrasound examinations in the asymptomatic patient flashes.332-335 There is evidence suggesting that concomitant use of
provide no advantage in survival or ability to palliate recurrent disease and tamoxifen with certain selective serotonin reuptake inhibitors (SSRIs) (eg,
are, therefore, not recommended.110,432 paroxetine, fluoxetine) may decrease plasma levels of endoxifen, an active
metabolite of tamoxifen.336,337 These SSRIs/SNRIs may interfere with the
The use of breast MRI in follow-up of patients with prior breast cancer is enzymatic conversion of tamoxifen to endoxifen by inhibiting a particular
undefined. It may be considered as an option in patients with high lifetime isoform of CYP2D6. However, the mild CYP2D6 inhibitors such as
risk (>20% based on models largely dependent on family history) of

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NCCN Guidelines Version 4.2024

Breast Cancer

citalopram, escitalopram, sertraline, and venlafaxine appear to have no or The Panel recommends that patients on an adjuvant AI or who experience
only minimal effect on tamoxifen metabolism.330,338,339 ovarian failure secondary to treatment should have monitoring of bone
health with a bone mineral density determination at baseline and
Follow-up also includes assessment of patient adherence to ongoing periodically thereafter. The use of estrogen, progesterone, or selective ER
medication regimens such as endocrine therapies. Predictors of poor modulators to treat osteoporosis or osteopenia in patients with breast
adherence to medication include the presence of side effects associated cancer is discouraged. The use of a bisphosphonate is generally the
with the medication, and incomplete understanding by the patient of the preferred intervention to improve bone mineral density. A single phase 3
benefits associated with regular administration of the medication.437 The study, ABCSG12, demonstrated improved outcomes with the addition of
Panel recommends the implementation of simple strategies to enhance zoledronic acid in premenopausal patients receiving endocrine therapy
patient adherence to endocrine therapy, such as direct questioning of the with ovarian suppression.442 Use of bisphosphonates in such patients and
patient during office visits, as well as brief, clear explanations on the value in other subgroups remains controversial. Denosumab has shown to
of taking the medication regularly and the therapeutic importance of longer significantly reduce fractures in postmenopausal patients receiving
durations of endocrine therapy. adjuvant therapy AIs, and improves bone mineral density.378
Lymphedema is a common complication after treatment for breast Optimal duration of bisphosphonate therapy has not been established.
cancer. Factors associated with increased risk of lymphedema include Factors to consider for duration of anti-osteoporosis therapy include bone
extent of axillary surgery, axillary radiation, infection, and patient mineral density, response to therapy, and risk factors for continued bone
obesity.438,439 The Panel recommends educating the patients on loss or fracture. Patients treated with a bisphosphonate should undergo a
lymphedema, monitoring for lymphedema, and referring for lymphedema dental examination with preventive dentistry prior to the initiation of
management as needed. therapy, and should take supplemental calcium and vitamin D.
Many young patients treated for breast cancer maintain or regain Evidence suggests that a healthy lifestyle may lead to better breast cancer
premenopausal status following treatment for breast cancer. For these outcomes. A nested case control study of 369 patients with ER-positive
patients, the NCCN Panel discourages the use of hormonal birth control
methods, regardless of the HR status of the tumor.440 Alternative birth tumors who developed a second primary breast cancer compared with
control methods are recommended, including intrauterine devices, barrier 734 matched control patients who did not develop a second primary tumor
methods, and, for those with no intent of future pregnancy, tubal ligation or showed an association between obesity (body mass index [BMI] ≥30),
vasectomy. Breastfeeding during endocrine or chemotherapy treatment is smoking, and alcohol consumption and contralateral breast cancer.443 A
not recommended by the NCCN Panel because of risks to the infant. prospective study of 1490 patients diagnosed with stage I–III breast
Breastfeeding after breast-conserving treatment for breast cancer is not cancer showed an association between high fruit and vegetable
contraindicated. However, lactation from an irradiated breast may not be consumption, physical activity, and improved survivorship, regardless of
possible, or may occur only with a diminished capacity.440,441 obesity.444 There is emerging evidence that obesity is associated with
poorer outcomes for certain subtypes of breast cancers. The study by the

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NCCN Guidelines Version 4.2024

Breast Cancer

Women’s Intervention Nutrition group randomized patients with

early-stage breast cancer to an intervention group and a control group.
The intervention consisted of eight one-on-one visits with a registered
dietitian who had been trained on a low-fat eating plan. OS analysis
showed no significant difference between the two study arms (17% for the
intervention vs. 13.6% without); however, subgroup analysis showed that
those with ER- and PR-negative disease who were part of the intervention
group saw a 54% improvement in OS.445

The NCCN Panel recommends an active lifestyle and ideal body weight
(BMI 20–25) for optimal overall health and breast cancer outcomes as
there are reports of proven benefits of exercise and active lifestyle during
and after treatment.446-448

For management of issues related to survivorship including late/long-term

effects of cancer and its treatment, see the NCCN Guidelines for
Survivorship.

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NCCN Guidelines Version 4.2024

Breast Cancer

Recurrent/Stage IV Breast Cancer the biopsy can be protected from harsh decalcification solution to preserve
Staging and Workup for Recurrent and Stage IV Breast Cancer more accurate biomarker assessment.

The staging evaluation of patients who present with recurrent or stage IV Determination of HR status (ER and PR) and HER2 status should be
breast cancer includes: history and physical examination; the performance repeated in all cases when diagnostic tissue is obtained. ER and PR
of a CBC, LFTs, chest diagnostic CT, bone scan, and radiographs of any assays may be falsely negative or falsely positive, and there may be
long or weight-bearing bones that are painful or appear abnormal on bone discordance between the primary and metastatic tumors.451,452 The
scan; diagnostic CT of the abdomen (with or without diagnostic CT of the reasons for the discordance may relate to change in biology of disease,
pelvis) or MRI scan of the abdomen; and biopsy documentation of first differential effect of prior treatment on clonal subsets, tumor heterogeneity,
recurrence if possible. The NCCN Panel generally discourages the use of or imperfect accuracy and reproducibility of assays.452 Discordance
sodium fluoride PET or PET/CT scans for the evaluation of patients with between the receptor status of primary and recurrent disease has been
recurrent disease. There is limited evidence (mostly from retrospective reported in a number of studies. The discordance rates are in the range of
studies) to support the use of PET/CT scanning to guide treatment 3.4% to 60% for ER-negative to ER-positive; 7.2% to 31% for ER-positive
planning through determination of the extent of disease in select patients to ER-negative; and 0.7% to 11% for HER2.453-462
with recurrent or metastatic disease.110,111,449,450 In general, the
non-diagnostic CT scans used for PET under-evaluate the lungs and the The NCCN Panel recommends that re-testing the receptor status of
liver compared with contrast-enhanced diagnostic CT scans. The Panel recurrent disease be performed, especially in cases when it was
considers biopsy of equivocal or suspicious sites to be more likely than previously unknown, originally negative, or not overexpressed. For
PET/CT scanning to provide accurate staging information in this patient patients with clinical courses consistent with HR–positive breast cancer, or
population. with prior positive HR results, the Panel has noted that a course of
endocrine therapy is reasonable, regardless of whether the receptor assay
The consensus of the NCCN Panel is that FDG-PET/CT is optional and is repeated or the result of the most recent HR assay.
most helpful in situations where standard imaging results are equivocal or
suspicious. The NCCN Panel recommends bone scan or sodium fluoride Genetic counseling is recommended if the patient is considered to be at
PET/CT (category 2B) to detect bone metastases. However, if the FDG- high risk for hereditary breast cancer, as defined by the NCCN Guidelines
PET results clearly indicate bone metastases, these scans can be omitted. for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and
Pancreatic.
The NCCN Panel recommends that metastatic disease at presentation or
first recurrence of disease should be biopsied as a part of the workup for Genetic testing: In the metastatic setting, results from genetic testing may
patients with recurrent or stage IV disease. This ensures accurate have therapeutic implications. Germline mutations in BRCA1/2 have
determination of metastatic/recurrent disease and tumor histology, and proven clinical utility and therapeutic impact. Therefore, germline BRCA1/2
allows for biomarker determination and selection of appropriate treatment. mutations should be assessed in all patients with recurrent or metastatic
Soft tissue tumor biopsy is preferred over bone sites unless a portion of breast cancer to identify candidates for PARP inhibitor therapy.

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NCCN Guidelines Version 4.2024

Breast Cancer

Management of Locally Recurrent Disease recurrent disease should be treated with RT if no prior radiation has been
Patients with local recurrence only are divided into three groups: 1) those given.
who had been treated initially by mastectomy alone; 2) those who had
In patients with a local breast recurrence after BCS and RT who had a
been treated initially by mastectomy plus RT; and 3) those who had
prior sentinel lymph node (SLN) biopsy, a repeat SLNB may be
received breast-conserving therapy plus RT.
considered although the accuracy of repeat SLNB is unproven, and the
In one retrospective study of local recurrence patterns in patients with prognostic significance of repeat SLNB after mastectomy is unknown and
breast cancer who had undergone mastectomy and adjuvant its use is discouraged.465,466 On the other hand, the prognostic significance
chemotherapy without RT, the most common sites of local recurrence of repeat SLNB after mastectomy is unknown and its use is discouraged.
were at the chest wall and the supraclavicular lymph nodes.463 The The consensus recommendation of the Panel for most patients with a local
recommendations for treatment of the population of patients experiencing recurrence following breast-conserving therapy and SLNB is mastectomy
a local recurrence only are supported by analyses of a combined database and a level I/II axillary dissection.
of patients from the EORTC 10801 and Danish Breast Cancer
The results of the CALOR trial found that after complete resection in
Cooperative Group 82TM trials. The analyses compared
patients with isolated locoregional recurrence, adjuvant chemotherapy
breast-conserving therapy with mastectomy in patients with stage I and
improves both DFS and OS.467 After a median follow-up of 4.9 years, the
stage II disease. The 133 (approximately 8%) patients experiencing a local
overall DFS was 69% in the chemotherapy group versus 57% in the group
recurrence as an initial event were approximately equally divided between
that did not receive chemotherapy (HR, 0.59; P = .046).467 Five-year OS in
those who had undergone mastectomy and those who had received
all patients in the study was also significantly improved with chemotherapy
breast-conserving therapy as initial treatment for breast cancer. Of those
(88% vs. 76%, P = .024).467 The benefit of adjuvant chemotherapy was
in the former group, 51 (76%) were able to undergo RT with or without
mostly seen in patients with ER-negative disease. Among patients with
surgery as treatment for local disease recurrence. No difference in survival
ER-negative disease, 5-year DFS was 67% versus 35% (HR, 0.32; 95%
emerged between patients receiving treatment after initial treatment with
CI, 0.14–0.73) and in those ER-positive disease, the 5-year DFS was 70%
mastectomy or breast-conserving therapy; approximately 50% of both
versus 69% (HR, 0.94; 95% CI, 0.47–1.89).467 However these patients
groups were alive at 10-year follow-up.464
received endocrine therapy.
According to the NCCN Panel, mastectomy-treated patients should
According to the NCCN Panel, after local treatment, patients with local
undergo surgical resection of the local recurrence (if it can be
recurrences only should be considered for limited duration systemic
accomplished with limited morbidity) and involved-field RT to the chest
chemotherapy or endocrine therapy similar to that outlined in the adjuvant
wall and supraclavicular area (if the chest wall was not previously treated
chemotherapy section. The Panel emphasized the importance of
or if additional RT may be safely administered). The use of surgical
individualizing treatment strategies in patients with a recurrence of disease
resection in this setting implies the use of limited excision of disease with
limited to a local site.
the goal of obtaining clear margins of resection. Unresectable chest wall

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NCCN Guidelines Version 4.2024

Breast Cancer

Management of Recurrent or Stage IV Disease no difference in the OS between the group that received surgery and the
From the time of diagnosis of recurrent/stage IV metastatic disease, group that did not (19.2 vs. 20.5 months; HR, 1.04; 95% CI, 0.81–1.34).475
patients should be offered appropriate supportive care and In a separate multicenter prospective registry study patients whose
symptom-related interventions as a routine part of their care. NCCN disease responded to first-line systemic therapy were randomized to
recognizes the importance of clinical trials and encourages participation management of the primary tumor by surgery or not. 477 Preliminary data
when applicable and available. showed no difference in OS between the two groups 477

Surgery for Recurrent or Stage IV Disease However, in another trial by the Turkish Federation (MF07-01), patients (n
The primary treatment approach recommended by the NCCN Panel for = 274) with de novo metastatic breast cancer who were randomized to
patients with metastatic breast cancer and an intact primary tumor is local management (mastectomy, or BCS with radiation) followed by
systemic therapy, with consideration of surgery after initial systemic systemic therapy versus systemic therapy only observed a benefit with
treatment for those requiring palliation of symptoms or with impending surgery.478 While no difference in survival was seen at 36 months, at 40
complications, such as skin ulceration, bleeding, fungation, and pain.468 months, patients treated with local management showed an improvement
Generally such surgery should be undertaken only if complete local in survival with locoregional treatment (46.4% vs. 26.4%; HR, 0.66; 95%
clearance of tumor may be obtained and if other sites of disease are not CI, 0.49–0.88).478 The design of this trial is different from the other, the first
immediately life-threatening. Alternatively, RT may be considered instead difference being the inclusion of two prospective studies described above
of surgery. Often such surgery requires collaboration between the breast in which patients were included only if they had experienced a response to
surgeon and the reconstructive surgeon to provide optimal cancer control systemic therapy. Second, randomization in the Turkish trial was not
and wound closure. balanced. Patients who received surgery had lower rates of triple-negative
disease (7% vs. 17%), visceral metastases (29% vs. 45%), and many had
Retrospective studies suggest a potential survival benefit from complete solitary bone metastases only (33% vs. 20%).478 In an unplanned
excision of the in-breast tumor in select patients with metastatic breast subgroup analysis, patients who appeared to derive the greatest OS
cancer.469-472 Substantial selection biases exist in all of these studies and benefit from local management included those with HR-positive disease
are likely to confound the study results.473,474 (HR, 0.63; 95% CI, 0.44–0.89; P = .008); those with HER2-negative
disease (HR, 0.64; 95% CI, 0.45–0.91; P = .01); those <55 years (HR,
Two prospective, randomized studies assessed whether or not surgery on 0.57; 95% CI, 0.38–0.86; P = .007); and those with solitary bone
the primary tumor in the breast is necessary for patients who are metastases (HR, 0.47; 95% CI, 0.23–0.98; P = .04). 478
diagnosed with metastatic/stage IV breast cancer.475,476 In the first
prospective trial, patients (n = 350) with de novo metastatic breast cancer The Panel recognizes the need for more data from randomized clinical
who achieved a partial or complete response to anthracycline-based trials that will address the risks and benefits of local therapy for patients
chemotherapy were randomly assigned to either surgery of the primary with stage IV disease while eliminating selection biases. Though the
tumor plus adjuvant radiation or no locoregional treatment.475 There was available data do not support broadly considering local therapy with

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NCCN Guidelines Version 4.2024

Breast Cancer

surgery and/or RT, this may be reasonable in select patients with disease health or dental procedures during treatment are known risk factors for
responding to initial systemic therapy. In such clinical scenarios, patient ONJ. Thus, a dental examination with preventive dentistry intervention is
engagement in the decision is encouraged. recommended prior to treatment with intravenous bisphosphonate or
denosumab, and dental procedures invasive of gum or bone during
Guideline Stratification for Systemic Therapy for Stage IV/Recurrent
treatment should be avoided if at all possible. Additional risk factors for the
Disease
development of ONJ include administration of chemotherapy or
The systemic treatment of breast cancer recurrence or stage IV disease
corticosteroids and poor oral hygiene with periodontal disease and dental
prolongs survival and enhances QOL but is not curative. Therefore,
abscess.480
treatments associated with minimal toxicity are preferred. Thus, the use of
the minimally toxic endocrine therapies is preferred to the use of cytotoxic Bisphosphonates
therapy whenever reasonable.479 Guidance for treatment of patients with There are extensive data from randomized trials in support of the use of
breast cancer and brain metastases is included the NCCN Guidelines for bisphosphonates for patients with metastatic disease to bone. The
Central Nervous System Cancers. randomized clinical trial data include the use of zoledronic acid and
pamidronate in the United States and ibandronate and clodronate in
Patients with recurrent or stage IV breast cancer at diagnosis are initially
European countries.481-488 In metastatic bone disease, bisphosphonate
stratified according to whether bone metastases are present. These two
treatment is associated with fewer SREs, fewer pathologic fractures, and
patient subsets (those with and without bony metastases) are then further
less need for RT and surgery to treat bone pain.
stratified by tumor HR and HER2 status.
The use of bisphosphonates in metastatic disease is a palliative care
Therapy for Bone Metastases
measure. No impact on OS has been observed in patients treated with
Complications from bone metastases include pain, decreased
bisphosphonates.
performance status, and decreased QOL, as well as skeletal-related
events (SREs), which are defined as the need for radiation or surgery to The data indicate that zoledronic acid and pamidronate may be given on a
bone, pathologic fractures, spinal cord compression, and hypercalcemia of 3- to 4-week schedule in conjunction with antineoplastic therapy (ie,
malignancy. endocrine therapy, chemotherapy, biologic therapy) or every 12 weeks.
Three randomized trials have compared zoledronic acid dosed every 4
The NCCN Panel recommends treatment with a bone-modifying agent
weeks versus every 12 weeks.489-491 Data from these trials show that
such as zoledronic acid, pamidronate, or denosumab (category 1) in
among patients with breast cancer and bone metastases zoledronic acid
addition to chemotherapy or endocrine therapy if bone metastasis is
administered once every 12 weeks versus once every 4 weeks does not
present; expected survival is ≥3 months. Patients should undergo a dental
compromise efficacy and has similar rates of SREs.489,490,492 In the ZOOM
examination with preventive dentistry prior to initiation of this therapy. The
trial,489 the rate of skeletal morbidities was 0.22 (95% CI, 0.14–0.29) in
bisphosphonates and denosumab are associated with a risk of
those receiving zoledronic acid every 4 weeks versus 0.26 (95% CI, 0.15–
development of osteonecrosis of the jaw (ONJ). Poor baseline dental
0.37) in those receiving zoledronic acid every 12 weeks. In the CALGB

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NCCN Guidelines Version 4.2024

Breast Cancer

70604 trial,490 the rate of SREs in the 4-week arm was 29.5% versus superiority) and time to first and subsequent SREs (rate ratio, 0.77; 95%
28.6% in the 12-week arm. In OPTIMIZE-2 trial,491 the rate of SREs was CI, 0.66–0.89; P = .001). No difference in time to progression or OS was
22% in the 4-week arm and 23.2% in the 12-week arm.491 The NCCN observed.494 Dosing of denosumab outside of every 3 to 6 weeks has not
Panel recommends an optimal dosing of every 12 weeks. been studied.
Systemic Therapy for Stage IV or Recurrent Metastatic HR-Positive,
The use of bisphosphonates should be accompanied by calcium and
HER2-Negative Breast Cancer
vitamin D supplementation with daily doses of calcium of 1200 to 1500 mg
Patients with stage IV or recurrent disease characterized by HR-positive,
and vitamin D3 of 400 to 800 IU. Recommended agents for use in the
HER2-negative tumors with no visceral crisis are treated with endocrine
United States are pamidronate 90 mg intravenously over 2 hours or
therapy alone or endocrine therapy in combination with targeted agents.
zoledronic acid 4 mg intravenously over 15 minutes. The original studies
Patients whose disease progresses after a year from the end of adjuvant
continued treatment for up to 24 months; however, there are limited
endocrine-based therapy and those who present with de novo stage
long-term safety data indicating treatment can continue beyond that
IV/metastatic breast cancer are eligible for first-line endocrine therapies.
time.484,486,493 The risk of renal toxicity necessitates monitoring of serum
creatinine prior to administration of each dose and dose reduction or Many premenopausal and postmenopausal patients with HR-positive
discontinuation if renal function is reduced. Current clinical trial results breast cancer benefit from sequential use of endocrine therapies at
support the use of bisphosphonates for up to 2 years. Longer durations of disease progression. Therefore, patients with breast cancers whose
bisphosphonate therapy may provide additional benefit, but this has not disease responds to an endocrine-based therapy with either shrinkage of
yet been tested in clinical trials. the tumor or long-term disease stabilization (clinical benefit) should
receive additional endocrine therapy at disease progression. For disease
Denosumab
progression on or within 12 months of completing adjuvant endocrine
Patients with metastatic breast cancer to bone who are candidates for
therapy or for disease progression on first-line endocrine therapy for
bisphosphonate therapy may also be considered for treatment with
metastatic disease, patients are eligible for second-line endocrine therapy
denosumab. This recommendation is based on the results of a single
either as monotherapy or in combination with a targeted agent. The
randomized trial comparing denosumab to zoledronic acid.494 All trial
optimal sequence for endocrine therapy is not well defined. The choice
patients were recommended to supplement with vitamin D and calcium.
would depend on previous tolerance of treatment and patient preference.
Patients on the experimental arm were given 120 mg of denosumab
injected subcutaneously every 4 weeks plus intravenous placebo versus Many trials in HR-positive patients have not included premenopausal
the control arm where patients were given an intravenous infusion of 4 mg patients. The NCCN Panel recommends that patients with HR-positive
of zoledronic acid every 4 weeks, and a subcutaneous placebo. In this trial disease should have adequate ovarian suppression/ablation and then be
with non-inferiority as the primary endpoint, denosumab was shown to treated in the same way as postmenopausal patients. The NCCN Panel
significantly delay time to first SRE by 18% as compared with zoledronic has outlined endocrine-based therapies that would be used in the first-line
acid (HR, 0.82; 95% CI, 0.71–0.95; P < .001 for non-inferiority; P = .01 for versus second- and subsequent-line settings.

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NCCN Guidelines Version 4.2024

Breast Cancer

Preferred First-Line Therapy for HR-Positive, HER2-Negative Breast cancer. The combination of abemaciclib with the AI improved PFS,
Cancer compared with the AI alone (median not reached vs. 14.7 months,
AI in combination with CDK 4/6 inhibitor: In postmenopausal patients or respectively; HR, 0.54; 95% CI, 0.41–0.72).497 The ORR was higher with
premenopausal patients receiving ovarian ablation or ovarian function the combination compared with AI monotherapy (59% vs. 44 %).497 The
suppression with a luteinizing hormone-releasing hormone (LHRH) most frequent grade 3 or higher adverse events for abemaciclib versus
agonist, combinations of AIs with CDK 4/6 inhibitors (palbociclib, ribociclib, placebo included diarrhea (9.5% vs.1.2%), neutropenia (21.1% vs. 1.2%),
or abemaciclib) have demonstrated improved progression-free survival leukopenia (8% vs. 0.6%), and fatigue (2% vs. 0%).497
(PFS) relative to an AI alone.
Most trials studying CDK 4/6 inhibitor with an AI have mainly included
Palbociclib in combination with letrozole was studied in a phase III study postmenopausal patients and only a small subset of premenopausal
that included postmenopausal patients (n = 666) with metastatic, patients on ovarian suppression. However, in the phase III
HR-positive, HER2-negative breast cancer who had not received prior MONALEESA-7 trial, 672 pre- or perimenopausal patients with
treatment for advanced disease.495 An improvement in PFS (24.8 vs. 14.5 HR-positive, HER2-negative advanced breast cancer were randomly
months; HR, 0.58; 95% CI, 0.46–0.72) and objective response rate (ORR; assigned to first-line treatment with ribociclib or placebo with goserelin
42% vs. 35%) was seen with the combination of palbociclib and letrozole plus either a nonsteroidal AI or tamoxifen.498 An improvement in PFS was
compared with letrozole alone.495 Grade 3 and 4 adverse effects seen with seen with the addition of ribociclib (median PFS, 24 vs. 13 months; HR,
the combination of palbociclib and letrozole included neutropenia (66.5% 0.55; 95% CI, 0.4–0.69).498
vs. 1.4%), leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%) and fatigue
(1.8% vs. 0.5%).495 At 3.5 years, an improvement in OS was reported with ribociclib (70% vs.
46%; HR, 0.71; 95% CI, 0.54–0.95).499 Grade 3 and 4 adverse events
Ribociclib in combination with letrozole was also studied as first-line reported in >10% of patients in either group included neutropenia (61% vs.
therapy in a phase III study of postmenopausal patients (n = 668) with 4%) and leukopenia (14% vs. 1%).498
HR-positive, HER2-negative recurrent/stage IV breast cancer. At a median
follow-up of 26.4 months, an improvement in PFS (25.3 vs. 16.0 months; Based on the above data, the NCCN Panel has included AI in combination
HR for progression or death was 0.56; 95% CI, 0.45–0.70) and improved with CDK 4/6 inhibitors as a category 1 first-line option for
ORR of 43% vs. 29% was seen with ribociclib plus letrozole compared postmenopausal patients and premenopausal patients with ovarian
with letrozole alone.496 Grade 3 or 4 adverse events were more common ablation/suppression with HR-positive, HER2-negative recurrent/stage IV
with the combination and included neutropenia (62% vs. 1.2%), breast cancer.
leukopenia (21.3% vs. 0.9%), and abnormal LFTs (10.2% vs. 2.4%).496
Single-Agent Fulvestrant: Fulvestrant is an ER antagonist and was
The phase III MONARCH trial studied the combination of abemaciclib with originally approved as a monthly intramuscular injection (250 mg per
either an AI (letrozole or anastrozole) or AI monotherapy as first-line month); higher dose has been proven to be more effective in subsequent
treatment of patients with advanced HR-positive, HER2-negative breast randomized trials. In the first-line setting, fulvestrant was found to be as

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effective as anastrozole in terms of ORR (36.0% vs. 35.5%; OR, 1.02; combination of ribociclib with fulvestrant showed improved PFS versus
95% CI, 0.56–1.87).500 An improved time to progression was seen with fulvestrant alone (21 vs. 13 months; HR, 0.59; 95% CI, 0.48–0.73).506 The
fulvestrant compared to anastrozole (median time to progression was 23.4 PFS benefits were consistent across patients with and without prior
months for fulvestrant vs. 13.1 months for anastrozole; HR, 0.63; 95% CI, endocrine treatment. In a subsequent analysis, a significant improvement
0.39–1.00; P = .0496).501 This study also used a higher loading dose of in OS was observed.507 At 42 months the estimated OS was 57.8% (95%
500 mg every 2 weeks for 3 doses and then maintenance dose of 500 mg CI, 52.0–63.2) in the ribociclib group and 45.9% (95% CI, 36.9–54.5) in
monthly.500 The median OS was observed to be longer in the fulvestrant the placebo group.507
group than in the anastrozole group (54.1 months vs. 48.4 months; HR,
0.70; P = .041).502 Comparison across multiple trials, including those in the second-line
settings studying combination of fulvestrant with palbociclib or abemaciclib
A separate phase III randomized study in postmenopausal patients with have shown statistically significant improvement in PFS. Based on the
metastatic HR-positive breast cancer compared fulvestrant 500 mg every results of the MONALEESA-3 trial and extrapolation results from the
2 weeks for 3 doses followed by 500 mg monthly versus fulvestrant 250 second-line setting, the NCCN Panel has included fulvestrant in
mg monthly. The PFS was superior with the fulvestrant 500 mg regimen combination with CDK 4/6 inhibitors as a category 1 first-line option for
(HR, 0.80; 95% CI, 0.68–0.94; P = .006),503 indicating an increased postmenopausal patients and premenopausal patients with ovarian
duration of response with the higher dose of fulvestrant. The final analyses ablation/suppression with HR-positive, HER2-negative recurrent/stage IV
demonstrated an increase in median OS (4.1 months) and reduced risk of breast cancer.
death (19%) with a dose of 500 mg compared with 250 mg. Median OS
was 26.4 versus 22.3 months (HR, 0.81; 95% CI, 0.69–0.96; P = .02).504 Fulvestrant + Nonsteroidal AI: The combination of two endocrine agents
as first-line treatment in postmenopausal patients with HR-positive,
Results from another phase III trial (FALCON) of first-line treatment with metastatic breast cancer has been reported from studies comparing
fulvestrant compared with anastrozole in endocrine therapy-naïve patients single-agent anastrozole versus anastrozole plus fulvestrant.
with metastatic ER-positive breast cancer, demonstrated improved PFS
with fulvestrant (at the higher dose, 500 mg) over anastrozole at a median In one study (FACT), combination of fulvestrant with anastrozole was not
follow-up of 25.0 months (16.6 vs. 13.8 months; HR for progression or superior to single-agent anastrozole (time to progression HR, 0.99; 95%
death, 0.797; 95% CI, 0.637–0.999).505 The QOL outcomes were similar CI, 0.81–1.20; P = .91).508 In a second phase III trial (SoFEA), the effect of
between the two groups, with the most common adverse effects being fulvestrant alone or in combination with anastrozole or exemestane was
arthralgia (17% vs. 10%) and hot flashes (11% vs. 10%) for fulvestrant studied in patients with advanced breast cancer with acquired resistance
and anastrozole, respectively.505 to a nonsteroidal AI.509 An AI had been given as adjuvant treatment to
18% of patients for a median of 27.9 months, and to 82% of patients for
Fulvestrant + CDK 4/6 Inhibitor: In the phase III trial, MONALEESA-3, in locally advanced/metastatic disease for a median of 19.3 months. Median
patients (n = 726) with advanced HR-positive breast cancer who had no PFS was 4.8 months, 4.4 months, and 3.4 months for patients treated with
prior endocrine therapy or had disease progression on prior therapy, the fulvestrant alone, anastrozole plus fulvestrant, and fulvestrant plus

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exemestane, respectively. No differences were observed for ORR, clinical patients.515 In postmenopausal patients, AI monotherapy has been shown
benefit rate, and OS. to have superior outcome compared with tamoxifen, although the
differences are modest.516-520 A randomized phase III trial comparing
In the trial by the Southwest Oncology Group (SWOG), S0226, PFS (HR, tamoxifen with exemestane as first-line endocrine therapy for
0.80; 95% CI, 0.68–0.94; stratified log-rank P = .007) and OS (HR, 0.81; postmenopausal patients with metastatic breast cancer showed no
95% CI, 0.65–1.00; stratified P = .049) were superior with combination significant differences in PFS or OS between the two arms.518
anastrozole plus fulvestrant.510 A subgroup analysis in this trial suggested
that patients without prior adjuvant tamoxifen experienced the greatest OS NCCN recommendations for first-line therapy: For postmenopausal
benefit with combination therapy compared with monotherapy (median, patients with HR-positive, HER2-negative recurrent/stage IV breast
52.2 months vs. 40.3 months, respectively; HR, 0.73; 95% CI, 0.58– cancer, NCCN category 1, preferred regimens include a cyclin-dependent
0.92).511 kinase CDK 4/6 inhibitor with an AI; fulvestrant with or without a CDK 4/6
inhibitor; and fulvestrant with a nonsteroidal AI. The NCCN category 2A,
The reasons for the divergent outcomes in the above trials is not very preferred regimen includes nonsteroidal AI (ie, anastrozole, letrozole);
clear. The three trials discussed above had slightly different patient steroidal AI (exemestane), and selective ER modulator (tamoxifen or
populations—there were more cases of patients with no prior endocrine toremifene). For premenopausal patients, first-line endocrine treatment
exposure (with de novo stage IV metastatic disease) in the SWOG S0226 includes ovarian suppression/ablation and endocrine therapy listed above
trial compared with the FACT trial. The FACT trial included a more for postmenopausal patients or alternately with a SERM alone.
heterogeneous population of both premenopausal and postmenopausal
patients with locally advanced and metastatic disease. The SoFEA trial Preferred Regimens for Second and Subsequent Lines of Therapy for
only enrolled patients with acquired endocrine resistance (who had HR-Positive, HER2-Negative Breast Cancer
disease progression while they were receiving an AI). Further studies are Fulvestrant-Containing Regimens
needed to confirm the results of the SWOG S0226 trial.
Fulvestrant + CDK 4/6 Inhibitors: Fulvestrant in combination with a CDK
The NCCN Panel has included an AI and fulvestrant as first-line therapy 4/6 inhibitor may be offered to patients who experienced disease
(category 1) for postmenopausal patients based on the above data. progression during prior treatment with AIs with or without one line of prior
chemotherapy (category 1), because PFS was improved compared with
Monotherapy with Endocrine Agents: In postmenopausal patients there is fulvestrant alone in a phase III trial (PALOMA-3).521 The NCCN Panel
evidence supporting the use of an AI as first-line therapy for their recurrent notes that treatment should be limited to those without prior exposure to
disease.512,513 CDK 4/6 inhibitors.
Prospective randomized trials comparing the AI head-to-head have The PALOMA-3 compared the combination of palbociclib and fulvestrant
demonstrated that all AIs are the same.514 Tamoxifen is the commonly to fulvestrant in pre- or postmenopausal patients with HR-positive,
used selective estrogen receptor modulator (SERM) for premenopausal HER2-negative advanced breast cancer, whose disease progressed on

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prior endocrine therapy. Pre- or perimenopausal patients also received 1.87; P = .947) in evaluable patients (n = 89 for fulvestrant and n = 93 for
goserelin. The median PFS was 9.5 months for the combination compared anastrozole).500 An improved time to progression was seen with fulvestrant
to 4.6 months for fulvestrant (HR, 0.46; P < .000001)522 Grade 3/4 adverse compared to anastrozole (median time to progression was 23.4 months for
events of palbociclib and fulvestrant were mainly confined to neutropenia fulvestrant vs. 13.1 months for anastrozole; HR, 0.63; 95% CI, 0.39–1.00;
(in 65% of patients). P = .0496).501 This study used a higher 500 mg loading dose every 2
weeks for 3 doses and then 500 mg monthly.500 The median OS was
In the MONARCH 2 phase III trial, patients who had disease progression observed to be longer in the fulvestrant group than in the anastrozole
while receiving endocrine therapy were randomly assigned to fulvestrant group (54.1 months vs. 48.4 months; HR, 0.70; P = .041).502
with or without abemaciclib.523 Those receiving combination therapy
experienced an improved PFS relative to those receiving fulvestrant alone A phase II study of fulvestrant in postmenopausal patients with advanced
(16.4 vs. 9.3 months; HR, 0.55; 95% CI, 0.45–0.68). The ORR was higher breast cancer and disease progression following AI therapy documented a
in those receiving abemaciclib and fulvestrant (48% vs. 21%).523 In partial response rate of 14.3% with an additional 20.8% of patients
addition, an improvement was seen in OS with abemaciclib plus achieving stable disease for at least 6 months.527 The clinical benefit rates
fulvestrant compared with fulvestrant alone (46.7 vs. 37.3 months; HR, of exemestane versus fulvestrant observed in a phase III trial of
0.757; 95% CI, 0.606–0.945).524 postmenopausal patients with HR-positive advanced breast cancer who
experienced disease progression on prior nonsteroidal AI therapy were
Based on the above data that shows addition of a CDK 4/6 inhibitor to comparable (32.2% vs. 31.5%; P = .853).528 In that study, fulvestrant was
fulvestrant in patients previously exposed to prior endocrine therapy administered as a 500 mg loading dose followed by doses of 250 mg on
provides a significant improvement in median PFS, the NCCN Panel has day 14, day 28, and then monthly.528
included fulvestrant in combination with a CDK 4/6 inhibitor as a category
1 option for postmenopausal patients and premenopausal patients with Fulvestrant Plus Alpelisib: In a randomized phase III trial, patients (n =
ovarian ablation/suppression with HR-positive, HER2- negative, 572) with advanced HR-positive breast cancer and confirmed PIK3CA
recurrent/stage IV breast cancer. The Panel notes that if there is disease status had received a prior AI either for local or advanced disease.
progression while on CDK 4/6 inhibitor therapy, there are limited data to Patients were enrolled into either the PIK3CA mutant (n = 341) cohort or
support an additional line of therapy with another CDK 4/6 the PIK3CA non-mutant cohort and each cohort was randomized to
inhibitor-containing regimen. receive fulvestrant plus the phosphoinositide 3-kinase (PI3K) inhibitor,
alpelisib versus fulvestrant plus placebo. Patients with a PIK3CA mutation
Fulvestrant Monotherapy: Fulvestrant monotherapy appears to be at least receiving alpelisib showed improved PFS compared to fulvestrant alone.
as effective as anastrozole in patients whose disease progressed on At a median follow-up of 20 months PFS was 11.0 months (95% CI, 7.5–
previous tamoxifen.525,526 A randomized phase II study compared 14.5) in the alpelisib group compared with 5.7 months (95% CI, 3.7–7.4) in
anastrozole versus fulvestrant in over 200 patients with advanced breast the group that received fulvestrant alone (HR for progression or death,
cancer.500,501 In the initial analysis, fulvestrant was as effective as 0.65; 95% CI, 0.50–0.85; P < .001); in the cohort without PIK3CA-mutated
anastrozole in terms of ORR (36.0% vs. 35.5%; OR, 1.02; 95% CI, 0.56–

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tumors, the HR was 0.85 (95% CI, 0.58–1.25). In the overall population, A phase III study (BOLERO-2) randomized postmenopausal patients with
the most frequently reported grade 3 or 4 adverse events seen with HR-positive advanced breast cancer that had disease progression or
alpelisib and fulvestrant versus fulvestrant alone were hyperglycemia recurrence during treatment with a nonsteroidal AI to exemestane with or
(36.6% vs. 0.7%), rash (9.9% vs. 0.3%), and diarrhea (6.7% vs. 0.3%) without the mTOR inhibitor everolimus.533 Final results reported after
(grade 3); no diarrhea or rash of grade 4 were reported.529 median 18-month follow-up show that median PFS (by central review)
remained significantly longer with everolimus plus exemestane versus
Everolimus Plus Endocrine Therapy: Resistance to endocrine therapy in placebo plus exemestane at 11.0 versus 4.1 months, respectively (HR,
patients with HR-positive disease is frequent. One mechanism of 0.38; 95% CI, 0.31–0.48; P < .0001).532 The adverse events (all grades)
resistance to endocrine therapy is activation of the mammalian target of that occurred more frequently in those receiving everolimus included
rapamycin (mTOR) signal transduction pathway. stomatitis, infections, rash, pneumonitis, and hyperglycemia.532,533 Analysis
of safety and efficacy in the older patients enrolled in this trial showed that
A randomized phase II study estimated the efficacy of tamoxifen alone
older patients treated with an everolimus-containing regimen had similar
versus tamoxifen combined with everolimus, an oral inhibitor of mTOR, in
incidences of these adverse events, but the younger patients had more
patients with HR-positive, HER2-negative metastatic breast cancer
on-treatment deaths.534 Based on the evidence from the BOLERO-2 trial,
previously treated with an AI.530 After a median follow-up of 13 months, an
the NCCN Panel has included everolimus plus exemestane as an option
intent-to-treat analysis showed that the clinical benefit was 42.1% (95%
for patients who fulfill the entry criteria for BOLERO-2. Tamoxifen or
CI, 29.1–55.9) with tamoxifen alone and 61.1% (95% CI, 46.9–74.1) with
fulvestrant in combination with everolimus have also been included as
tamoxifen plus everolimus. An improvement in median time to progression
options. The NCCN Panel also notes that if there is disease progression
was seen when everolimus was combined with tamoxifen compared with
while on an everolimus-containing regimen, there are no data to support
tamoxifen alone. Median time to progression was 4.5 months (95% CI,
an additional line of therapy with another everolimus regimen.
3.7–8.7) with tamoxifen alone versus 8.5 months (95% CI, 6.01–13.9) with
everolimus and tamoxifen.530 Aromatase Inhibitors: AIs as monotherapy are options as subsequent-line
therapy. The three AIs (anastrozole, letrozole, and exemestane) have
In a phase III trial in postmenopausal patients with advanced, HR-positive
shown similar efficacy in the second-line setting.514,535,536 AI monotherapy
breast cancer with no prior endocrine therapy for advanced disease,
maybe be useful in patients desiring single-agent treatment, if they have
randomized subjects to letrozole with or without the mTOR inhibitor
not received an AI as first-line treatment or if they may not be suitable for
temsirolimus,531 PFS was not different between the treatment arms (HR,
combination therapy. Patients who have received a prior nonsteroidal AI
0.89; 95% CI, 0.75–1.05; log-rank P = .18).
may benefit from a steroidal AI as a subsequent line of therapy or vice
The results of this trial differ from that of the BOLERO-2 trial (described versa.
below). The reasons for the differences in the outcomes of these two
randomized phase III studies531,532 is uncertain, but may be related to the
issues of patient selection and extent of prior endocrine therapy.

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Selective ER Modulator: An analysis of two randomized studies of first-line analysis, at 18 months, median OS was 22.3 months (95% CI, 17.7–not
treatment with anastrozole followed by second-line tamoxifen and vice reached).542 Diarrhea was the most frequent adverse event reported in
versa showed that tamoxifen is effective as a second-line option.537 90.2% of patients. Other common adverse events were fatigue (65.2%),
nausea (64.4%), and decreased appetite (45.5%). Grade 3 and 4
NCCN Recommendations for Second-line Therapy: For postmenopausal neutropenia occurred in 26.9% of patients.542 The NCCN Panel has
patients with HR-positive, HER2-negative recurrent/stage IV breast included single-agent abemaciclib as an option for those with disease
cancer, the preferred options available include fulvestrant with a CDK 4/6 progression on prior endocrine therapy and prior chemotherapy in the
inhibitor (ie, palbociclib, ribociclib, abemaciclib) (category 1), or for those metastatic setting.
with tumor PIK3CA mutations, fulvestrant with alpelisib; everolimus with
either an AI, tamoxifen, or fulvestrant; monotherapy with fulvestrant; Systemic Therapy for Stage IV or Recurrent HR-Negative, HER2-Positive
nonsteroidal or steroidal AI; or SERM. Estrogen receptor 1 (ESR1) Breast Cancer
activating mutations are frequently detected in patients with prior exposure For patients with HER2-positive, HR-negative recurrent/stage IV breast
to AIs. Tumors with these mutations are generally resistant to both AIs and cancer, the treatment approach is HER2-targeted therapy in combination
tamoxifen. Certain tumors with these mutations retain sensitivity to with systemic chemotherapy. The NCCN Panel notes that an
fulvestrant. All may benefit by adding one of the following to fulvestrant: a FDA-approved biosimilar is an appropriate substitute for trastuzumab.
CDK 4/6-inhibitor, or an mTOR-inhibitor, or alpelisib, if the tumor has Also, trastuzumab and hyaluronidase-oysk injection for subcutaneous use
PIK3CA mutation. may be substituted for trastuzumab. This subcutaneous option has
different dosage and administration instructions compared to intravenous
Regimens Useful in Certain Circumstances for Therapy for HR-Positive, trastuzumab. Doses and schedules of representative regimens for use in
HER2-Negative Breast Cancer HER2-positive metastatic breast cancer are also included in NCCN
Megestrol acetate,512,538-540 estradiol541 androgens such as Guidelines.
fluoxymesterone, and single-agent abemaciclib have been listed as
Patients with disease progression while being treated with HER2-targeted
options useful in certain circumstances.
therapy should be offered an additional line of treatment with a
The phase II MONARCH 1 trial evaluated the activity of abemaciclib as a HER2-targeted therapy since it is beneficial to continue suppression of the
single agent in patients (n = 132) with refractory HR-positive, HER2 pathway. The choice of the HER2-targeted therapy will depend on
HER2-negative metastatic breast cancer who had disease progression previously administered therapy, relapse-free interval, and patients’
while on endocrine therapy and already received multiple systemic preference and access.
therapies (average of three prior systemic regimens).542 Ninety percent of
The optimal sequence of available HER2-targeted therapies and the
patients had visceral disease and 50.8% had more than three sites of
optimal duration of HER2-targeted therapy for recurrent/stage IV breast
metastases.542 Single-agent abemaciclib induced a partial response in 26
cancer is currently unknown. The NCCN Panel recommends continuing
patients (19.7%) and demonstrated an ORR of 19.7% (95% CI, 13.3–
HER2-targted therapy until progression/unacceptable toxicity.
27.5).542 Median PFS was 6 months (95% CI, 4.2–7.5). At the final
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Preferred Regimens for Stage IV/Recurrent HER2-Positive Breast Cancer Phase II trials have also found activity and tolerability for pertuzumab,
A randomized, double-blind, phase III study (CLEOPATRA) compared the pertuzumab with trastuzumab, and for other regimens combining
efficacy and safety of pertuzumab in combination with trastuzumab and pertuzumab and trastuzumab together with other active cytotoxic agents
docetaxel versus trastuzumab and docetaxel as first-line treatment for 808 (ie, paclitaxel, vinorelbine).548,549,550 Phase III trials of pertuzumab plus
patients (n = 808) with HER2-positive metastatic breast cancer.543 This chemotherapy without trastuzumab have not been reported.
trial included patients (about 10%) who had previously received
trastuzumab in the adjuvant or neoadjuvant setting. At a median follow-up The NCCN Panel recommends pertuzumab plus trastuzumab in
of 19 months, the addition of pertuzumab to docetaxel plus trastuzumab combination with a taxane as a preferred option for first-line treatment of
resulted in improvement in PFS compared with placebo (median, 18.5 vs. patients with HER2-positive metastatic breast cancer. Pertuzumab plus
12.4 months; HR, 0.62; 95% CI, 0.51–0.75; P < .001).543 At a median trastuzumab in combination with docetaxel is an NCCN category 1 and in
follow-up of 30 months the results showed a statistically significant combination with paclitaxel is an NCCN category 2A recommendation.
improvement in OS in favor of the pertuzumab-containing regimen, with a
Other Regimens for Stage IV/Recurrent HER2-Positive Breast Cancer
34% reduction in the risk of death (HR, 0.66; 95% CI, 0.52–0.84; P =
.0008).544 The most common adverse reactions reported in the Ado-trastuzumab emtansine (T-DM1): T-DM1 is an antibody-drug
pertuzumab group compared to the control group were diarrhea (67% vs. conjugate that stably links the HER2-targeting property of trastuzumab to
46%), rash (34% vs. 24%), mucosal inflammation (27% vs. 20%), febrile the cytotoxic activity of the microtubule-inhibitory agent DM1 (derivative of
neutropenia (14% vs. 8%), and dry skin (10% vs. 4%). Peripheral edema maytansine).
and constipation were greater in the control group.543 Cardiac adverse
events or left ventricular systolic dysfunction were reported slightly more In a phase III trial (MARIANNE), 1095 patients with locally advanced or
frequently in the control group.545 HRQOL was not different in the two metastatic breast cancer were randomized to first-line treatment with
treatment groups.546 In the PERUSE study, patients (n = 1436) with T-DM1 with or without pertuzumab or trastuzumab plus a taxane. The
advanced HER2-positive breast cancer and no prior systemic therapy primary endpoints were safety and PFS assessed by independent review.
(except endocrine therapy) received docetaxel, paclitaxel, or The PFS for T-DM1 with pertuzumab was found to be non-inferior to
nab-paclitaxel with trastuzumab and pertuzumab until disease progression trastuzumab and a taxane (15.2 and 13.7 months, respectively; HR, 0.87;
or unacceptable toxicity. The preliminary results after 52 months of median 97.5% CI, 0.69–1.08; P = .14).551 The PFS for T-DM1 alone was
follow-up show that median PFS was comparable between docetaxel, non-inferior to trastuzumab plus a taxane (14.1 and 13.7, respectively; HR,
paclitaxel, and nab-paclitaxel (median PFS reported was 19.6, 23.0, and 0.91; 97.5% CI, 0.73–1.13; P = .31).551 The incidence of grade 3–5
18.1 months with docetaxel, paclitaxel, and nab-paclitaxel, respectively).547 adverse events was 54.1%, 45.4%, and 46.2% in the trastuzumab plus a
Compared with docetaxel-containing therapy, paclitaxel-containing therapy taxane arm, T-DM1 arm, and T-DM1 plus pertuzumab arm, respectively.
was associated with more neuropathy (31% vs. 16%), but less febrile HRQOL was maintained for a longer duration with a median of 7.7 months
neutropenia (1% vs. 11%) and mucositis (14% vs. 25%). for T-DM1 (HR, 0.70; 95% CI, 0.57–0.86) and a median of 9 months for

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T-DM1 plus pertuzumab (HR, 0.68; 95% CI, 0.55–0.84) compared with a trastuzumab-containing regimen.559-561 However, the optimal duration of
median of 3.9 months for trastuzumab and a taxane.551 trastuzumab in patients with long-term control of disease is unknown.

Based on the MARIANNE trial data demonstrating T-DM1 and T-DM1 with Pertuzumab is active in patients beyond the first-line setting. The results of
pertuzumab being non-inferior, with better QOL compared with a multicenter, open-label, single-arm, phase II study (n = 66) show that the
trastuzumab plus a taxane and possibly better tolerated for some patients, combination of pertuzumab and trastuzumab is active and well tolerated in
551 the NCCN Panel included T-DM1 as an option for treatment of patients patients with HER2-positive metastatic breast cancer that has progressed
with HER2-positive metastatic breast cancer. Pertuzumab, trastuzumab, on prior trastuzumab therapy.562 The trial reported an ORR of 24.2% (16
and a taxane, however, remains the preferred first-line regimen for patients out of 66). The median PFS time observed with pertuzumab and
HER2-positive metastatic disease based on data demonstrating improved trastuzumab combination was 15.5 months (range, 0.9–17.0 months; 80%
OS compared to trastuzumab and a taxane. TDM-1 as first-line therapy CI, 18–31 months).562 The reported median duration of response with the
should be considered only in those not suitable for the preferred treatment. combination was 5.8 months (range, 2.9–15.3 months).562

First-line trastuzumab in combination with selected chemotherapy552 are To determine whether the clinical benefit seen in the study was from
additional options for patients with HER2-positive metastatic breast pertuzumab alone or was a result of the combined effect of pertuzumab
cancer. Randomized trials demonstrate benefit from adding trastuzumab and trastuzumab, a cohort of patients (n = 29) whose disease progressed
to other agents including paclitaxel with or without carboplatin,552-555 during prior trastuzumab-based therapy received pertuzumab
docetaxel,553 and vinorelbine,553 for patients with HER2-positive metastatic monotherapy until progressive disease or unacceptable toxicity. Of these,
disease. In addition, the combination of trastuzumab and capecitabine has patients with disease progression (n = 17) continued to receive
also shown efficacy as a first-line trastuzumab-containing regimen in this pertuzumab with the addition of trastuzumab. In the 29 patients who
setting.556,557 The NCCN Panel believes the 27% frequency of significant received pertuzumab monotherapy, the ORR and clinical benefit rate
cardiac dysfunction in patients treated with the combination of reported were 3.4% and 10.3%, respectively, whereas in the patients who
trastuzumab and doxorubicin/cyclophosphamide chemotherapy in the received dual blockade after disease progression while on pertuzumab,
metastatic setting is too high for use of this combination outside the the ORR and clinical benefit rate were 17.6% and 41.2%, respectively.563
confines of a prospective clinical trial.552,557,558
According to the NCCN Panel, for patients with disease progression after
In those with disease progression on first-line trastuzumab-containing treatment with trastuzumab-based therapy without pertuzumab, a line of
regimens, the NCCN Panel recommends continuation of HER2 blockade. therapy containing both trastuzumab plus pertuzumab with or without a
This recommendation also applies to patients who are diagnosed with cytotoxic agent (such as vinorelbine or taxane) may be
HER2-positive metastatic disease after prior exposure to trastuzumab in considered. Further research is needed to determine the ideal sequencing
the adjuvant setting. Several trials have demonstrated benefit of strategy for HER2-targeted therapy.
continuation of trastuzumab therapy following disease progression on a

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NCCN Guidelines Version 4.2024

Breast Cancer

T-DM1 also has also shown activity in the second-line setting. A 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%). Based on this
randomized, international, multicenter, open-label, phase III study study and the approval from the FDA, the NCCN Panel has included this
(EMILIA) evaluated the safety and efficacy of T-DM1 compared with as an option for HER2-positive metastatic disease noting that it is
lapatinib plus capecitabine for HER2-positive patients with locally indicated in patients after two or more lines of prior HER2-targeted therapy
advanced breast cancer or metastatic breast cancer previously treated in the metastatic setting and contraindicated for those with a history of or
with trastuzumab and a taxane.564 The primary endpoints of this study active ILD.
were PFS, OS, and safety. T-DM1 demonstrated a statistically significant
improvement in both primary endpoints of PFS and OS. PFS (assessed by Lapatinib in combination with capecitabine or trastuzumab are options for
independent review) was significantly improved with T-DM1 with median patients with HER2-positive disease following disease progression on a
PFS of 9.6 months vs. 6.4 months with lapatinib plus capecitabine; HR for trastuzumab-containing regimen.
progression or death from any cause was 0.65 (95% CI, 0.55–0.77; P <
A phase III study compared lapatinib plus capecitabine with capecitabine
.001). At the first interim analysis, T-DM1 also demonstrated significant
alone in patients with advanced or metastatic breast cancer refractory to
improvement in OS. The stratified HR for death from any cause with
trastuzumab in the metastatic setting and with prior treatment with an
T-DM1 versus lapatinib plus capecitabine was 0.62 (95% CI, 0.48–0.81; P
anthracycline and a taxane in either the metastatic or adjuvant setting.566
= .0005).564 Rates of grade 3 or 4 adverse events were higher with
Time to progression was increased in the group receiving combination
lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The
therapy when compared with the group receiving capecitabine
incidences of thrombocytopenia and increased serum aminotransferase
monotherapy (8.4 months vs. 4.4 months; HR, 0.49; 95% CI, 0.34–0.71; P
levels were higher with T-DM1 (frequency >25%), whereas the incidences
< .001). The patients who had disease progression on monotherapy were
of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were
allowed to cross over to the combination arm. This resulted in insufficient
higher with lapatinib plus capecitabine.564
power to detect significant differences in OS; an exploratory analysis
A phase II single-arm study evaluated fam-trastuzumab deruxtecan-nxki, a demonstrated a trend toward a survival advantage with lapatinib plus
HER2 antibody conjugated with a topoisomerase I inhibitor, in adults (n = capecitabine.567 The analysis reported a median OS of 75.0 weeks for the
184) with pathologically documented HER2-positive metastatic breast combination arm and 64.7 weeks for the monotherapy arm (HR, 0.87; 95%
cancer who had received multiple previous treatments including treatment CI, 0.71–1.08; P = .210).567
with T-DM1.565 After a median duration of follow-up of 11.1 months (range
Results from a phase III trial in which patients with heavily pretreated
0.7–19.9), the median response duration with fam-trastuzumab metastatic breast cancer and disease progression on trastuzumab therapy
deruxtecan-nxki was 14.8 months (95% CI, 13.8–16.9), and the median
randomly assigned to trastuzumab plus lapatinib or lapatinib monotherapy
PFS was 16.4 months (95% CI, 12.7–not reached).565 Most commonly showed that PFS was increased from 8.1 weeks to 12 weeks (P = .008)
reported adverse events (grade 3 or higher) were a decreased neutrophil with the combination.568 The OS analysis data showed that lapatinib plus
count (20.7%), anemia (8.7%), nausea (7.6%), and fatigue (6%).565 trastuzumab improved median survival by 4.5 months, with median OS of
Interstitial lung disease (ILD) was reported in 13.6% of the patients (grade 14 months for the combination therapy and 9.5 months for lapatinib alone

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NCCN Guidelines Version 4.2024

Breast Cancer

(HR, 0.74; 95% CI, 0.57–0.97; P = .026). 569 This improvement in OS months were 90.2% versus 87.5% with neratinib + capecitabine compared
analysis included patients who were initially assigned to monotherapy and with 72.5% versus 66.7% for lapatinib in combination with capecitabine
crossed over to receive combination therapy at the time of progression.569 (HR, 0.88; 95% CI, 0.72–1.07; P = .2086). Diarrhea was the most
Based on the absence of data, the Panel does not recommend the frequently reported side effect in the NALA trial in both arms, but a higher
addition of chemotherapy to the trastuzumab and lapatinib combination. rate was observed in patients in the neratinib group (any grade diarrhea,
83% vs. 66%; grade 3/4 diarrhea, 24% vs. 13%).
In a phase II trial of patients (n = 49) with progressive, HER2-positive
disease and brain metastases (92% received CNS surgery and/or Based on the results of the NALA trial and the recent FDA approval,
radiotherapy),570 patients were treated with capecitabine plus neratinib, NCCN has included neratinib plus capecitabine as a category 2A option in
a second-generation (irreversible) pan-HER tyrosine kinase inhibitor (TKI) this setting.
of the tyrosine kinase domains of EGFR, HER2, and HER4. The patients
Systemic Therapy for Recurrent or Stage IV HR-Positive, HER2-Positive
were separated based on prior lapatinib treatment. The combination
Breast Cancer
therapy resulted in a CNS ORR of 49% (95% CI, 32%–66%), among
Patients with stage IV or recurrent disease characterized by tumors that
lapatinib-naïve patients, and 33% (95% CI, 10%–65%) among those with
are HR-positive, HER2-positive tumors have the option of receiving
prior lapatinib treatment.570 Median PFS and OS among lapatinib-naïve
HER2-directed therapy as a component of their treatment plan. Options
patients was 5.5 and 13.3 months, and 3.1 and 15.1 months among those
include treatment with a HER2-targeted therapy plus chemotherapy or
with prior lapatinib treatment. Grade 3 diarrhea occurred in 29% of
endocrine therapy alone or in combination with HER2-targeted therapy.
patients.570
Endocrine therapy alone or in combination with HER2-targeted therapy is
A prospective randomized phase III trial (NALA) randomized patients (n = a less toxic approach compared with HER2-targeted therapy combined
621) with HER2-positive breast cancer to neratinib in combination with with chemotherapy. Premenopausal patients treated with HER2-targeted
capecitabine or lapatinib plus capecitabine until disease progression.571 All therapy and endocrine therapy should receive ovarian suppression or
enrolled patients received a least two lines of prior HER2-targeted ablation.
treatment in the metastatic setting. Approximately 30% had received ≥3
Adding trastuzumab or lapatinib to an AI has demonstrated a PFS
prior treatment lines. About a third of all patients had received prior
advantage compared with AI alone in postmenopausal patients with stage
treatment with trastuzumab, pertuzumab, and T-DM1.
IV or recurrent HR-positive, HER2-positive tumors.
The ORR (32.8% vs. 26.7%; P = .1201), clinical benefit rate (44.5% vs.
In the TAnDEM study, postmenopausal patients (n = 207) with metastatic
35.6%; P = .0328), and median duration of response (8.5 vs. 5.6 months)
HR-positive and HER2-positive tumors were randomized to receive
all favored the neratinib arm. Fewer patients required intervention for CNS
anastrozole alone or anastrozole plus trastuzumab.572 Compared with
metastases with neratinib. The risk of progression was reduced by 24% in
single-agent anastrozole, an improvement in PFS was seen with
the neratinib group (HR, 0.76; 95% CI, 0.63–0.93; P = .0059). There was a
combination therapy (4.8 vs. 2.4 months; HR, 0.63; 95% CI, 0.47–0.84; P
non-significant trend towards improved survival. The OS rates at 6 and 12

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NCCN Guidelines Version 4.2024

Breast Cancer

= .0016). The combination was associated with a higher incidence of was stopped, endocrine therapy may be added to the trastuzumab plus
toxicities (all grades), fatigue (21% vs. 9%), diarrhea (20% vs. 8%), pertuzumab.
vomiting (21% vs. 4%), and pyrexia (18% vs. 7%); serious (grade 3/4)
toxicities were rare in both treatment arms. In the ALTERNATIVE trial, postmenopausal patients (n = 355) with
HER2-positive, HR-positive metastatic breast cancer were randomized to
The phase III eLEcTRA trial studied the efficacy and safety of trastuzumab receive lapatinib plus trastuzumab plus an AI, lapatinib plus an AI, or
plus letrozole in patients (n = 93) with HER2-positive and HR-positive trastuzumab plus an AI without chemotherapy.576 All patients in the trial
metastatic breast cancer. Median time to progression was 3.3 months with received prior trastuzumab and prior endocrine therapy, either in the
letrozole and 14.1 months with trastuzumab plus letrozole. The results are adjuvant or metastatic disease setting. An AI in combination with lapatinib
consistent with the TAnDEM trial; however, due to smaller numbers of plus trastuzumab demonstrated a significant increase in PFS compared
patients enrolled in this trial, this was not statistically significant (HR, 0.67; with trastuzumab without lapatinib (11 vs. 5.7 months; HR, 0.62; 95% CI,
95% CI, 0.35–1.29; P = .23).573 0.45–0.88, P = .0064).576 The most common adverse events with the
combination compared with trastuzumab or lapatinib monotherapy were
In a phase III study of postmenopausal patients (n = 219) with HER2- diarrhea (69%, 9%, 51%), rash (36%, 2%, 28%), nausea (22%, 9%, 22%),
positive and HR-positive disease, first-line treatment with lapatinib plus and paronychia (30%, 0%, 15%).
letrozole reduced the risk of disease progression compared to treatment
with letrozole alone (median PFS, 8.2 months vs. 3.0 months; HR, 0.71; The NCCN Panel has also included other combinations of available
95% CI, 0.53–0.96; P = .019).574 The combination of letrozole plus endocrine therapies such as fulvestrant or tamoxifen with trastuzumab as
trastuzumab was associated with a higher rate of grade 3 or grade 4 options for HR-positive and HER2-positive metastatic disease. These
toxicities, including diarrhea (10% vs. 1%) and rash (1% vs. 0%).574 options would be mostly considered after completion of chemotherapy
plus HER2-therapy or in a few patients with indolent or asymptomatic
In the randomized phase II study (PERTAIN), postmenopausal patients (n disease based on the need for continuing HER2-targeted therapy for
= 258) were randomly assigned to either first-line pertuzumab plus disease control. The selection of appropriate endocrine therapy would
trastuzumab and an AI (anastrozole or letrozole) or trastuzumab plus an depend on agents the patient has already received.
AI. There was an improvement in PFS with the three-drug combination
(18.9 vs. 15.8 months; HR, 0.65; 95% CI, 0.48–0.89).575 Grade 3 or higher Systemic Therapy for Recurrent or Stage IV Disease with Germline
adverse events observed were higher trastuzumab and pertuzumab BRCA1/2 Mutations
versus pertuzumab alone (50% vs. 39%). Of note, about half of patients About 5% of all patients with breast cancer carry the germline breast
received induction therapy with a taxane for 18 to 24 weeks prior to the cancer susceptibility gene (BRCA) mutations, and rates of these mutations
initiation of endocrine therapy. Based on the results of the PERTAIN are higher among those with HER2-negative disease. 577,578
trial,575 the NCCN Panel notes that if treatment was initiated with
PARP Inhibitors: The phase III OlympiAD trial randomized patients (n =
chemotherapy and trastuzumab plus pertuzumab, and the chemotherapy
302) with metastatic breast cancer harboring the germline BRCA

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Breast Cancer

mutations to the PARP inhibitor, olaparib (n = 205) or physician’s choice (n indicated in HER2-negative disease, the NCCN Panel supports use in any
= 97) of non-platinum chemotherapy (capecitabine, eribulin, or breast cancer subtype associated with germline BRCA1/2 mutations.
vinorelbine).579 An improvement in PFS was seen in those receiving
olaparib relative to those receiving chemotherapy [7.0 vs. 4.2 months; HR, Platinums: The phase III TNT trial compared docetaxel with carboplatin in
0.58; 95% CI, 0.43–0.80; P < .001].579 The study, included all subtypes— the first-line setting in patients (n = 376) with triple-negative breast cancer.
those with HR-positive, HER2-negative and -positive, and triple-negative In the unselected population, carboplatin was not more active than
disease. The PFS improvements noted with olaparib were noted in all docetaxel (ORR, 31.4% vs. 34.0%; P = .66). 582 Patients with a germline
subtypes and were greatest in the triple-negative population. Subsequent BRCA1/2 mutation had a significantly better response to carboplatin than
follow-up did not show a statistically significant difference in OS between docetaxel (ORR, 68.0% vs. 33.3%, absolute difference, 34.7%; P = .03).
treatment arms and the study was also not powered to evaluate OS. The
582
PFS was also improved with carboplatin treatment in patients with
median OS with olaparib compared with treatment of physician’s choice a germline BRCA1/2 mutation (median PFS, 6.8 months vs. 4.4 months);
was 19.3 months versus 17.1 months, respectively (HR, 0.90; 95% CI, no difference was found in OS. However, patients with somatic BRCA1/2
0.66–1.23; P = .513).580 The QOL was significantly better in the olaparib mutation in the tumor DNA did not appear to have the same advantage.
arm. It is interesting to note that patients who had not received prior
For those with triple-negative recurrent/stage IV breast cancer and
chemotherapy in the metastatic setting achieved a 7.9-month longer
germline BRCA1/2 mutations, the NCCN Panel has included platinum
median OS with olaparib compared with treatment of physician’s choice.580
agents (cisplatin and carboplatin) as preferred treatment options. It is
The phase III EMBRACA trial of patients with advanced breast cancer unknown how PARP inhibitors compare with platinums in this setting.
harboring the germline BRCA mutations and no prior exposure to a PARP
Systemic Therapy for PD-L1–Positive, Triple-Negative, Recurrent or Stage
inhibitor, were randomized to talazoparib (n = 287) or to physician’s choice IV Disease
of single-agent chemotherapy (n = 144).581 The median PFS among In a randomized trial (IMpassion130), patients (n = 902) with triple-
patients in the talazoparib group was longer than in the control group (8.6 negative breast cancer who had not received treatment in the metastatic
months [95% CI, 7.2–9.3] vs. 5.6 months [95% CI, 4.2–6.7]; HR for setting were randomized to the programmed death ligand 1 (PD-L1)
disease progression or death, 0.54; 95% CI, 0.41–0.71; P < .001).581 inhibitor, atezolizumab plus albumin-bound paclitaxel, or placebo plus
albumin-bound paclitaxel.583
Based on the results of the above phase III trials, the two FDA-approved
PARP inhibitors, olaparib and talazoparib, are included as category 1, All patients enrolled in the trial had to have completed previous
preferred options for those with germline BRCA1/2 mutations. The NCCN chemotherapy (preoperative or adjuvant) at least 12 months before
Panel recommends assessing for germline BRCA1/2 mutations in all randomization and not received any chemotherapy in the metastatic
patients with recurrent or metastatic breast cancer to identify candidates setting. At a median follow-up of 12.9 months, there was a statistically
for PARP inhibitor therapy. While olaparib and talazoparib are FDA- significant difference in PFS in those receiving atezolizumab plus
albumin-bound paclitaxel compared to those receiving placebo plus

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NCCN Guidelines Version 4.2024

Breast Cancer

albumin-bound paclitaxel (7.2 vs. 5.5 months; HR for progression or death, higher rates of objective response and longer time to progression, in
0.80; 95% CI, 0.69–0.92), and a nonsignificant trend towards improved OS comparison to single-agent chemotherapy. Combination chemotherapy is,
(21.3 vs. 17.6 months; HR for death, 0.84; 95% CI, 0.69–1.02).583 however, associated with an increase in toxicity and is of little survival
However, in a planned subset analysis of patients with PD-L1–expressing benefit.586-590 Furthermore, administering single agents sequentially
tumors, treatment with atezolizumab plus albumin-bound decreases the likelihood that dose reductions will be needed. Thus, the
paclitaxel showed statistically significant improvement in PFS (7.5 vs. 5 NCCN Panel finds no compelling evidence that combination
months; HR, 0.62; 95% CI, 0.49–0.78) and OS (25 vs. 15.5 months; HR, chemotherapy is superior to sequential single agents. Therefore,
0.62; 95% CI, 0.45–0.86).583 Grade 3 or higher adverse events occurred in sequential monotherapy is preferred and combination therapy is useful in
48.7% of patients receiving atezolizumab plus albumin-bound patients with rapid clinical progression or need for rapid symptom and/or
paclitaxel versus 42.2% receiving placebo plus albumin-bound paclitaxel. disease control.
Grade 3 or 4 neuropathy was more frequently seen among those receiving
atezolizumab (5.5% vs. 2.7%). There were three treatment-related deaths Usually the first-line regimens are given until progression or unacceptable
among the patients who received atezolizumab, consistent with other toxicity. Considering what is unacceptable toxicity and considering no
studies of checkpoint inhibitors. Adverse events led to treatment further cytotoxic therapy should be decided together with the patient.
discontinuation in 16% of patients in the atezolizumab arm versus 8% in Adverse effects may require dose reduction and cessation of
the control arm.583 PD-L1–positive expression in tumor-infiltrating immune chemotherapy prior to disease progression.
cells of ≥1% has been associated with a better outcome with PD-L1
The NCCN Panel recommends considering scalp cooling to reduce
inhibitor treatment.584 A subsequent 18-month follow-up analysis
incidence of chemotherapy-induced alopecia for patients receiving
confirmed PFS and OS benefits among those with PD-L1–expressing
chemotherapy. The data on efficacy of scalp cooling is mainly from the
tumors.585 Atezolizumab plus albumin-bound paclitaxel is included as a
adjuvant setting and also show that results may be less effective with
preferred option for those with advanced triple-negative breast cancer with
anthracycline-containing regimens.591-595
PD-L1 expression in ≥1% tumor-infiltrating immune cells.
A meta-analysis showed favorable impact on OS by prolonging treatment
Systemic Chemotherapy for Recurrent or Stage IV Disease
until disease progression.596 In this analysis, data from four studies
Patients with HR-negative tumors not localized to the bone or soft tissue
involving 666 patients indicated that median OS was increased by 23%
only, or that are associated with symptomatic visceral metastasis
(95% CI, 9–38%; P = .01) in patients receiving longer durations of
irrespective of HR- or HER-status, or that have HR-positive tumors that
chemotherapy versus a limited number of cycles.596 In a systematic
are refractory to endocrine therapy should receive systemic
review, longer durations of chemotherapy demonstrated a marginal
chemotherapy.
increase in OS (HR, 0.91; 95% CI, 0.84–0.99) and a significant
A variety of chemotherapy regimens are felt to be appropriate, as outlined improvement in PFS (HR, 0.66; 95% CI, 0.6–0.72), compared with shorter
in the treatment algorithm. Combination chemotherapy generally provides durations.590

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NCCN Guidelines Version 4.2024

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A more recent study of patients (n = 420) with HER2-negative, advanced Paclitaxel can be administered weekly (80 mg/m2)598 or every 3 weeks
breast cancer showed that intermittent first-line treatment with paclitaxel (175 mg/m2).599 A meta-analysis of randomized controlled trials that
plus bevacizumab was not inferior to continuous treatment. The median compared weekly and every-3-week taxane regimens in advanced breast
overall PFS for intermittent versus continuous treatment was 7.4 months cancer showed that compared with every-3-week treatment, weekly
and 9.7 months, respectively (HR, 1.17; 95% CI, 0.88–1.57). Median OS administration of paclitaxel resulted in an improvement in OS (HR, 0.78;
was 17.5 months versus 20.9 months for intermittent versus continuous 95% CI, 0.67–0.89).600
treatment (HR, 1.38; 95% CI, 1.00–1.91).597
Doxorubicin (60–75 mg/m2) every 3 weeks, or 20 mg/m2 weekly has
Determining the duration of chemotherapy in an individual patient typically shown an ORR between 30% to 47%.601-604 Liposomal doxorubicin (50
depends on the efficacy and tolerability and shared decision-making mg/m2 every 4 weeks) has been shown to have efficacy similar to
between the treating physician and patient. doxorubicin (60 mg/m2 every 3 weeks).605 It has also been shown to have
efficacy in the second-line setting for patients with metastatic breast
Most patients will be candidates for multiple lines of systemic therapy for cancer.605 Compared with doxorubicin, liposomal doxorubicin has a less
palliation. At each reassessment clinicians should assess the value of frequent dosing schedule, decreased risk of cardiotoxicity (7% vs. 26%;
ongoing treatment, the risks and benefits of an additional line of systemic HR, 3.16; 95% CI, 1.58–6.31), decreased rate of nausea (37% vs. 53%)
therapy, patient performance status, and patient preferences through a and vomiting (19% vs. 31%), lower rates of alopecia (20% vs. 66%), and
shared decision-making process. lower rates of neutropenia (4% vs. 10%).605 However, compared with
doxorubicin it was associated with a higher rate of palmar-plantar
Preferred Chemotherapy Regimens for Stage IV or Recurrent Metastatic
erythrodysesthesia (48% vs. 2%), stomatitis (22% vs. 15%), and mucositis
Disease
(23% vs. 13%).605
The NCCN Panel has classified the chemotherapy agents into three
categories: preferred, other recommended, and useful in certain The benefit of capecitabine as a treatment option for patients with
circumstances. The treatment decision should be individualized and metastatic breast cancer has been demonstrated in multiple phase II trials.
consider previous therapies, pre-existing comorbidities, nature of the Results of one study of patients (n = 126) treated with capecitabine
disease, toxicity profiles, patient preferences, and in some cases access showed an ORR of 28%, median time to progression of 4.9 months, and
to agents. median OS of 15.2 months (95% CI, 13.5–19.6 months).606 In another
study, patients (n = 95) were randomized to receive capecitabine or
Among preferred single agents, the NCCN Panel has included taxanes
cyclophosphamide, methotrexate, and fluorouracil (CMF).607 Treatment
(paclitaxel), anthracyclines (doxorubicin and liposomal doxorubicin),
with single-agent capecitabine resulted in a higher ORR compared with
antimetabolites (capecitabine and gemcitabine), microtubule inhibitors
CMF (30% vs. 16%). The median time to progression and OS were similar
(eribulin and vinorelbine), and platinum agents for patients with triple-
in both groups.607
negative tumors and germline BRCA1/2 mutations.

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Eribulin is a non-taxane microtubule inhibitor used for the treatment of (95% CI, 5.7–10.2 months), and 22.0 months (95% CI, 15.6–27.0 months)
patients with metastatic breast cancer who have previously received at in the first-line setting;619 12% (95% CI, 4.7%– 26.5%), 10.4 months, and
least two chemotherapeutic regimens for the treatment of metastatic 7.9 months for the taxane-resistant patients;620 and 11.5% (95% CI, 6.3%–
disease. Prior therapy should have included an anthracycline and a taxane 18.9%), 5.7 months, and 8.6 months for the patients previously treated
in either the adjuvant or metastatic setting. In a phase III trial, patients (n = with an anthracycline, a taxane, and capecitabine.621 In the study by Perez
762) with metastatic breast cancer were randomized 2:1 to eribulin or et al,621 grade 3/4 treatment-related toxicities included peripheral sensory
treatment of physician’s choice. OS was improved in patients assigned to neuropathy (14%) and neutropenia (54%).
eribulin (median 13.1 months; 95% CI, 11.8–14.3) compared with those
receiving other treatments (10.6 months, 9.3–12.5), a 19% statistically The NCCN Panel has included combination chemotherapy regimens as
significant risk reduction (HR, 0.81; 95% CI, 0.66–0.99; P = .041).608 useful in certain circumstances. The combination regimen options include
doxorubicin/cyclophosphamide (AC)622,623; epirubicin/cyclophosphamide
A phase III trial compared eribulin with capecitabine in patients with (EC)624; docetaxel/capecitabine588; gemcitabine/paclitaxel (GT)625;
metastatic breast cancer and showed that both treatments were similar cyclophosphamide/methotrexate/fluorouracil (CMF)626; gemcitabine/
with respect to OS and PFS.609 The median PFS times for eribulin and carboplatin627-629; carboplatin with paclitaxel or albumin-bound paclitaxel630-
capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 632; and paclitaxel/bevacizumab.633-635

0.93–1.25; P = .30), and the OS with eribulin versus capecitabine was

15.9 months versus 14.5 months (HR, 0.88; 95% CI, 0.77–1.00). 609 For the doublet regimens that are included, randomized phase III trials
have shown that the ORR with first-line AC treatment ranges from 47% to
In addition to the above, gemcitabine610 and vinorelbine are both active as 54% and OS is around 20 months.622,623 For first-line EC, a phase III trial
a single agents even in heavily pretreated patients with metastatic breast reported the ORR of 55%, PFS of 7.1 months, and OS of 14 months.624
cancer.611-613 For first-line capecitabine/docetaxel, a phase III trial reported an ORR of
53% and time to progression of 11 months.636 In the second-line setting,
Among other recommended single agents, the NCCN Panel has included another phase III trial compared the efficacy and tolerability of
taxanes (docetaxel,614 albumin-bound paclitaxel615-617), anthracyclines capecitabine/docetaxel therapy in anthracycline-pretreated patients and
(epirubicin 618), and ixabepilone619-621 as other recommended regimens. showed significantly superior efficacy in time to disease progression (HR,
0.652; 95% CI, 0.545–0.780; P = .0001; median, 6.1 vs. 4.2 months), OS
Ixabepilone as monotherapy has been evaluated in several phase II trials
(HR, 0.775; 95% CI, 0.634–0.947; P = .0126; median, 14.5 vs. 11.5
of patients with metastatic breast cancer: in a first-line setting in patients
months), and ORR (42% vs. 30%, P = .006) compared with single-agent
previously treated with anthracycline chemotherapy 619; in patients with
docetaxel.588
taxane-resistant metastatic breast cancer620; and in patients with
advanced breast cancer resistant to an anthracycline, a taxane, and Combination chemotherapy regimens containing a platinum agent or a
capecitabine.621 In the phase II trials, ORR, median duration of response, taxane have been shown to be efficacious in patients with metastatic
and median OS duration were 41.5% (95% CI, 29.4%–54.4%), 8.2 months triple-negative breast cancer. A randomized phase II study compared the

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addition of iniparib to gemcitabine/carboplatin versus treatment with docetaxel and bevacizumab or docetaxel and placebo.637
gemcitabine/carboplatin in patients with triple-negative breast cancer who This trial also documented increased PFS in the arm containing
had received no more than two prior chemotherapies. ORR was similar in bevacizumab (10.1 months vs. 8.2 months with docetaxel alone; HR, 0.77;
both groups, 30.2% (95% CI, 24.6–35.8) with gemcitabine/carboplatin,627 P = .006). An additional trial, RIBBON-1, combined bevacizumab with
and the median OS was 11.1 months with gemcitabine/carboplatin (HR, capecitabine, with a taxane (docetaxel, nab-paclitaxel), with anthracyclines
0.88; 95% CI, 0.69–1.12).627 (FEC, CAF, AC, or EC), or with the same chemotherapy alone. Results of
this trial show a statistically significant increase in PFS with bevacizumab
Several phase II studies have evaluated the efficacy of and capecitabine (8.6 months vs. 5.7 months; HR, 0.69; P < .001) and
paclitaxel/carboplatin as first-line treatment for patients with metastatic taxane- or anthracycline- (9.2 months vs. 8.0 months; HR, 0.64; P < .001)
breast cancer and found the combination to be an effective therapeutic containing arms.634,635 In a subset analysis of the phase III CALGB 40502
option in this setting.631,632 The randomized trial, tnAcity, evaluated the trial of patients (n = 201) with metastatic triple-negative breast cancer,
efficacy and safety of first-line albumin-bound paclitaxel plus first-line albumin-bound paclitaxel in combination with bevacizumab
carboplatin, albumin-bound paclitaxel plus gemcitabine, and gemcitabine resulted in a median PFS of 7.4 months.638
plus carboplatin in patients with metastatic triple-negative breast cancer.630
The results of this trial reported that median PFS was significantly longer The NCCN Panel notes that albumin-bound paclitaxel may be substituted
with albumin-bound paclitaxel plus carboplatin versus albumin-bound for paclitaxel or docetaxel due to medical necessity (ie, hypersensitivity
paclitaxel/gemcitabine (8.3 vs. 5.5 months; HR, 0.59; 95% CI, 0.38– reaction). If substituted for weekly paclitaxel or docetaxel, then the weekly
0.92; P = .02) or gemcitabine/carboplatin (8.3 vs. 6.0 months; HR, 0.58; dose of nab-paclitaxel should not exceed 125 mg/m2.
95% CI, 0.37–0.90; P = .02). The median OS was also longer
with albumin-bound paclitaxel plus carboplatin versus albumin-bound The data from the above-mentioned randomized trials document that the
paclitaxel/gemcitabine (16.8 vs. 12.1 months; HR, 0.73; 95% CI, 0.47– addition of bevacizumab to first- or second-line chemotherapy agents
1.13; P = .16) or gemcitabine/carboplatin (16.8 vs. 12.6 months; HR, 0.80; modestly improves time to progression and response rates. The
95% CI, 0.52–1.22; P = .29). The ORR was 73%, 39%, and 44%, time-to-progression impact may vary among cytotoxic agents and appears
respectively.630 greatest with bevacizumab in combination with weekly paclitaxel. None of
these studies demonstrate an increase in OS or QOL when analyzed
A series of trials have sought to define the role of bevacizumab in the alone or in a meta-analyses of the trials.639 Therefore, the NCCN Panel
treatment of metastatic breast cancer. The E2100 trial randomized 722 has included bevacizumab in combination with paclitaxel as an option
patients with recurrent or metastatic breast cancer to first-line useful in only select circumstances.
chemotherapy with paclitaxel with or without bevacizumab.633 This trial
documented superior PFS (11.8 months vs. 5.9 months; HR, 0.60; P The only triplet regimen listed as an option in the metastatic setting is
<.001) favoring bevacizumab plus paclitaxel compared with paclitaxel CMF. This regimen was compared in the first-line setting with capecitabine
alone. A similar trial enrolled 736 patients who were randomized to monotherapy, and results show similar ORR and PFS.626 However, CMF

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resulted in a shorter OS (median, 22 vs. 18 months; HR, 0.72; 95% CI, Monitoring Metastatic Disease
0.55–0.94) compared to capecitabine. Monitoring the treatment of metastatic breast cancer involves a wide array
of assessments and the need for the clinician to integrate several different
Additional Targeted Therapies for Stage IV Disease Useful in Certain
Circumstances forms of information to decide on the effectiveness of treatment and the
NTRK gene fusions are seen in a few rare types of cancer, such as acceptability of toxicity. The information includes those from direct
secretory carcinoma of the breast or salivary gland and infantile observations of the patient, including patient-reported symptoms,
fibrosarcoma and also infrequently in some common cancers, such as performance status, change in weight, and physical examination;
melanoma, glioma, and carcinomas of the thyroid, lung, and laboratory tests such as alkaline phosphatase, liver function, blood counts,
colon.640 NTRK fusions are identified by fluorescence in situ hybridization and calcium; radiographic imaging; functional imaging; and, where
(FISH), next-generation sequencing (NGS), or polymerase chain reaction appropriate, tumor biomarkers. The results of these evaluations generally
(PCR). Larotrectinib641-643 and entrectinib643,644 are two NTRK inhibitors are classified as response, continued response to treatment, stable
that are FDA-approved for the treatment of solid tumors that have an disease, uncertainty regarding disease status, or progression of disease.
NTRK gene fusion without a known acquired resistance mutation and The clinician typically must assess and balance multiple different forms of
have no satisfactory alternative treatments or that have progressed information to decide, along with the patient, whether disease is being
following treatment. If a patient with recurrent/stage IV breast cancer controlled and the toxicity of treatment is acceptable. Sometimes individual
presents with a tumor with an NTRK fusion, treatment with an NTRK pieces of information can be conflicting with regard to disease response,
inhibitor is an option if no satisfactory alternative treatments exist or for and clinical judgment along with patient input is critical.
disease progression following treatment.
The NCCN Panel recommends using widely accepted criteria for reporting
Pembrolizumab is FDA-approved for the treatment of patients with response, stability, and progression of disease such as the RECIST
unresectable or metastatic, microsatellite instability-high (MSI-H) or criteria649 and the WHO criteria.650 The Panel also recommends using the
mismatch repair deficient (dMMR) solid tumors that have progressed same method of response assessment over time. For example, an
following prior treatment and who have no satisfactory alternative abnormality initially found on diagnostic CT scan of the chest should be
treatment options.645-647 Pembrolizumab has demonstrated anti-tumor monitored with repeat diagnostic CT scans of the chest.
activity in heavily pretreated patients with metastatic breast cancer and
The optimal frequency of testing is uncertain and primarily based on the
high tumor mutational burden (≥9 mutations/megabase) determined by
monitoring strategies utilized in breast cancer clinical trials. The page titled
commercially available tests.648 If a patient with recurrent/stage IV breast
Principles of Monitoring Metastatic Disease in the algorithm provides a
cancer presents with a tumor with MSI-H/mismatch repair (MMR)
table outlining general recommendations for the frequency and type of
mutation, whose disease has progressed following prior treatments and no
monitoring as a baseline before initiation of a new therapy, for monitoring
satisfactory alternative treatment options, treatment pembrolizumab is an
the effectiveness of cytotoxic chemotherapy and endocrine therapy, and
option.
as an assessment when there is evidence of disease progression. The

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Panel has indicated in a footnote that the frequency of monitoring can be

reduced in patients who have long-term stable disease. These are
guidelines and should be modified for the individual patient using clinical
judgment, especially for those with stable or responding disease for long
periods of time.

The clinical use of circulating tumor cells (CTC) or circulating tumor DNA
(ctDNA) in metastatic breast cancer is not yet included in the NCCN
Guidelines for Breast Cancer for disease assessment and monitoring.
Patients with persistently increased CTC after 3 weeks of first-line
chemotherapy have a poor PFS and OS.651 In spite of its prognostic ability,
CTC count has failed to show a predictive value. A prospective,
randomized, phase 3 trial (SWOG S0500) evaluated the clinical utility of
serial enumeration of CTC in patients with metastatic breast cancer. 651
According to the study results, switching to an alternative cytotoxic therapy
after 3 weeks of first-line chemotherapy in patients with persistently
increased CTC did not affect either PFS or OS.651

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Special Situations WBRT.657-661 The risk of ipsilateral breast recurrence after

Paget Disease breast-conserving NAC resection and RT with or without an associated
cancer is similar to that with BCS and RT with the typical invasive or in situ
Paget disease of the breast is a rare manifestation of breast cancer
cancer.
characterized by neoplastic cells in the epidermis of the NAC.652 It most
commonly presents with eczema of the areola, bleeding, ulceration, and For Paget disease without an associated cancer (ie, no palpable mass or
itching of the nipple. The diagnosis is often delayed because of the rare imaging abnormality), it is recommended that BCS consist of removal of
nature of the condition and confusion with other dermatologic conditions. the entire NAC with a negative margin of underlying breast tissue. In
There is an associated cancer elsewhere in the breast in up to about 80% cases with an associated cancer elsewhere in the breast, the surgery
to 90% of cases.653-655 The associated cancers are not necessarily located includes removal of the NAC with a negative margin and removal of the
adjacent to the NAC and may be either DCIS or invasive cancer. peripheral cancer using standard breast-conserving technique to achieve
a negative margin. It is not necessary to remove the NAC and the
Patients with clinical signs that raise suspicion for Paget disease require a
peripheral cancer in continuity in a single surgical specimen or through a
complete history and physical examination and diagnostic breast imaging.
single incision. Mastectomy also remains an appropriate treatment option.
Any breast lesion identified by imaging or examination should be
evaluated according to the NCCN Guidelines for Breast Cancer Screening ALN staging is not necessary when breast-conserving therapy is used to
and Diagnosis. The skin of the NAC should undergo surgical biopsy, treat Paget disease with underlying DCIS without evidence of invasive
including the full thickness of the epidermis including at least a portion of cancer following clinical examination, imaging evaluation, and
any clinically involved NAC. When biopsy of the NAC is positive for Paget full-thickness skin biopsy of the involved NAC. In the presence of an
disease, breast MRI is recommended to define the extent of disease and underlying invasive breast cancer treated with BCS, axillary surgery
identify additional disease.655,656 should be performed according to the Considerations for Surgical Axillary
Staging outlined in the NCCN Guidelines algorithm. In cases treated by
There are no category 1 data that specifically address local management
total mastectomy, axillary staging is recommended for patients with
of Paget disease. Systemic therapy is based on the stage and biological
invasive disease and should also be considered for patients with
characteristics of any underlying cancer, and is supported by the evidence
underlying DCIS without evidence of invasive disease. This is because the
cited in the relevant stage-specific breast cancer treatment guidelines.
final pathology may reveal an invasive cancer in the mastectomy
Management of Paget disease has traditionally been total mastectomy specimen and the mastectomy precludes subsequent sentinel node
with axillary dissection. Total mastectomy remains a reasonable option for biopsy. Two retrospective studies have provided evidence for a high
patients regardless of the absence or presence of an associated breast degree of accuracy in the identification of the sentinel node(s) in patients
cancer.654 Data demonstrate that satisfactory local control may be with Paget disease.662,663 Patients treated with breast conservation should
achieved with BCS including the excision with negative margins of any receive whole breast radiation. Extended-field radiation to regional lymph
underlying breast cancer along with resection of the NAC followed by nodes should be used in cases of an associated invasive breast cancer

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with involved lymph nodes as for any breast cancer as described in the
initial sections of the NCCN Guidelines. A radiation boost should be
considered for the site of the resected NAC and any associated resected
cancer site, if applicable.

Patients with an associated invasive cancer have substantial risk of

developing metastases. Adjuvant systemic therapy should be
administered according to the stage of the cancer. Patients with Paget
disease treated with breast conservation and without an associated cancer
or those with associated ER-positive DCIS should consider tamoxifen for
risk reduction. Those with an associated invasive cancer should receive
adjuvant systemic therapy based on the stage and HR status.

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Phyllodes Tumors of the Breast examination.669 In those patients who experience a local recurrence,
(also known as phyllodes tumors, cystosarcoma phyllodes) resection of the recurrence with wide, tumor-free surgical margins should
Phyllodes tumors of the breast are rare tumors comprised of both stromal be performed. Some Panel members recommend local RT of the
and epithelial elements.664 Phyllodes tumors exist in benign, borderline, remaining breast or chest wall following resection of a local recurrence,
and malignant subtypes, although there is not uniform agreement on the but this recommendation is controversial (category 2B).670
criteria for assigning subtype or for predicting biological behavior.665 The
subtype of phyllodes tumor appears less important for risk of recurrence
While the epithelial component of most phyllodes tumors contains ER
than does the margin of tumor-free resection achieved by surgical
(58%) and/or PR (75%),671 endocrine therapy has no proven role in the
treatment. Diagnosis of phyllodes tumors prior to excisional
treatment of phyllodes tumors. Similarly, there is no evidence that adjuvant
biopsy/lumpectomy is uncommon. Phyllodes tumors occur in an older age
cytotoxic chemotherapy provides benefit in reduction of recurrences or
distribution than fibroadenoma, a younger age distribution than the
death. In the rare patient who experiences a systemic recurrence (usually
invasive ductal and lobular cancers, and with a mean age of 40 years.666
in the lung), treatment should be as recommended in the NCCN
Phyllodes tumors often enlarge rapidly and are usually painless. Phyllodes
Guidelines for Soft Tissue Sarcoma.
tumors often appear on ultrasound and mammography as fibroadenomas,
and FNA cytology and even core needle biopsy are inadequate to reliably
distinguish phyllodes tumors from fibroadenomas.666 Thus, in the setting of
a large or rapidly enlarging clinical fibroadenoma, excisional biopsy should
be considered to pathologically exclude a phyllodes tumor. Patients with
Li-Fraumeni syndrome (germline TP53 mutation, see NCCN Guidelines for
Genetic/Familial High Risk Assessment: Breast, Ovarian, and Pancreatic)
have an increased risk for phyllodes tumors.667 Local recurrences of
phyllodes tumors are the most common site of recurrence. Most distant
recurrences occur in the lung, and may be solid nodules or thin-walled
cavities.

Treatment of phyllodes tumors (which includes benign, borderline, and

malignant subtypes) is with local surgical excision with tumor-free margins
of ≥1 cm. Lumpectomy or partial mastectomy is the preferred surgical
therapy. Total mastectomy is necessary only if negative margins cannot
be obtained by lumpectomy or partial mastectomy.668 Since phyllodes
tumors rarely metastasize to the ALNs, surgical axillary staging or ALND is
not necessary unless the lymph nodes are pathologic on clinical

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NCCN Guidelines Version 4.2024

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Breast Cancer During Pregnancy the treatment plan and influence the patient’s decision regarding
Breast cancer occurring concurrently with pregnancy is an infrequent maintenance of the pregnancy. Assessment of the pregnancy should
clinical event. In a California registry study, there were 1.3 breast cancers include a maternal fetal medicine consultation and review of antecedent
diagnosed per 10,000 live births.672 Unfortunately, breast cancer during maternal risks such as hypertension, diabetes, and complications with
pregnancy is most often ALN-positive and with larger primary tumor size. prior pregnancies. Documentation of fetal growth and development and
Histologically the tumors are poorly differentiated, are more frequently fetal age by means of ultrasonographic assessment is appropriate.
ER/PR-negative, and approximately 30% are HER2-positive.673,674 The Estimation of the date of the delivery will help with systemic chemotherapy
diagnosis is often delayed because neither the patient nor the physician planning. In addition, maternal fetal medicine consultation should include
suspects malignancy. counseling regarding maintaining or terminating pregnancy. Counseling of
the pregnant patient with breast cancer should include a review of the
Evaluation of the pregnant patient with suspected breast cancer should treatment options, which include mastectomy or BCS as well as the use of
include a physical examination with particular attention to the breast and systemic therapy. The most common surgical procedure has been
regional lymph nodes. Mammogram of the breast with shielding can be modified radical mastectomy. However, BCS is possible if RT can be
done safely and the accuracy is reported to be >80%.675 Ultrasound of the delayed to the postpartum period,676 and breast-conserving therapy during
breast and regional lymph nodes can be used to assess the extent of pregnancy does not appear to have a negative impact on survival.676,677
disease and also to guide biopsy. Ultrasound has been reported to be When surgery is performed at 25 weeks of gestation or later, obstetrical
abnormal in up to 100% of breast cancers occurring during pregnancy.675 and prenatal specialists must be onsite and immediately available in the
Biopsies for cytologic evaluation of a suspicious breast mass may be done event of precipitous delivery of a viable fetus.
with FNA of the breast and suspicious lymph nodes. However, the
preferred technique is core needle biopsy. This provides tissue for Although there are a limited number of isolated case reports and small
histologic confirmation of invasive disease as well as adequate tissue for retrospective studies evaluating use of SLNB in pregnant patients,678,679
HR and HER2 analyses. the sensitivity and specificity of the procedure have not been established
in this setting. Thus, there are insufficient data on which to base
Staging assessment of the pregnant patient with breast cancer may be recommendations for its use in pregnant patients. Decisions related to use
guided by clinical disease stage. The staging studies should be tailored to of SLNB in pregnancy should be individualized. A review of the relative
minimize fetal exposure to radiation. For clinically node-negative T1–T2 and absolute contraindications to sentinel node biopsy concluded that
tumors, a chest x-ray (with shielding), liver function and renal function sentinel node biopsy should not be offered to pregnant patients <30 weeks
assessment, and a CBC with differential are appropriate. In patients who gestation.680 There are limited data with only case reports and estimations
have clinically node-positive or T3 breast lesions, in addition to the of fetal radiation dose regarding use of radioactive tracer (eg, technetium
aforementioned tests an ultrasound of the liver and consideration of a 99m sulfur colloid).681-683 Isosulfan blue or methylene blue dye for sentinel
screening MRI of the thoracic and lumbar spine without contrast may be node biopsy procedures is discouraged during pregnancy.
employed. The documentation of the presence of metastases may alter

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The indications for systemic chemotherapy are the same in the pregnant of these case reports indicated oligohydramnios or anhydramnios with
patient as in the non-pregnant patient with breast cancer, although administration of trastuzumab; fetal renal failure occurred in one case. If
chemotherapy should not be administered at any point during the first trastuzumab is otherwise indicated, it should be administered in the
trimester of pregnancy. The largest experience in pregnancy has been postpartum period; the Panel recommends against its use during
with anthracycline and alkylating agent chemotherapy.684,685 Collected data pregnancy.
of chemotherapy exposure in utero indicate that the first trimester has the
greatest risk of fetal malformation.686,687 Fetal malformation risks in the A single case report of first-trimester exposure to lapatinib during
second and third trimester are approximately 1.3%, not different than that treatment for breast cancer reported an uncomplicated delivery of a
of fetuses not exposed to chemotherapy during pregnancy. If systemic healthy female neonate.701
therapy is initiated, fetal monitoring prior to each chemotherapy cycle is
Endocrine therapy and RT are contraindicated during pregnancy.
appropriate. Chemotherapy during pregnancy should not be given after
Endocrine therapy and RT, if indicated, should thus not be initiated until
week 35 of pregnancy or within 3 weeks of planned delivery in order to
the postpartum period.
avoid the potential for hematologic complications during delivery. Data
from a single-institution prospective study indicate that FAC chemotherapy Communication between the oncologist and maternal fetal medicine
(5-fluorouraci 500 mg/m2 IV days 1 and 4, doxorubicin 50 mg/m2 by IV specialist is essential at every visit and for every treatment decision point
infusion over 72 hours, and cyclophosphamide 500 mg/m2 IV day 1) may for the patient.
be given with relative safety during the second and third trimesters of
pregnancy.685 As reported by Gwyn et al, the median gestational age at
delivery was 38 weeks, more than 50% of the patients had a vaginal
delivery, and there were no fetal deaths.673 An update of this experience
reported on 57 patients treated with FAC in the adjuvant or neoadjuvant
setting. There were 57 live births. A survey of parents/guardians reported
on the health of 40 children. There was one child with Down syndrome
and two with congenital abnormalities (club foot, congenital bilateral
ureteral reflux). The children are reported to be healthy and progressing
well in school.685,688 Ondansetron, lorazepam, and dexamethasone can be
used as part of the pre-chemotherapy antiemetic regimen.

There are limited data on the use of taxanes during pregnancy.689-692 If

used, the NCCN Panel recommends weekly administration of paclitaxel
after the first trimester if clinically indicated by disease status. There are
only case reports of trastuzumab use during pregnancy.693-700 The majority

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Inflammatory Breast Cancer The NCCN Panel acknowledges that studies focusing on genetic
IBC is a rare, aggressive form of breast cancer estimated to account for characterization of IBC are needed to more clearly define IBC as a
1% to 6% of breast cancer cases in the United States.702,703 IBC is a disease entity and to optimize treatment.714,715 Nevertheless, current
clinical diagnosis that requires erythema and dermal edema (peau evidence provides justification for a separate guideline for the workup and
d’orange) of a third or more of the skin of the breast. treatment of patients diagnosed with IBC.

IBC is usually HR-negative and is more frequently HER2-positive than the StageT4d, N0–N3, M0
usual ductal breast cancers. Studies on gene expression profiling of IBC Workup
have demonstrated that all the subtypes of IBC exist, but basal and HER2 Patients with a clinical/pathologic diagnosis of IBC without distant
overexpressed are more frequent.704-707 According to the 7th edition of the metastasis (stage T4d, N0–N3, M0) should undergo a thorough staging
AJCC Cancer Staging Manual, IBC is classified as stage IIIB, stage IIIC, evaluation by a multidisciplinary team.
or stage IV breast cancer, depending on the degree of nodal involvement
Recommendations for workup include a complete history and physical
and whether distant metastases are present. The primary tumor of IBC is
examination involving a CBC and platelet count.
classified as T4d by definition, even when no mass is specifically apparent
in the breast. On radiographic imaging, findings of skin thickening and, in A pathology review and pre-chemotherapy determinations of tumor
some cases, an underlying mass are observed. Despite use of the term HR- and HER2- status should be performed. HER2 has a predictive role in
“inflammatory,” the characteristic clinical features of IBC are due to determining which patients with IBC will benefit from HER2-targeted
blockage of dermal lymphatics by tumor emboli. Although a biopsy is therapy. The NCCN Panel endorses the CAP protocol for pathology
required to evaluate for the presence of cancer in breast tissue and the reporting (www.cap.org) and endorses the ASCO CAP recommendations
dermal lymphatics, a diagnosis of IBC is based on clinical findings, and for quality control performance of HER2 testing and interpretation of IHC
dermal lymphatic involvement is neither required, nor sufficient by itself, to and ISH results.716
assign a diagnosis of IBC.708,709 The differential diagnosis includes cellulitis
of the breast and mastitis. Imaging studies help facilitate image-guided biopsy, delineate locoregional
disease, and identify distant metastases. Evaluation of all patients
In the past, IBC has often been placed under the general heading of suspected with IBC must include diagnostic bilateral mammogram, with
locally advanced breast cancer. There is a growing body of evidence that the addition of ultrasound as necessary. A breast MRI scan is optional.
patients with IBC, when compared with patients with noninflammatory
forms of locally advanced breast cancer, are more likely to have a less Evaluations for the presence of distant metastasis in the asymptomatic
favorable prognosis710-712 and to be younger at the time of disease patient include LFTs, bone scan or sodium fluoride PET/CT (category 2B),
presentation.713 and diagnostic CT imaging of the chest, abdomen, and pelvis (category
2B; category 2A for diagnostic CT imaging of the chest when pulmonary
symptoms are present).

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FDG-PET/CT may be most helpful in situations where standard imaging disease-specific survival were reported for the combined modality
results are equivocal or suspicious. However, there is limited evidence approach.719 Results from a large retrospective study of patients with IBC
suggesting that PET/CT may be a useful adjunct to standard imaging of performed over a 20-year period at The University of Texas MD Anderson
IBC due to the increased risk of regional lymph node involvement and Cancer Center demonstrated that initial treatment with doxorubicin-based
distant spread of disease in this group of patients.110,111,717,718 chemotherapy followed by local therapy (ie, RT or mastectomy, or both)
Nevertheless, equivocal or suspicious sites identified by FDG-PET/CT and additional postoperative chemotherapy resulted in a 15-year DFS rate
scanning or other imaging methods should be biopsied for confirmation of of 28%.720
stage IV disease whenever possible. FDG-PET/CT is a category 2B
recommendation. The consensus of the Panel is that FDG-PET/CT can be A retrospective study demonstrated that the addition of a taxane to an
performed at the same time as diagnostic CT. If FDG-PET and diagnostic anthracycline-based regimen improved PFS and OS in patients with
CT are performed and both clearly indicate bone metastases, bone scan ER-negative IBC.721 A systematic review found evidence for an
or sodium fluoride PET/CT may not be needed. association between the intensity of preoperative therapy and the
likelihood of a pCR.722 A study of IBC patients, with cytologically confirmed
Genetic counseling is recommended if the patient is considered to be at ALN metastases, treated with anthracycline-based chemotherapy with or
high risk for hereditary breast cancer as defined by the NCCN Guidelines without a taxane indicated that more patients receiving the
for Genetic/Familial High-Risk Assessment: Breast, Ovarian and anthracycline-taxane combination achieved a pCR compared with those
Pancreatic. who received only anthracycline-based therapy. In addition, patients who
had a pCR in the ALNs had superior OS and DFS compared with those
Treatment
with residual axillary disease.723
The treatment of patients with IBC should involve a combined modality
approach702 comprising preoperative systemic therapy followed by surgery The NCCN Panel recommends preoperative systemic therapy with an
(mastectomy) and radiotherapy. anthracycline-based regimen with or without taxanes for the initial
treatment of patients with IBC. The Panel also recommends completing
Preoperative Chemotherapy
the planned chemotherapy prior to mastectomy. If the chemotherapy was
There are no large randomized trials evaluating the optimal systemic
not completed preoperatively, it should be completed postoperatively.
treatment of IBC, since it is a rare disease. The systemic therapy
recommendations are based on data from retrospective analyses, small Targeted Therapy
prospective studies, and data from non-IBC, locally advanced breast All patients with HR-positive IBC are recommended to receive endocrine
cancer. therapy sequentially after completing the planned preoperative systemic
therapy.
The benefit of preoperative systemic therapy followed by mastectomy over
preoperative systemic therapy alone in patients with IBC was shown in a HER2-positive IBC is associated with a poor prognosis.706,724 For patients
retrospective analysis in which lower local recurrence rates and longer with HER2-positive disease, the addition of trastuzumab to primary

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NCCN Guidelines Version 4.2024

Breast Cancer

systemic chemotherapy is associated with better response rates.414,725-728 Mastectomy with level I/II ALND is the recommended surgical procedure
A prospective study that randomized patients with locally advanced breast recommended by the NCCN Panel for patients whose tumor responds to
cancers, including those with IBC, to neoadjuvant anthracycline-based neoadjuvant chemotherapy. The NCCN Panel has listed delayed breast
chemotherapy with or without trastuzumab for 1 year demonstrated that reconstruction as an option that can be recommended to patients with
the addition of trastuzumab significantly improved the response rate and IBC who have undergone a modified radical mastectomy. Reconstruction
event-free survival.414 The NCCN Panel recommends inclusion of of the breasts soon after mastectomy may compromise the
trastuzumab in the chemotherapy regimen and is recommended for post-mastectomy RT outcomes.733
patients with HER2-positive disease. There are no available data to
indicate the optimal duration of trastuzumab, specifically among patients For patients with IBC who do not respond to preoperative systemic
with IBC. However, based on the available data,414 the Panel recommends therapy, mastectomy is not generally recommended. Additional systemic
continuing trastuzumab therapy for up to 1 year. chemotherapy and/or preoperative radiation should be considered for
these patients. Patients with tumors responding to this secondary
Results of small phase II trials indicate that other HER2-targeting agents therapy should undergo mastectomy and subsequent treatment as
such as lapatinib and pertuzumab have a clinical benefit in IBC.729,730 The described above.
results of the NEOSPHERE trial that included patients with IBC showed
Radiation
increased pCR with the pertuzumab-containing regimens. Therefore, the
NCCN Panel has included in a footnote that a pertuzumab-containing After mastectomy, RT is recommended after the completion of the
regimen may be administered preoperatively in patients with planned chemotherapy.
HER2-positive IBC.730
The probability of locoregional lymph node involvement is high for
Determination of response to neoadjuvant chemotherapy in IBC should patients with IBC. To reduce the risk of local recurrence, the Panel
include a combination of physical examination and radiologic assessment. recommends RT to the chest wall and the supraclavicular region. If the
internal mammary lymph node(s) is clinically or pathologically involved,
Surgery RT should include the internal mammary nodes. If the internal mammary
Patients with a clinical/pathologic diagnosis of IBC should always be nodes are not clinically or pathologically involved, then including the
treated with chemotherapy before surgery. It has been known for many internal mammary nodes in the RT field is at the discretion of the treating
years that surgical treatment as primary treatment of patients with IBC is radiation oncologist (category 3). For HER2-positive disease,
associated with poor outcomes.731 SLN dissection is not a reliable method trastuzumab may be administered concomitantly with RT.
of assessing ALNs among patients with IBC.732 Use of BCS in patients
Stage IV or Recurrent IBC
with IBC has been associated with poor cosmesis, and limited data
suggest that rates of local recurrence may be higher when compared with Patients with stage IV or recurrent IBC should be treated according to
mastectomy. Breast-conserving therapy is not recommended for patients the guidelines for recurrence/stage IV breast cancer.
with IBC.

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Breast Cancer

Axillary Breast Cancer without any signs of a primary tumor. A small subset of these patients
Occult breast cancer presenting with axillary metastases is an unusual may have a primary cancer in the axillary tail of the breast.
presentation that can be a diagnostic and therapeutic challenge. Adenocarcinoma with positive axillary nodes and mediastinal nodes is
Evidence to support recommendations for patients presenting with highly suggestive of a breast primary. Adenocarcinoma in the
axillary breast cancer comes from a limited number of retrospective supraclavicular nodes, chest, peritoneum, retroperitoneum, liver, bone,
studies involving small numbers of patients734-736 (see also references or brain could also indicate primary breast cancer in patients. The
therein). Although treatment of patients with axillary metastases from an guidelines suggest the use of a mammogram and breast ultrasound for
unknown primary tumor has typically involved mastectomy and axillary such patients.
nodal dissection, some of these patients have also been successfully
Testing for immunohistochemical markers including ER/PR and HER2 is
treated with axillary nodal dissection followed by RT.735,736
recommended. Elevated ER/PR levels provide strong evidence for a
Patients with a suspected occult primary breast cancer will typically breast cancer diagnosis.738 MRI of the breast should be considered for a
present to the oncologist after undergoing an initial biopsy: core needle patient with histopathologic evidence of breast cancer when
biopsy (preferred), and/or FNA. Accurate pathologic assessment of the mammography and ultrasound are not adequate to assess the extent of
biopsied material is most important. Therefore, the pathologist must be the disease. MRI may be especially helpful in patients with dense breast
consulted to determine whether the available biopsy material is tissue, positive axillary nodes, and suspected occult primary breast
adequate, or if additional biopsy material is necessary (eg, core needle, tumor or to evaluate the chest wall.739 Breast MRI has been shown to be
incisional, or excisional biopsy) to provide an accurate and complete useful in identifying the primary site in patients with occult primary breast
diagnosis. cancer and may also facilitate breast conservation in selected patients by
allowing for lumpectomy instead of mastectomy.735,740 In one report, the
Workup for Possible Primary Breast Cancer primary site was identified using MRI in about half of the patients
MRI of the breast can facilitate the identification of occult breast cancer, presenting with axillary metastases, irrespective of the breast density.741
and can help select those patients most likely to benefit from
mastectomy.737 For example, in a study of 40 patients with biopsy-proven The NCCN Guidelines for Occult Primary also provide recommendations
breast cancer in the axilla, and a negative or indeterminate for additional workup, including chest and abdominal CT to evaluate for
mammogram, MRI identified the primary breast lesion in 70% of the evidence of distant metastases for patients diagnosed with
patients.735 In addition, of the 7 patients with a negative MRI who adenocarcinoma (or carcinoma not otherwise specified) of the axillary
subsequently underwent ALND and RT to the whole breast, no evidence nodes without evidence of a primary breast lesion. In particular, breast
of local recurrence was evident at a median follow-up of 19 months. MRI and ultrasound are recommended. Axillary ultrasound should also
be performed.
The NCCN Guidelines for Occult Primary provide guidance on the
diagnosis and initial workup of patients with a suspicious axillary mass

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Treatment for Possible Primary Breast Cancer

Patients with MRI-positive breast disease should undergo evaluation with
ultrasound or MRI-guided biopsy and receive treatment according to the
clinical stage of the breast cancer. Treatment recommendations for those
with MRI-negative disease are based on nodal status. For patients with
T0, N1, M0 disease, options include mastectomy plus axillary nodal
dissection or axillary nodal dissection plus whole breast irradiation with
or without nodal irradiation. Systemic chemotherapy, endocrine therapy,
or trastuzumab is given according to the recommendations for stage II or
III disease. Neoadjuvant chemotherapy, trastuzumab, and endocrine
therapy should be considered for patients with T0, N2–N3, M0 disease
followed by axillary nodal dissection and mastectomy as for patients with
locally advanced disease.

Summary
The therapeutic options for patients with noninvasive or invasive breast
cancer are complex and varied. In many situations, the patient and
physician have the responsibility to jointly explore and select the most
appropriate option from among the available alternatives. With few
exceptions, the evaluation, treatment, and follow-up recommendations in
these guidelines are based on the results of past and present clinical
trials. However, there is not a single clinical situation in which the
treatment of breast cancer has been optimized with respect to either
maximizing cure or minimizing toxicity and disfigurement. Therefore,
patient/physician participation in prospective clinical trials allows patients
to not only receive state-of-the-art cancer treatment but also to contribute
to improving the treatment outcomes.

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Breast Cancer

10. Cobleigh MA, Anderson SJ, Siziopikou KP, et al. Comparison of

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Breast Cancer

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Breast Cancer

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Breast Cancer

652. Sakorafas GH, Blanchard K, Sarr MG, Farley DR. Paget's disease 660. Pierce LJ, Haffty BG, Solin LJ, et al. The conservative management
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Breast Cancer

669. Mangi AA, Smith BL, Gadd MA, et al. Surgical management of 677. Annane K, Bellocq JP, Brettes JP, Mathelin C. Infiltrative breast
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Breast Cancer

685. Johnson PH, Gwyn K, Gordon N, et al. The treatment of pregnant metastatic breast cancer during pregnancy. Lancet Oncol 2007;8:79-81.
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Breast Cancer

702. Dawood, S, Cristofanilli M. What progress have we made in 711. Panades M, Olivotto IA, Speers CH, et al. Evolving treatment
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NCCN Guidelines Version 4.2024

Breast Cancer

718. Chia S, Swain SM, Byrd DR, Mankoff DA. Locally advanced and 725. Hurley J, Doliny P, Reis I, et al. Docetaxel, cisplatin, and
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NCCN Guidelines Version 4.2024

Breast Cancer

731. Kell MR, Morrow M. Surgical aspects of inflammatory breast cancer. 739. Bleicher RJ, Morrow M. MRI and breast cancer: role in detection,
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