Breast Cancer

Seminar
Breast cancer
Nadia Harbeck, Michael Gnant
Lancet 2017; 389: 1134–50 Breast cancer is one of the three most common cancers worldwide. Early breast cancer is considered potentially
Published Online curable. Therapy has progressed substantially over the past years with a reduction in therapy intensity, both for
November 16, 2016 locoregional and systemic therapy; avoiding overtreatment but also undertreatment has become a major focus.
http://dx.doi.org/10.1016/
S0140-6736(16)31891-8
Therapy concepts follow a curative intent and need to be decided in a multidisciplinary setting, taking molecular
subtype and locoregional tumour load into account. Primary conventional surgery is not the optimal choice for all
Breast Center, Department of
Gynecology and Obstetrics, patients any more. In triple-negative and HER2-positive early breast cancer, neoadjuvant therapy has become a
Comprehensive Cancer Center commonly used option. Depending on clinical tumour subtype, therapeutic backbones include endocrine therapy,
of the Ludwig-Maximilians- anti-HER2 targeting, and chemotherapy. In metastatic breast cancer, therapy goals are prolongation of survival and
University, Munich, Germany
maintaining quality of life. Advances in endocrine therapies and combinations, as well as targeting of HER2, and the
(Prof N Harbeck MD); and
Department of Surgery and promise of newer targeted therapies make the prospect of long-term disease control in metastatic breast cancer an
Comprehensive Cancer increasing reality.
Center, Medical University
of Vienna, Vienna, Austria
(Prof M Gnant MD)
Breast cancer: epidemiology situations, such as hereditary breast cancers, dense tissue
Breast cancer is the most common malignancy in and lobular histology, and suspected multi centric
Correspondence to:
Prof Nadia Harbeck, Breast women, and one of the three most common cancers disease.4 A large meta-analysis5 (two randomised trials
Center, University of Munich, worldwide, along with lung and colon cancer. In 2012, and seven comparative cohorts, 3112 patients) suggested
81377 Munich, Germany almost 1·7 million people were diagnosed worldwide and an unfavourable harm–benefit ratio for routine use of
nadia.harbeck@med.uni-
about half a million people died from this disease.1,2 One preoperative MRI with an increased initial proportion of
muenchen.de
in eight to ten women will get breast cancer during their women with initial mastectomy (16·4% for preoperative
lifetime. Mortality from breast cancer in North America MRI vs 8·1% for no preoperative MRI; odds ratio [OR]
and the European Union (EU) has decreased, and this 2·22; p<0·001) and no reduction in the proportion of
decrease is mostly attributable to early detection and women who had a re-excision after initial breast
efficient systemic therapies. In 2016, mortality from conservation (11·6% for preoperative MRI vs 11·4% for
breast cancer in the EU is expected to drop by 8%.3 no preoperative MRI; OR 1·02; p=0·87).
Nevertheless, breast cancer is still the most common Staging and search for metastases is only needed in
cause of death from cancer in less developed countries symptomatic patients or in those at high risk for relapse.
and second to lung cancer in more developed countries. The prevalence of metastasis in asymptomatic patients is
In South America, Africa, and Asia, the incidence of high in large tumours (diameter >5 cm [15%]) or in
breast cancer is increasing—most probably because of patients with extensive nodal disease (>three involved
lifestyle changes and initiated screening programmes. lymph nodes [4%]).6 Routine staging examinations consist
Mortality from breast cancer in these regions is also still of chest radiograph, abdominal ultrasound, and bone scan.
increasing, partly because of a lack of access to state-of- Yet, CT scans might be better suited for patients who are at
the-art diagnosis and therapy.2 high risk or symptomatic because of their high sensitivity.
Early breast cancer: treatment concepts

and biology Search strategy and selection criteria
Early breast cancer without detectable distant metastases We searched MEDLINE between June 16, 2015, and June 19,
is a potentially curable disease. After diagnosis, therapy 2016 with no language restrictions. We used the search terms
concepts need to be decided in a multidisciplinary team “breast cancer” in combination with specific terms covering
meeting (tumour board). Primary surgery and removal the different steps of diagnosis and treatment as appropriate.
of the tumour might not be the best option for every We largely selected publications in the past 5 years, but did
patient even though this could be the patient’s initial not exclude commonly referenced and highly regarded older
logical request. Yet, for certain biological tumour publications. We also searched the reference lists of articles
subtypes such as triple-negative breast cancer or HER2- identified by this search strategy and selected those we
positive disease, primary systemic therapy could be judged relevant. Review articles and book chapters are also
better suited, on the basis of the multidisciplinary team cited to provide readers with more details and more
meeting recommendation and shared decision making references than this Seminar was able to. We also added
with the patient. research from the 2015 and 2016 ASCO conferences, and
Before finalising the therapeutic concept, clinical from ESMO 2015 and 2016, as well as the 2014 and 2015
examination and thorough breast imaging (mam San Antonio Breast Cancer Symposia that have not yet been
mography, breast ultrasound) need to be completed. published as full papers. Our reference list was modified based
Diagnosis of malignancy is usually verified by core on comments from the peer reviewers.
biopsy. Breast MRI needs to be restricted to specific
1134 www.thelancet.com Vol 389 March 18, 2017

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Since the groundbreaking work of Perou, Sørlie, and end—the issue of margin details. The evidence since
colleagues7,8 at the beginning of this millennium, breast 2012 speaks for “no ink on tumour” as the state-of-the-art
cancer is considered to consist of at least four different strategy,18,19 rather than surgical fighting for millimetres of
clinically relevant molecular subtypes: luminal A, clearance—this strategy has an enormous implication for
luminal B, HER2-enriched, and basal like. Yet, both diagnostic and therapeutic strategies. For example,
scientifically, up to ten different molecular subtypes re-excisions after breast-conserving surgery should
have been identified using gene copy number and virtually disappear unless grossly involved margins are
expression analyses.9 present after primary surgery, maybe even more so after
In formalin-fixed paraffin-embedded tumour samples, newly emerged surgical techniques such as cavity
the four original subtypes can either be directly shaving.20 The continuing controversy about intraoperative
determined with a multigene assay such as Prosigna frozen section is less a scientific one, since it is clear that
(NanoString Technologies) or Blueprint (Agendia) or intraoperative margin assessment further improves
indirectly reconstructed with immunohistochemically surgical results21 and reduces the occurrence of re-
determined steroid hormone receptor (oestrogen excision, but rather a discussion about health-care
receptor [ER], progesterone receptor [PgR]) and HER2 resources and their availability.22
status, as well as tumour proliferation measured by Ki67 Breast conservation is nowadays technically feasible in
as follows: luminal A-like subtype (ER or PgR positive, or many clinical situations that had earlier led to primary
both, HER2 negative, low proliferation); luminal B-like mastectomy because of advances in oncoplastic surgical
subtype (ER or PgR positive, or both, HER2 negative, techniques23 and the increased success of neoadjuvant
high proliferation); HER2 subtype, non-luminal (HER2 tumour-shrinking drug therapies. Yet, a concerning
positive and ER and PgR negative) or luminal (HER2 development is the increase in voluntary mastectomy,
positive and ER or PgR positive, or both); basal-like including voluntary contralateral (prophylactic) breast
subtype (HER2 negative and ER and PgR negative; triple- amputation, observed particularly in the USA.24 Although
negative breast cancer). In accordance with the St Gallen it is certainly correct to eventually accept patient’s choice,
consensus, systemic therapy for early breast cancer could physicians have a clear ethical responsibility to
be guided by these molecular subtypes (figure 1).11,12 impartially and completely inform patients about the
In daily clinical practice, the difficulty is distinguishing options and consequences, including the fact that fear is
between luminal A and luminal B tumours on the basis not a good indication for mutilating surgery. Clear
of proliferation assessed by local non-standardised Ki67 evidence exists that contralateral mastectomy does
values. Values of 10% or less are generally considered low neither lower mortality nor improve survival.25,26
risk, and values between 20% and 29% are considered as Neoadjuvant systemic treatment has emerged as a
a minimum criterion for high proliferation.12 Yet, because standard of care for treatment situations in which primary
of the lack of a prospectively validated cutoff, intermediate breast conservation is not possible because of tumour size
Ki67 values between 10% and about 30% should not be or the association of the tumour and breast size,27 provided
used as the sole criterion for indicating adjuvant that the patient has a chemotherapy indication at all. Both
chemotherapy in luminal B tumours. International
standardisation for Ki67 is still missing and the measured
interlaboratory variability is rather high.13 Thus, Luminal-like Triple negative
(ER or PgR positive, or both; (ER and PgR and HER2 HER2 positive
internationally developed standards14 urgently need to be HER2 negative) negative)
implemented on a local level.
The final multidisciplinary management plan in early Offer BRCA testing (also
breast cancer is based on molecular subtype, locoregional without family history—
Lymph node involvement; grade; Ki67; in case of therapeutic
tumour load, and patients’ wishes. multigene signature or uPA/PAI-1 test consequences)
Early breast cancer: local therapy Indication for chemotherapy if tumour stage ≥T1b N0:
Surgery Luminal A or low risk Luminal B or high risk preferably neoadjuvant
Breast conservation is established as the intended surgical (only in pN0–1) (always in pN2–3)
standard of care for most clinical situations in breast
cancer.15 Developments in surgical techniques (oncoplastic Anthracycline and taxane- Chemotherapy
containing chemotherapy + trastuzumab
procedures)16 and multidisciplinary approaches (primary Endocrine therapy Chemotherapy (offer to add neoadjuvant (and pertuzumab)*
systemic therapy), as well as increased treatment of → endocrine therapy platinum) ± endocrine therapy
patients in dedicated and certified breast units, have
improved women’s access to this organ-saving surgical Figure 1: Principles of systemic therapy in early breast cancer
approach.17 Summary of general treatment strategies, updated after the publication of Harbeck and colleagues, 2010.10 For an
individual patient, therapy decisions can differ since tumour and disease characteristics and patients’ preferences
While the overarching principle of achieving clear are key elements in deciding the individual treatment strategy. ER=oestrogen receptor. PgR=progesterone
margins remains the surgical standard of care, a receptor. *Dual HER2 blockade only registered for neoadjuvant setting. Endocrine therapy always indicated if ER or
decade-long surgical debate appears to have come to an PgR positive, or both.
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cytotoxic chemotherapy and endocrine therapy are used, and avoidable side-effects of axillary surgery.39,40 A variety
and targeted therapy is used depending on the tumour of methods to reliably detect the sentinel node have been
biology.28 For HER2-positive disease and triple-negative established and used in clinical practice.39,41,42 The issue of
breast cancer, pathological complete response is high (60% axillary surgery after neoadjuvant systemic treatment
or more),29 and correlated with long-term outcome,30 which remains controversial: pretreatment sentinel node biopsy
is less clear for luminal breast cancer. Even in subtypes appears to be an option; post-treatment sentinel node
that allow a pathological complete response in more than surgery is less reliable.43 The differentiation regarding
50% of patients, surgery to remove the remaining tumour better or worse response of the disease and its respective
or verify pathological complete response remains implications on surgical strategies remains unclear.44 It
necessary, even though this option might be questioned by definitely makes a difference for further surgical (and
future clinical research. With a high pathological complete radiotherapy) management, irrespective of whether the
response occurrence and proven long-term benefit, lymph nodes are affected before any therapy or not, and
particularly in the HER2-positive subtype, surgical issues efforts are being made to clarify this differential impact
might become less relevant in determination of the on management by imaging and histology before the
optimum primary treatment approach. Some clinicians start of neoadjuvant therapy.45–47
might even advocate primary systemic therapy Moreover, the need for completion axillary dissection
(chemotherapy plus anti-HER2 treatment) for all in patients with a limited number of positive sentinel
HER2-positive tumours, almost irrespective of tumour nodes remains a huge controversy: the pivotal ACOSOG
size (most experts suggest 1 cm as a reasonable limit). Yet, Z0011 trial41 described no outcome difference between
overtreatment for simple local tumour reduction needs to dissection of axillary lymph node or no dissection, but
be avoided and neoadjuvant systemic therapy should only severe criticism of some aspects of the methods of this
be given if the same therapy was indicated in the adjuvant trial and a few other trials was voiced. Although reports
setting. Nevertheless, neoadjuvant treatment offers a that axillary lymph node dissection can be safely omitted
situation in which new drugs can be explored, even though after a positive-sentinel node are accumulating,48 it
reliable surrogate parameters for long-term outcomes are appears wise to remain cautious on this issue until
not always available.31 reliable long-term (10 years or more) data and exact
Surgery after neoadjuvant chemotherapy has dramat description of radiotherapy approaches49 in all studies
ically changed. From the rule of excising the original have been reported.
tumour bed that had initially weakened the effect of
neoadjuvant therapies on the prevalence of breast Radiotherapy
conservation, the development has gone to no ink on Another option of handling a positive-sentinel node could
tumour after primary systemic treatment as well.32 be axillary radiotherapy: the AMAROS trial50 established
However, not all tumours shrink concentrically, and after this technique as a non-inferior option versus axillary
neoadjuvant endocrine therapy the assessment of lymph node dissection. However, several concerns about
margins can be particularly challenging.33 Definitely, the methods have to be raised—the inadequate prevalence
clear margins must be achieved in this surgical situation of level III dissections and wound infections in the
as well. Mastectomies after pathological complete surgery group might have affected the shoulder mobility
response, as reported in earlier trials,29,34 should be data—and suggest caution when interpreting the results.
avoided whenever possible. Since 2014, margin With respect to radiotherapy approaches to breast
assessment after neoadjuvant systemic therapy has been cancer, there are conflicting developments to note: less-
standardised, which should allow for better cross-trial invasive radiotherapy strategies have been established,
comparison in the future.35,36 such as partial breast irradiation51,52 or hypofractionated
The value of preoperative MRI remains controversial. radiotherapy53 that decrease patient burden.54
Although high-quality MRI in a multidisciplinary setting Intraoperative radiotherapy has been used as boost55 or
can clearly improve surgical planning, the concern stand-alone radiation therapy,56 both again aiming to
remains that the lack of specificity in detecting reduce side-effects and logistical efforts for patients. Trials
multicentric lesions could lead to unnecessarily aiming to omit radiotherapy after breast conservation
increased mastectomy rates.37,38 Thus, reason and altogether in low-risk situations have not yielded
common sense should be applied: although a truly convincing results. Yet, in the scientific community, a
multicentric tumour needs to be diagnosed properly belief remains that such a population exists and could be
before surgical planning (biopsy), a mastectomy identified in the future.57 Although a small numerical
indication solely based on an MRI is a mistake. benefit might exist in terms of local control, also for older
Over the past two decades, axillary surgery has patients (eg, older than 70 years), this difference is highly
substantially changed. Although level I/II lymph node unlikely to translate into any relevant differences in
dissection used to be the standard approach, the sentinel longer-term survival.58–60
node procedure is now the state-of-the-art approach, Based on recent pivotal trials, current clinical practice
saving patients with negative nodes from the unnecessary tends to extend radiotherapy fields to the axilla, and

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supraclavicular and parasternal radiation fields.61 The results for test validation only exist for Onkotype DX and
EORTC trial62 suggested a 5-year overall survival benefit MammaPrint. For Oncotype DX, the TAILORx Trial for
at borderline statistical significance (82·3% in the nodal- pN074 and the WSG PlanB Trial for pN0–175 prospectively
irradiation group vs 80·7% in the control group [hazard confirmed its prognostic effect. For MammaPrint, the
ratio for death with nodal irradiation, 0·87; 95% CI MINDACT trial76 showed that patient outcome is not
0·76–1·00; p=0·06]). The MA-20 trial63 reported that compromised if adjuvant chemotherapy is omitted in
among women with node-positive or high-risk node- clinically high-risk and genomically low-risk early breast
negative breast cancer, the addition of regional nodal cancer. All other multigene assays have only been
irradiation to whole-breast irradiation did not improve retrospectively validated. Prospective outcome data are
overall survival but reduced the recurrence of breast still missing from the randomised comparisons of the
cancer. In a meta-analysis64 and investigation of these two large international trials that used Onkotype DX for risk
trials62,63 and the French trial, both overall and group assessment (ie, TAILORx [pN0], RxPONDER [pN1]).
metastasis-free survival benefits were significant,65 and The protein-based ELISA assay for uPA/PAI-1
the approach of extended radiotherapy approaches (Femtelle [American Diagnostica/Sekisui]) has also been
appeared to gain momentum.64 validated at the highest level of evidence for its prognostic
Nodal irradiation is increasingly advocated because of and predictive effect by a prospective clinical trial77 and a
omission of axillary surgery even in cases of positive or European Organisation for Research and Treatment of
suspicious nodes. Yet, many experienced clinicians remain Cancer-pooled analysis.78 By contrast with multigene
concerned that we might partially be giving up the assays, this test requires fresh-frozen tumour tissue; but
advantages we have gained for our patients by limiting if the logistics can be implemented, it can be an
surgical aggressiveness in breast and axilla by implementing alternative option for risk assessment because of its low
more aggressive radiotherapy strategies, which ultimately overall costs.79 Last, but not least, prognosis can also be
could even lead to increased long-term toxicity.66 However, estimated on the basis of prognostication tools driven by
modern radiation-field planning will almost certainly clinical data, such as the PREDICT algorithm.80
improve the previous occurrence of cardiac toxicity.67
The issue of radiotherapy for patients with one to three Endocrine therapy
involved lymph nodes remains controversial, with only In all luminal—ie, hormone-receptor-positive (ER or
part of the studies indicating an overall survival benefit.68 PgR positive, or both)—early breast cancer, adjuvant
However, modern radiotherapy has resolved some endocrine therapy over the course of 5–10 years is
previously discussed issues, such as the boost (dose).69 considered standard. Current guidelines consider any ER
or PgR staining (ie, ≥1%) as being positive; endocrine
Early breast cancer: systemic therapy sensitivity is directly correlated to the degree of hormone
Indication for systemic therapy receptor positivity.81
The most frequent tumour biology is HER2-negative In premenopausal patients, 20 mg tamoxifen per day is
luminal tumours (around 70%) in which the indication for the standard endocrine therapy. The Early Breast Cancer
neoadjuvant or adjuvant chemotherapy depends on further Trialists’ Collaborative Group (EBCTCG) meta-analysis81
criteria such as proliferation, tumour grade, or lymph showed that 5 years of tamoxifen treatment reduced the
node involvement. Since only a few breast cancer centres recurrence not just in the first 4 years (risk ratio [RR]
routinely determine molecular subtype by a multigene 0·53; p<0·0001), but also in years 5–9 (RR 0·68;
assay, immunohistochemistry is mostly used to distinguish p<0·0001) in patients with ER-positive disease. This
luminal A biology from luminal B. Yet, in tumours that are effect was independent of PgR status, age, nodal status,
hormone-receptor positive with an intermediate Ki67 and chemotherapy use. Breast cancer mortality was
between 10% and 30%, this distinction cannot be made reduced by about a third throughout the first 15 years of
easily. Thus, other criteria for assessing risk of recurrence follow-up.82
and response to chemotherapy are needed. In premenopausal patients at a high risk for relapse (ie,
In general, patients with an estimated relapse risk of after chemotherapy or age ≤35 years), the addition of
more than 10% over the course of 10 years are viewed as ovarian suppression drugs (gonadotropin-releasing
potential candidates for neoadjuvant or adjuvant hormone agonist [GnRH]) to tamoxifen or even
chemotherapy. In intermediate-risk patients (pN0–1) administering GnRH together with an aromatase inhibitor
with luminal tumours, several multigene assays (eg, might enhance efficacy, according to the SOFT and TEXT
Endopredict [Myriad Genetics],70 MammaPrint trial82,83 results. So far, the data from SOFT and TEXT82,83
[Agendia], Oncotype DX [Genomic Health],72 Prosigna73)
71
only show superior disease-free survival for GnRH with
have been validated for risk assessment and a few have tamoxifen or GnRH with aromatase inhibitor, but no
been validated for prediction of chemotherapy response overall survival advantage. As the final analysis of ABCSG
(table 1). Most of these assays give information not only trial 1284 showed a significantly higher mortality in
about risk of early recurrence (first 5 years), but also premenopausal patients after 3 years of GnRH with
about risk of late recurrence (>5 years). Prospective trial aromatase inhibitor versus GnRH with tamoxifen (hazard

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Oncotype DX Endopredict Mammaprint Prosigna

Manufacturer Genomic Health Sividon Agendia NanoString Technologies
(distribution by Myriad)
Assay 21 gene recurrence score 11 gene assay 70 gene assay 50 gene assay
(PAM 50, ROR score)
Tissue FFPE FFPE FFPE (technical FFPE
validation of original
fresh-frozen tissue assay)
Method Quantitative RT-PCR Quantitative RT-PCR RNA microarray nCounter Technology
Laboratory Centralised (USA) Decentralised Centralised Decentralised
(Netherlands)
Registration or accreditation Clinical Laboratory Improvement CE-Mark FDA (In Vitro Diagnostic FDA (510k), CE-Mark
Amendment, College of American Multivariate Index Assay)
Pathologists
Determination of molecular No No Yes (using Blueprint) Yes (not reported in USA)
subtype
Prognostic information Yes Yes Yes Yes
(outcome)
Risk groups Low, intermediate, high Low vs high Low vs high Low, intermediate, high
Predictive information Yes No data so far Yes No data so far
(response to adjuvant
chemotherapy)
Evidence-based test indication pN0-1, ER-positive, endocrine pN0-1, ER-positive, pN0-1 pN0-1, ER-positive, HER2-
therapy HER2-negative, negative, endocrine therapy,
endocrine therapy postmenopausal
Retrospective clinical NSABP B14 and B20; TransATAC; ABCSG 6 and 8; Multicentre ABCSG 8; TransATAC;
validation* ECOG 9127; SWOG 8814 TransATAC MA.21
Prospective clinical trials WSG-Plan B (3198 patients); WSG TUM (DI unicentre study, MINDACT (BIG; WSG for Several European DI studies:
ADAPT (around 5000 patients); 167 patients) Germany; 6693 WSG (11 centres,
TAILORx (pN0; 10 253 patients); patients); WSG PRIME 200 patients); GEICAM;
RxPONDER (pN1; around (DI study; 34 centres; French multicentre study
9000 patients) 452 patients)
FFPE=formalin-fixed, paraffin-embedded. FDA=Food and Drug Administration. ER=oestrogen receptor. DI=decision impact. *Cohort for translational research only,
a subgroup of total study collective.
Table 1: Commonly used multigene assays for risk assessment in early breast cancer
ratio [HR] 1·63; 95% CI 1·05–1·45; p=0·030), the Non-breast-cancer mortality was similar between
indication for GnRH with aromatase inhibitor and the aromatase inhibitor and tamoxifen.
respective side-effect profiles need to be carefully discussed So far, trial data have supported use of aromatase
with premenopausal patients. inhibitors for a total of 5 years, either in the upfront86 or
In postmenopausal patients, tamoxifen and aromatase in the extended adjuvant therapy setting.88 The results of
inhibitors are both valid therapeutic options, either as the Australian LATER trial89 showed that late introduction
monotherapy for 5 years or in sequence. In the sequence of letrozole in women after 4 years or more of adjuvant
setting, aromatase inhibitors significantly reduce endocrine therapy for more than 1 year before study
recurrences by about 30%, but not mortality, compared entry significantly reduced late invasive events of breast
with tamoxifen. In the upfront setting, 5 years of cancer. The results of the MA17.R trial90 showed that after
treatment with aromatase inhibitors significantly reduces 5 years of tamoxifen, prolongation of extended adjuvant
breast cancer mortality by about 15% compared with therapy with letrozole from 5 years to 10 years in total is
5 years of tamoxifen treatment.85 In postmenopausal beneficial in postmenopausal patients regarding disease-
patients at a high risk for relapse86 or with a lobular free survival (5-year disease-free survival of 95% for
histology,87 upfront aromatase inhibitor therapy is letrozole treatment for 10 years vs 91% for letrozole
preferred. In all other patients, choice and sequence treatment for 5 years; HR 0·66; p=0·01) and particularly
need to be decided on an individual basis, since both regarding prevention of contralateral disease (0·21%
options have distinct side-effect patterns: in the EBCTCG annual incidence after letrozole treatment vs 0·49% after
meta-analysis,85 fewer endometrial cancers were reported placebo; p=0·007). Overall survival did not differ
with aromatase inhibitor than with tamoxifen (10-year significantly between the two study arms. The ATLAS
incidence of 0·4% for aromatase inhibitor vs 1·2% for trial91 showed that continuation of tamoxifen for another
tamoxifen), but more bone fractures occurred (5-year risk 5 years, up to 10 years in total, significantly reduced
of 8·2% for aromatase inhibitor vs 5·5% for tamoxifen). breast cancer recurrence and mortality. The trialists

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concluded that 10 years of tamoxifen almost halves administered before surgery to maintain dose intensity;
breast cancer mortality during the second decade after sandwich chemotherapy thus needs to be avoided outside
diagnosis compared with 5 years of tamoxifen. However, of clinical trials.
this conclusion remains controversial since longer Adjuvant chemotherapy should be started within the
tamoxifen therapy was also associated with increased first few weeks after surgery as each additional week after
side-effects, and some earlier studies92,93 did not report 3–4 weeks could impair outcome.102 However, not all
better outcomes with longer duration of tamoxifen studies give such a narrow time window. In 2016, a
therapy. population-based analysis showed that delays beyond
When prolonging adjuvant endocrine therapy beyond 91 days between surgery and start of adjuvant
5 years, potential risks and benefits need to be carefully chemotherapy are associated with an impaired outcome,
balanced.94 Multigene assays are able to also assess long- particularly in triple-negative breast cancer.103
term relapse risk and could therefore be helpful for The current chemotherapy standards in early breast
decisions on duration of adjuvant endocrine therapy.95 cancer are anthracylines and taxanes, given as a
If chemotherapy is also indicated, adjuvant endocrine combination or in sequence over a period of 18–24 weeks
therapy should be given consecutively,96 even though other (table 2). Generally, recommended regimens do not differ
data exist that show no difference in efficacy either way.97 between neoadjuvant and adjuvant settings. The EBCTCG
meta-analysis99 suggested that anthracycline-containing
Chemotherapy and taxane-containing chemotherapy reduced 10-year
In early breast cancer, preoperative chemotherapy is breast cancer mortality by about a third. An anthracycline
equally effective as postoperative chemotherapy regarding and taxane sequence is as effective as their
disease-free survival and overall survival.98 However, combination.104,105 Four times anthracycline followed by
neoadjuvant chemotherapy should only be performed if four times docetaxel is equally effective as the combination
the patient has an indication for adjuvant chemotherapy. of the same drugs (six times TAC [docetaxel, doxorubicin,
Here, locoregional tumour load, molecular subtype, and and cyclophosphamide]) but has a different toxicity
risk of relapse need to be considered as “low absolute risk pattern.106 TAC requires granulocyte-colony-stimulating
implies low absolute benefit”.99 Although high nodal factor support because of its high rate of febrile
involvement is associated with high relapse risk, the issue neutropenia. After four cycles of anthracyclines, weekly
of micrometastases in sentinel lymph nodes appears to paclitaxel and three-weekly docetaxel are the preferred
be settled—they have little, if any, effect on outcome and taxane regimens.107 The addition of 5-fluorouracil to an EC
can be ignored in clinical decision making.100,101 (epirubicin and cyclophosphamide)-paclitaxel sequence
Next to the advantage of better operability after does not seem to improve efficacy or patient outcome.108
neoadjuvant chemotherapy, this concept is particularly Similarly, the addition of other drugs such as
recommended in patients with triple-negative breast capecitabine109 or gemcitabine105 to an anthracycline-
cancer and HER2-positive disease. These subtypes have a taxane regimen was not successful in phase 3 trials. Most
good correlation of pathological complete response with probably, additional drugs require dose modifications for
patient outcome.30 This association might help to inform the standard drugs that then affect efficacy.
patients about their prognosis after surgery. Moreover, The anthracycline-free combination of four times
international clinical trials are now available for patients docetaxel and cyclosphosphamide (TC) is superior to four
without pathological complete response. In the times anthracycline and cyclophosphamide (AC) regarding
neoadjuvant setting, all chemotherapy should be disease-free survival (81% for TC vs 75% for AC; HR 0·74;
Drugs Dose Interval Remarks

Four times epirubicin (E; or E (or A) + C, P or T 90 mg/m² E (or 60 mg/m² A) and EC (or AC) every 21 or every Dose dense every 14 days;
doxorubicin [A]) + cyclophosphamide 600 mg/m² C, 80 mg/m² P 14 days, P weekly requires primary GCSF
(C)—12 times paclitaxel (P; or four times (or 100 mg/m² T) (T every 21 days) prophylaxis
docetaxel [T])
Six times docetaxel (T), doxorubicin (A), TAC 75 mg/m² T, 50 mg/m² A, Every 21 days Requires primary GCSF
cyclophosphamide (C) 500 mg/m² C prophylaxis
Four or six times docetaxel (T) and TC 75 mg/m² T and 600 mg/m² C Every 21 days Anthracycline-free
cyclophosphamide (C)
Epirubicin (E), paclitaxel (T), ETC 150 mg/m² E, 225 mg/m² T, Each 3 times, every 14 days Dose dense requires
cyclophosphamide (C) and 2000 mg/m² C primary GCSF prophylaxis
Carboplatin Added to P weekly AUC=5 or 6, AUC=2 AUC 5 or 6 every 21 days; Optional in triple-negative
AUC 2 weekly breast cancer
GCSF=granulocyte-colony stimulating factor. AUC=area under curve.
Table 2: Commonly used evidence-based chemotherapy regimens for patients with early breast cancer

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95% CI 0·56–0·98; p=0·033) and overall survival (87% for (every 2 weeks)-weekly paclitaxel sequence improved
TC vs 82% for anthracycline; HR 0·69; 0·50–0·97; pathological complete response but not patient outcome in
p=0·032).110 In an early prespecified interim pooled CALGB 40603.120 While preclinical data and data from the
analysis for futility of the US ABC trials,111 statistical non- TNT trial of metastatic breast cancer121 suggest that the
inferiority could not be shown for six cycles of TC versus benefit of platinum could be greatest in BRCA1/2 mutation
anthracycline followed by paclitacel or docetaxel carriers, exploratory analyses from GeparSixto122 suggest
(4242 patients; HR 1·202; 0·97–1·49). A small but that the platinum benefit is also present in patients with
significant difference (2·5%) in invasive disease-free wildtype BRCA.
survival existed, favouring the standard anthracycline- In summary, since platinum adds toxicity and
taxane sequence but no difference in overall survival. conflicting data exist regarding a pathological complete
Thus, four to six cycles of TC are not a standard for all response123 and a potential survival benefit118 (table 3), the
patients, but are an effective chemotherapy option if addition of platinum to standard chemotherapy should
anthracyclines need to be avoided. be carefully discussed with all patients with triple-
Results of several trials in node-positive high-risk negative breast cancer. BRCA1/2 mutations are present
disease have shown that dose-dense chemotherapy in more than 10% of unselected patients with
improves outcome in early breast cancer compared with triple-negative breast cancer with significantly higher
standard interval chemotherapy. In the GIM trial mutation rates in patients younger than 40 years.124
(2091 patients, node-positive),108 dose-dense (every 14 days)
administration of an anthracycline-taxane sequence Management of HER2-positive disease
(FEC-paclitaxel or EC-paclitaxel) significantly improved Adding trastuzumab to an anthracycline-taxane
5-year disease-free survival compared with standard sequence and then continuing the antibody therapy for
administration every 21 days (81% for treatment every up to 1 year substantially improves overall survival
14 days vs 76% for treatment every 21 days; HR 0·77; (HR 0·63, 0·54–0·73; p<0·001);125 concurrent
0·65–0·92; p=0·004) and overall survival (94% for administration of trastuzumab with the taxane seems
treatment every 14 days vs 89% for treatment every more effective.126 The role of anthracyclines in HER2-
21 days; 0·65, 0·51–0·84; p=0·001). In patients with more positive disease remains controversial. Docetaxel,
than four involved lymph nodes, dose-dense and dose- carboplatin, and trastuzumab (TCH) is an
intensified epirubicin, paclitaxel, and cyclophosphamide anthracycline-free alternative to the anthracycline-taxane
(IDD-ETC) led to a significant reduction in relapse (28%, sequence. With TCH, cardiac toxicity is significantly
p<0·001) and mortality (24%, p=0·0285), but also to more less, but efficacy is also lower than with the anthracycline-
haematological and non-haematological toxicities than taxane sequence plus trastuzumab (5-year disease-free
EC-paclitaxel treatment every 21 days.112 Similar survival of 81% for TCH vs 84% for anthracycline-taxane
superiority of dose-dense EC-paclitaxel every 14 days sequence plus trastuzumab).127 This outcome was
versus every 21 days was seen in the CALGB 9741 trial.104 confirmed by the long-term (10 year) data,128 and TCH
In the MA21 trial,113 dose-dense and dose-intensified EC thus constitutes a valid option for HER2-positive disease,
followed by paclitaxel weekly was superior to standard particularly for patients with cardiac comorbidities.
three-weekly AC-paclitaxel but equivalent to CEF Standard duration of trastuzumab therapy in patients
(cyclophosphamide, epirubicin, and 5-fluorouracil; 60 mg with early breast cancer remains at 1 year total. The
epirubicin per m² given on days 1 and 8). results of the HERA trial129 showed that 2 years of
Data from chemotherapy trials exist for patients with trastuzumab did not improve efficacy compared with
early breast cancer up to about age 70 years; however, 1 year of tratsuzumab. The PHARE130 and a HORG131
biological age is more important than chronological age trials did not show non-inferiority of treatment for
when indicating chemotherapy in elderly patients. 6 months versus 12 months.
Standard chemotherapies are preferred for fit older The therapy benefit of adjuvant trastuzumab is
patients.114 Dose and schedule can be tailored according to independent of tumour size.132 Nevertheless, overtreatment
the special requirements of an elderly patient, as stated by of low-risk patients is a relevant clinical issue, and not all
the International Society of Geriatric Oncology (SIOG).115 patients with HER2-positive tumours need combination
For patients with triple-negative breast cancer, standard chemotherapy (or neoadjuvant therapy with dual antibody
regimens containing anthracycline and taxane should be blockade). In node-negative patients with tumour
used, preferably as neoadjuvant therapy. Since 2014, trials diameters up to 3 cm, 12 times weekly paclitaxel plus
have indicated that adding platinum to a neoadjuvant trastuzumab rendered an excellent 3-year invasive disease-
anthracycline-taxane combination or sequence improves free survival of 98·7% (95% CI 97·6–99·8) and could thus
pathological complete response.116–118 Additionally, the be considered an option for this low-risk collective group.
GeparSixto trial119 showed a disease-free survival advantage Only 12 of 406 patients had invasive disease events at
after adding carboplatin weekly (area under the curve 1·5) 3 years: two distant metastasis, four locoregional
to an anthracycline-taxane combination. Yet, the addition of recurrence, four contralateral breast cancer, and two non-
carboplatin every 3 weeks to a four times dose dense AC breast cancer deaths.133 For HER2-positive luminal early

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Number of patients Tumour biology Therapy arms pCR rates Significance

(platinum vs
standard)
Japanese phase 2 75 with Immunohistochemistry: Four times carboplatin AUC=5 every 61·2% vs 26·3% p=0·003
trial 2; Ando et al, triple-negative ER, PgR, and HER2 21 days + 80 mg/m² paclitaxel (pCR breast) (subgroup analysis)
2014116 breast cancer weekly—four times CEF (500 mg/m²
cyclophosphamide, 100 mg/m²
epirubicin, 500 mg/m² 5-fluorouracil)
vs P-CEF
Geparsixto; 315 with ER and PgR <1%; HER2- 80 mg/m² paclitaxel + 20 mg/m² non- 53·2% vs 36·9% p=0·005 (planned
von Minckwitz et al, triple-negative negative pegylated liposomal doxorubicin ± (ypT0 ypN0) subgroup analysis)
2014117 breast cancer carboplatin AUC=2 (later 1·5) weekly
CALGB 40603 443 ER and PgR ≤10%; HER2- 80 mg/m² paclitaxel weekly—four 60% vs 44% p=0·0018
(Alliance); negative times doxorubicin and (pCR breast)
Sikov et al, 2015118 cyclophosphamide every 2 weeks
± carboplatin AUC=6 every 3 weeks
(± 10 mg/kg bevacizumab every
2 weeks)
GEICAM 2006/03; 94 Basal-like Four times epirubicin, then four times 30% vs 35% p=0·61
Alba et al, 2012123 (immunohistochemistry): docetaxel every 3 weeks ± carboplatin (pCR breast) (not significant)
ER-negative, PgR-negative, AUC=6 every 3 weeks
HER2-negative, and
cytokeratin 5/6-positive or
EGFR-positive
pCR=pathological complete response. ER=oestrogen receptor. PgR=progesterone receptor. AUC=area under curve. P-CEF=paclitaxel followed by cyclophosphamide,
epirubicin, and 5-fluorouracil.
Table 3: Evidence from phase 2 trials for platinum-based chemotherapy in neoadjuvant therapy of triple-negative early breast cancer
breast cancer, no data exist for an endocrine not translate into a significant survival advantage.
therapy-trastuzumab combination without systemic Similarly, the ALTTO trial,138 which used standard
chemotherapy. adjuvant chemotherapy, did not see a survival advantage
Since pathological complete response is correlated with when comparing the sequential or combined use of
patient outcome in HER2-positive disease, particularly in trastuzumab and lapatinib versus trastuzumab alone in
HER2-positive, hormone-receptor-negative disease,30,134 the adjuvant setting. Thus, vertical HER2 blockade has
neoadjuvant therapy has become a preferred option for no clinical role in patients with early breast cancer.
these patients. Response at surgery allows counselling By contrast, the combination of the two anti-HER2—
about the expected individual outcome. Results from the antibodies trastuzumab and pertuzumab (with a docetaxel
KATHERINE trial (NCT01772472), which randomised backbone)—did receive conditional approval by the US
patients without pathological complete response to Food and Drug Administration (FDA; and subsequent
standard trastuzumab versus trastuzumab emtansine European Medicines Agency [EMA] approval) for the
(TDM-1) for the completion of anti-HER2 therapy for neoadjuvant setting and thus constitutes an important
1 year, are still pending. Moreover, in some countries therapy option for HER2-positive early breast cancer. The
dual blockade with pertuzumab and trastuzumab approval was based on the results from NeoSphere:34
together with chemotherapy is already available—but pathological complete response in the breast was 45·8%
only in the neoadjuvant setting. When using an after four cycles of docetaxel plus dual blockade
anthracycline-taxane sequence in the neoadjuvant (trastuzumab and pertuzumab) every 21 days versus
setting, adding trastuzumab to the anthracycline does 29·0% with docetaxel plus trastuzumab alone (p=0·0141).
not improve pathological complete response 135 and is The approval was certainly influenced by the totality of
thus optional. the data with the survival advantage in the metastatic
Dual anti-HER2 blockade has been explored in the setting (CLEOPATRA)139 and a fully recruited phase 3
neoadjuvant setting with vertical HER2 blockade adjuvant trial (APHINITY; NCT01358877). No data for
(trastuzumab and lapatinib) and dual antibody-based adjuvant use of the dual antibody blockade will exist until
(horizontal) HER2 blockade (trastuzumab and the results of the APHINITY trial become available.
pertuzumab). The neoadjuvant results regarding the
dual vertical blockade are controversial: it did not result Bone-stabilising drugs
in significantly better pathological complete response In early breast cancer, bisphosphonates were initially
than trastzumab alone in NSABP B-41136 and used to prevent or treat the side-effects of adjuvant
CALGB 40601.137 Yet, it had a significant pathological endocrine treatments (particularly aromatase inhibitor)
complete response advantage in NeoALTTO,29 which did on bone.140 Current guidelines call for risk assessment at

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the beginning of adjuvant therapy and bisphosphonate radiotherapy, endocrine, and antibody therapy need to be
treatment, if appropriate.141,142 This recommendation is postponed until after delivery. Multidisciplinary
based on several trials that showed the usefulness of management, including obstetrics and perinatal
adjuvant bisphosphonates for prevention and therapy of medicine specialists, is key to a successful outcome for
treatment-induced bone loss, in both premenopausal143 mother and child.
and postmenopausal women.144,145 Patients older than 70 years constitute almost a third of
Yet, adjuvant bisphosphonates do not only prevent all patients with breast cancer in European countries.158
bone loss, but might also prevent bone and even other Since individual comorbidities and overall life expectancy
metastases. Whether their anticancer effect is more can differ substantially, special management recom
cytotoxic or reflects indirect effects on the bone marrow mendations are available by SIOG and EUSOMA.159
environment remains controversial.146 The results of Genetic testing for BRCA1 and BRCA2 should be
several large clinical trials have shown outcome benefits offered to all patients meeting the respective national
for oral and intravenous adjuvant bisphosphonates.147 guideline criteria, such as those with strong family
The beneficial effect appears to be confined to history, triple-negative breast cancer, or patients younger
postmenopausal patients,148,149 or to premenopausal than 35 years.4 Regarding chances for cure, treatment of
patients receiving adjuvant ovarian suppression.150 BRCA1/2-mutation carriers does not need to differ from
Preclinical data also suggest that menopausal status that of patients with sporadic breast cancer: locoregional
could be important in determining the efficacy of therapy can be performed as indicated by the individual
adjuvant antiresorptive treatment.151 tumour load. Yet, patients need to be counselled about
The controversy about adjuvant bisphosphonates their individual risk for contralateral disease160 since
appeared to have been finally settled by a large EBCTCG patient preferences about prophylactic mastectomies
meta-analysis,152 which showed that adjuvant bisphos need to be discussed before finalising the locoregional
phonates reduced the prevalence of breast cancer therapy concept. This process helps to avoid potentially
recurrence in bone, and improved breast cancer survival, unnecessary procedures, such as adjuvant radiotherapy
with clear evidence for a benefit only in postmenopausal after breast-conserving therapy, that might then affect
women. How this finding will be implemented into cosmesis of immediate reconstructive surgery after
clinical practice, and whether bisphosphonates could be secondary mastectomy, for example. Moreover, ongoing
substituted by the anti-RANK-ligand antibody denosumab, clinical trials in early breast cancer with PARP inhibitors
after results were published regarding a reduction of suggest BRCA testing as early as possible during the
fracture risk under concomitant aromatase inhibitor course of disease in patients at risk.
therapy153 and a disease-free survival improvement,154
remains to be determined. Metastatic breast cancer: therapy concepts
In contrast with early breast cancer, metastatic breast
Early breast cancer: special situations cancer is considered incurable with currently available
Evidence is scarce on special situations in early breast therapies. Based on data from 1996, long-term survivors
cancer, such as age extremes or patients who are pregnant. do exist but are very rare—ie, less than 5%.161 Whether
Generally, therapy of young and elderly patients with and how this percentage will change with current
breast cancer should not deviate from standard therapies that have shown an overall survival advantage
management unless individualisation is required because is still unknown.
of comorbidities and personal situations. Nowadays, patients with metastatic breast cancer differ
For young patients (<40 years), who represent less than substantially from patients 10–20 years ago and are much
7% of all patients in high-income countries, a biannual more difficult to treat because they have usually received
international consensus conference (breast cancer in very potent adjuvant therapies. Consequently, results
young women [BCY]) establishes the international from therapy trials started several years ago might not be
standards.155 Particularly, family planning and fertility completely transferable to current patients. Nevertheless,
preservation156 are issues in these patients that need to be trials published since 2012,139,162 particularly in HER2-
addressed before therapy concepts are finalised. positive disease, have shown not just prolongation of
Moreover, genetic testing needs to be considered in progression-free survival, but also overall survival. These
young patients (<35 years) even without a family history.4 results indicate that the concept of metastatic breast
If young women present with breast cancer in pregnancy, cancer as a chronic disease controlled by sequential
the pregnancy can be continued until term from an therapies over a long period is realistic, at least for certain
oncological point of view. Stage-adjusted prognosis is subgroups.
similar in women who are or are not pregnant, and thus, Next to prolongation of survival, therapeutic goals in
therapy should be as close to the guidelines as possible.157 metastatic breast cancer are maintenance of quality of life
Surgery, including radioisotope-based sentinel lymph and palliation of symptoms. Therapy concepts are usually
node biopsy, and chemotherapy (second and third more individualised in metastatic breast cancer than in
trimesters only), can be administered during pregnancy; early breast cancer, since patients differ regarding

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preferences, pretreatments, and residual side-effects

from previous therapies. Tumour biology is important Symptoms or metastasis location*
together with duration of response to previous therapies

and tumour burden with associated symptoms (figure 2).
Therapy concepts need to be decided by a multidisciplinary Slow disease progression Rapid therapy response required
team right from the beginning.
The biannual Advanced Breast Cancer Conference (ABC) ER and PgR negative
in Lisbon, Portugal, provides evidence-based inter Steroid hormone receptor status (ER, PgR) HER2 status
national and multidisciplinary consensus guidelines for
ER or PgR positive, or both
diagnosis and treatment of metastatic breast cancer.
Generally, systemic therapy is the first therapeutic choice Endocrine therapy† Selected Chemotherapy (±targeted therapy)
(± targeted therapy) postmonopausal patients: HER2+ +trastuzumab + pertuzumab
in metastatic breast cancer and locoregional therapy TDM-1 single agent
AI + trastuzumab or
(eg, surgery, radiotherapy) can be added in specific lapatinib (if HER2+) +lapatinib/+ trastuzumab
AI (eg, letrozole) beyond progression
situations (eg, primary metastatic disease, symptomatic + palbociclib‡ HER2 ± bevacizumab (only first line)
–
bone, or brain metastases).164

If clinically feasible, biopsy of the first metastatic site is
recommended to verify breast cancer histology and Exemestane + everolimus
or fulvestrant + palbociclib‡
determine again the tumour biology (ER, PgR, and
Depending on clinical situation§
HER2).164 Histology might differ between primary
tumour and metastasis because of tumour heterogeneity
or merely because of problems with the methods. Figure 2: Principles of systemic therapy in metastatic breast cancer
Numerous retrospective reports exist of discordance Previous treatments and patients’ preferences are key elements in deciding the individual therapeutic steps.
rates as high as 30–40%. In prospective series, these rates Figure updated after the publication of Bossung and Harbeck, 2010.163 Treatment decisions can thus differ for an
seem somewhat lower and lead to treatment changes in individual patient. In patients with HR-positive HER2-negative tumours, endocrine therapy should be the first
option unless there is life-threatening disease. Chemotherapy is always an additional therapy option depending on
about 15%. Because of potential heterogeneity even the course of disease. ER=oestrogen receptor. PgR=progesterone receptor. AI=aromatase inhibitor.
between metastases, gain of a therapeutic target is TDM-1=trastuzumab emtansine. *If bone metastases: + bisphosphonates or denosumab. †Always combine with
important for choice of therapy. In case of loss of target, ovarian suppression or ablation in premenopausal patients. ‡So far, only one line of palbociclib therapy is
evidence-based. §Only applicable if ER or PgR positive, or both.
methodological problems need to be addressed first
before omitting targeted therapy.
Bone-modifying drugs, such as bisphosphonates or suppression is recommended with all endocrine options,
denosumab, are standard as maintenance therapy from even with tamoxifen.168
first bone metastasis until intolerable toxic effects. Prolongation of progression-free survival has been
Schedules differ from the setting of early breast cancer. shown by adding targeted therapies to endocrine therapy.
Although denosumab was shown to be more effective The m-TOR inhibitor everolimus substantially improved
than bisphosphonates in preventing skeletal-related progression-free survival by 4·6 months (HR 0·45;
events,165 a survival advantage has not been reported. 0·38–0·54; p<0·0001) but not overall survival (median
31 months for exemestane plus everolimus vs 26·6 months
Endocrine-responsive metastatic breast cancer for non-steroidal aromatase inhibitor only; HR 0·89;
International guidelines recommend endocrine therapy 0·73–1·1; p=0·14) in postmenopausal patients after failure
as the first therapeutic choice in patients with of a non-steroidal aromatase inhibitor.169 The cyclin-
HER2-negative luminal metastatic breast cancer unless dependant kinase 4/6 (CDK 4/6) inhibitor palbociclib
visceral crisis or another life-threatening situation together with letrozole also improved median progression-
requires chemotherapy.164 Endocrine therapy is usually free survival in postmenopausal patients without previous
feasible if symptoms allow a wait of about 3–4 months systemic treatment for metastatic breast cancer
until best response. Endocrine drugs for metastatic (20·2 months [95% CI 13·8–27·5] for palbociclib and
breast cancer include tamoxifen, aromatase inhibitors, letrozole vs 10·2 months [95% CI 5·7–12·6 months] for
fulvestrant, and progestins. These drugs are ideally given letrozole alone; HR 0·488; 0·319–0·748; p=0·0004).170 On
sequentially, each until progression or intolerable toxic the basis of the PALOMA 1 phase 2 data,170 palbociclib
effects. Aromatase inhibitors were the preferred first-line received fast-track approval in the USA, while in Europe,
therapy in postmenopausal women; however, the phase 2 approval was announced on Nov 10, 2016. The phase 3
FIRST study166 suggested an overall survival benefit of PALOMA 2 trial171 confirmed this progression-free survival
fulvestrant 500 mg versus anastrozole 1 mg in this advantage: median progression-free survival was
setting. Results of the confirmatory phase 3 FALCON 24·8 months for letrozol and palbociclib versus
study (NCT01602380) showed a progression-free survival 14·5 months for letrozole alone (HR 0·58; 0·46–0·72;
advantage (but not an overall survival advantage) for p<0·0001). After progression from, or relapse after,
fulvestrant 500 mg versus anastrozole 1 mg in the first- previous endocrine therapy, PALOMA 3172 showed efficacy
line setting.167 For premenopausal patients, ovarian of palbociclib together with fulvestrant: median

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No (neo-) adjuvant trastuzumab therapy (Neo-) adjuvant trastuzumab therapy
Disease progression Disease progression HR+, postmenopausal

≥12 months (potentially ≤6 months and special situation
also >6 months) (eg, oligometastatic,
elderly, very low-risk)
Taxane-chemotherapy + trastuzumab + pertuzumab TDM-1 Aromatase inhibitor plus

trastuzumab or lapatinib
Continue as suggested
after DFS ≥12 months,
unless individual
Capecitabine + situation requires
TDM-1
lapatinib different approach
Evidence-based further line options include: trastuzumab + lapatinib; chemotherapy + trastuzumab beyond progression; trastuzumab + pertuzumab*
Figure 3: Evidence-based sequence of systemic therapy in HER2-positive metastatic breast cancer

Please note, the currently available evidence does not cover all situations because of individual differences in pretreatment. Thus, extrapolations from available
evidence were applied when needed. Solid lines represent evidence-based and dotted lines are reasonable options without evidence. HR+= hormone-receptor positive
(ER or PGR positive, or both). TDM-1=trastuzumab emtansine. DFS=disease-free survival. *If no previous pertuzumab.
first-line registration trial (MONALEESA 2; NCT01958021)

HER2 status? ± Anti-HER2 agents* showed a substantial progression-free survival benefit for
Bone metastases? ± Bisphosphonates/denosumab
letrozole plus ribociclib versus letrozole alone.173
Adjuvant chemotherapy? First line Rapid progression: combination chemotherapy Given the promising evidence, endocrine therapy plus
DFS >12 months? Anthracycline + taxane; anthracycline + cyclophosphamide; a targeted drug is most probably going to be the future
anthracycline-free regimens: XDoc, Pac/Doc + Gem
Pretreatment: for treatment of patients with luminal metastatic breast
Anthracycline? Slow progression: monotherapy
Anthracycline (free, liposomal); taxane cancer. Unfortunately, beside ER and PgR, biomarkers
Taxane?
Second line Further evidence-based chemotherapy options:
for patient selection are still missing. Moreover, unless a
• Capecitabine survival advantage can be shown for the new therapeutic
• Vinorelbine approaches, endocrine monotherapy is still a valid
• Eribulin
• Platinum compounds option, particularly in slowly progressing disease with
• Oral cyclophosphamide/metronomic CMF good response to previous endocrine therapy.
• Re-challenge
Third line • In any therapy line, consider treatment in
clinical trials
Management of HER2-positive metastatic
breast cancer
Further treatment lines Anti-HER2 therapy is recommended as early as possible
in patients with HER2-positive metastatic breast cancer.
Figure 4: Chemotherapy for metastatic breast cancer
DFS=disease-free survival. XDoc= capecitabine and docetaxel. Pac=paclitaxel. Doc=docetaxel. Gem=gemcitabine.
Even though efficacy of trastuzumab or lapatinib together
CMF=cyclophosphamide, methotrexate, and 5-fluorouracil. *Approved targeted drugs for addition to with endocrine therapy (aromatase inhibitor) was shown
chemotherapy: trastuzumab, pertuzumab, or lapatinib for HER2-positive tumours; bevacizumab (first-line therapy) in several phase 2–3 trials for postmenopausal patients174
for HER2-negative tumours. and led to registration of these combinations,
combination with chemotherapy is currently recom
progression-free survival was 9·2 months (95% CI 7·5 to mended in early lines of therapy because of the overall
not estimable) for palbociclib and fulvestrant versus survival advantage.
3·8 months (95% CI 3·5–5·5) for fulvestrant alone Based on the pivotal data,175 trastuzumab plus taxane
(HR 0·42; 95% CI 0·32–0·56; p<0·001). Premenopausal chemotherapy has been the first-line standard for at least a
patients received additional goserelin; the effect size of decade. The results of the CLEOPATRA trial139 showed an
palbociclib was similar in premenopausal and unprecedented median overall survival advantage of
postmenopausal patients.172 An overall survival advantage 15·7 months, favouring docetaxel plus trastuzumab and
versus standard therapy has not been reported for any pertuzumab in first-line treatment of HER2-positive
CDK 4/6 inhibitor. For the PALOMA studies, final overall disease. Median overall survival with dual blockade was
survival analyses are still pending. Ribociclib and 56·5 months (95% CI 49·3 to not reached) versus
abemaciclib are two additional CDK 4/6 inhibitors that are 40·8 months (95% CI 35·8–48·3) with standard (HR 0·68;
being assessed in clinical trials. Data from the ribociclib 95% CI 0·56–0·84; p<0·001).139 This combination has

Seminar
therefore become the new first-line standard (figure 3). EMA but not by FDA, and thus constitutes a therapy
The results from the MARIANNE trial176 showed that option only in individual countries.
TDM-1 (with pertuzumab) is non-inferior but not superior
to first-line taxane plus trastuzumab. The toxicity profile Future perspectives for metastatic breast cancer
favoured the TDM-1 groups. Pertuzumab did not add to Next-generation sequencing and mutation analysis have
the efficacy of TDM-1 in the overall study population. transformed management of other solid tumours, but not
In second-line treatment, after treatment with taxane yet those of patients with metastatic breast cancer. So far,
and trastuzumab or with rapid progression after adjuvant the only clinically relevant biomarkers and validated
trastuzumab (≤6 months), TDM-1 was more effective than therapeutic targets in metastatic breast cancer are ER,
lapatinib and capecitabine in the phase 3 EMILIA trial:162 PgR, and HER2. Nevertheless, metastatic breast cancer is
median overall survival crossed the stopping boundary for heterogeneous and several clinically potentially relevant
efficacy at the second interim analysis (30·9 months TDM- mutations have been identified. Yet, personalised
1 for vs 25·1 months for lapatinib and capecitabine; approaches are currently only available for a few patients.183
HR 0·68; 95% CI 0·55–0·85; p<0·001). Consequently, Ongoing trials and initiatives such as AURORA184 (Breast
TDM-1 has become the second-line standard. International Group) or PRAEGNANT185 provide valuable
Evidence-based further-line therapy options in patients opportunities to assess the value of molecular
with HER2-positive metastatic breast cancer include characterisation of metastatic breast cancer and
lapatinib and capecitabine,177 lapatinib and trastuzumab,178 subsequent molecular-targeted therapy. Moreover,
chemotherapy and trastuzumab beyond progression,179 participation in clinical trials with new targeted therapies
or trastuzumab and pertuzumab.180 Sequencing of might benefit patients by adding effective additional
anti-HER2 therapies in metastatic breast cancer for an therapy steps in the treatment sequence for metastatic
individual patient will depend on the evidence (figure 3), breast cancer and should therefore always be considered.
but also on approval and reimbursement in the respective Contributors
therapy setting. All authors did the literature search, wrote the manuscript, and approved
the final manuscript.
Chemotherapy for metastatic breast cancer Declaration of interests
Chemotherapy is always indicated in triple-negative NH reports personal fees from Agendia, Amgen, AstraZeneca, Celgene,
Genomic Health, NanoString Technologies, Novartis, Pfizer, Roche, and
breast cancer after endocrine options have been Sandoz, outside the submitted work. MG reports grants and personal fees
exhausted in luminal disease or if rapid response is from AstraZeneca, Novartis, Pfizer, and Roche, and personal fees from
needed in life-threating situations or in patients who Celgene, GlaxoSmithKline, and Accelsior, outside the submitted work.
are highly symptomatic. Unless patient symptoms References
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Seminar

Early breast cancer: treatment concepts

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Oncotype DX Endopredict Mammaprint Prosigna

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Drugs Dose Interval Remarks

GCSF=granulocyte-colony stimulating factor. AUC=area under curve.

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Number of patients Tumour biology Therapy arms pCR rates Significance

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preferences, pretreatments, and residual side-effects

together with duration of response to previous therapies

bone, or brain metastases).164

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No (neo-) adjuvant trastuzumab therapy (Neo-) adjuvant trastuzumab therapy

Disease progression Disease progression HR+, postmenopausal

Taxane-chemotherapy + trastuzumab + pertuzumab TDM-1 Aromatase inhibitor plus

Figure 3: Evidence-based sequence of systemic therapy in HER2-positive metastatic breast cancer

first-line registration trial (MONALEESA 2; NCT01958021)

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