Epidemiology of Prostate Cancer: Review

Review World J Oncol.
2019;10(2):63-89
Epidemiology of Prostate Cancer

Prashanth Rawla
Abstract netic factors. Although 2,293,818 new cases are estimated un-
til 2040, a small variation in mortality will be observed (an
Prostate cancer is the second most frequent cancer diagnosis made in increase of 1.05%) [4].
men and the fifth leading cause of death worldwide. Prostate cancer Prostate cancer may be asymptomatic at the early stage
may be asymptomatic at the early stage and often has an indolent and often has an indolent course, and may require minimal or
course that may require only active surveillance. Based on GLOBO- even no treatment. However, the most frequent complaint is
CAN 2018 estimates, 1,276,106 new cases of prostate cancer were difficulty with urination, increased frequency, and nocturia,
reported worldwide in 2018, with higher prevalence in the developed all symptoms that may also arise from prostatic hypertrophy.
countries. Differences in the incidence rates worldwide reflect differ- More advanced stage of the disease may present with urinary
ences in the use of diagnostic testing. Prostate cancer incidence and retention and back pain, as axis skeleton is the most common
mortality rates are strongly related to the age with the highest inci- site of bony metastatic disease.
dence being seen in elderly men (> 65 years of age). African-Amer- Many prostate cancers are detected on the basis of ele-
ican men have the highest incidence rates and more aggressive type vated plasmatic levels of prostate-specific antigen (PSA > 4
of prostate cancer compared to White men. There is no evidence yet ng/mL), a glycoprotein normally expressed by prostate tissue.
on how to prevent prostate cancer; however, it is possible to lower However, because men without cancer have also been found
the risk by limiting high-fat foods, increasing the intake of vegeta- with elevated PSA, a tissue biopsy is the standard of care to
bles and fruits and performing more exercise. Screening is highly confirm cancer’s presence.
recommended at age 45 for men with familial history and African- Diet and physical activity play an important role in pros-
American men. Up-to-date statistics on prostate cancer occurrence tate cancer development and progression. Dietary factors are
and outcomes along with a better understanding of the etiology and mainly associated with the observed worldwide and ethnic dif-
causative risk factors are essential for the primary prevention of this ferences in the incidence rates of prostate cancer [5-9].
disease. Most studies are devoted not only into identifying genes
involved in the inherited form of prostate cancer but also the
Keywords: Prostate cancer; Epidemiology; Incidence; Mortality; mutations occurring in the acquired form. Therefore, a de-
Trends; Survival; Etiology; Risk factors; Prevention tailed analysis of prostate cancer epidemiology and evaluation
of risk factors can help to understand the connection between
genetic mutations and the role of the environment in triggering
these mutations and/or favoring tumor progression. Increased
understanding of the etiology and causative risk factors of
Introduction prostate cancer will provide ways to identify at-risk males and
support the development of effective screening and prevention
Prostate cancer is the second most frequent malignancy (after methods.
lung cancer) in men worldwide, counting 1,276,106 new cas-
es and causing 358,989 deaths (3.8% of all deaths caused by
cancer in men) in 2018 [1, 2]. The incidence and mortality of Epidemiology
prostate cancer worldwide correlate with increasing age with
the average age at the time of diagnosis being 66 years. Of Based on GLOBOCAN 2018 estimates, we have evaluated
note, for African-American men, the incidence rates are higher worldwide prostate cancer incidence and mortality rates, as
when compared to the White men, with 158.3 new cases diag- well as analyzed incidence and mortality, temporal trends and
nosed per 100,000 men and their mortality is approximately survival rates.
twice as White men [3]. Reasons for this disparity have been
hypothesized to differences in social, environmental and ge-
Incidence
Manuscript submitted February 20, 2019, accepted March 15, 2019

The incidence rate of prostate cancer varies across the regions
Hospitalist, Department of Internal Medicine, SOVAH Health, Martinsville, and populations (Fig. 1) [2]. In 2018, 1,276,106 new cases of
VA 24112, USA. Email: rawlap@gmail.com prostate cancer were registered worldwide, representing 7.1%
of all cancers in men [1]. Prostate cancer incidence rates are
doi: https://doi.org/10.14740/wjon1191 highly variable worldwide. The age-standardized rate (ASR)
Articles © The authors | Journal compilation © World J Oncol and Elmer Press Inc™ | www.wjon.org
This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits 63
unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited
Epidemiology of Prostate Cancer World J Oncol. 2019;10(2):63-89
Figure 1. Map showing estimated age-standardized incidence rates for prostate cancer worldwide in 2018, in males including all
ages. Created with mapchart.net. Data obtained from Globocan 2018 [2].
was highest in Oceania (79.1 per 100,000 people) and North and disparities in healthcare access.
America (73.7), followed by Europe (62.1). Conversely, Afri-
ca and Asia have incidence rates that are lower than those from
developed countries (26.6 and 11.5, respectively) [2]. Differ- Mortality
ences in incidence rates were 190-fold between the popula-
tions at the highest rate (France, Guadeloupe, 189.1), and the International mortality rates for prostate cancer vary consid-
populations with the lowest rate (Bhutan, 1.0). erably worldwide (Fig. 2) [2]. In 2018, the highest mortal-
Prostate cancer incidence increases with age [2]. Although ity rates were recorded in Central America (10.7 per 100,000
only 1 in 350 men under the age of 50 years will be diagnosed people), followed by Australia and New Zealand (10.2) and
with prostate cancer [10], the incidence rate increases up to 1 Western Europe (10.1) [2]. The lowest rate was reported in
in every 52 men for ages 50 to 59 years. The incidence rate is the countries of Asia (South-Central, 3.3; Eastern, 4.7 and
nearly 60% in men over the age of 65 years [11]. South-Eastern, 5.4) and Northern Africa (5.8) (Fig. 3) [2].
The reason for these differences among the countries is not One-third of the deaths for prostate cancer occurred in Asia
entirely clear. The worldwide variations in prostate cancer in- (33.0%, 118,427 of deaths), followed by Europe (29.9%,
cidence might be attributed to PSA testing [12]. For example, 107,315 of deaths). The mortality rate of prostate cancer rises
in Europe, prostate cancer is the most frequently diagnosed with age, and almost 55% of all deaths occur after 65 years
cancer among men, accounting for 24% of all new cancers of age [2].
in 2018, with around 450,000 new prostate cancer cases esti- US Preventive Task Force (USPSTF, 2018) has reported
mated in 2018 [13]. While in the USA, prostate cancer is the that there is a potential benefit of decreasing deaths from pros-
second most common cancer accounting for 9.5% of all new tate cancer in men aged 55 - 69 years with PSA screening [19].
cancer cases (164,690 new cases of prostate cancer) registered However, for men above 70 years of age for all races, the data
in 2018 [14]. According to recently conducted research stud- are less convincing [20].
ies, around 20-40% of the prostate cancer cases in the USA and African-American men have the highest prostate cancer
Europe could be due to overdiagnosis through extensive PSA incidence and mortality rates. This suggests not only that Af-
testing [12, 15, 16]. rican-American men may possess some specific genes that are
Research has shown that African-American men have more susceptible to mutations in prostate cancer, but mainly
the highest incidence of prostate cancer worldwide and more that these mutations are associated with a more aggressive type
likely to develop disease earlier in life when compared to other of cancer. However, a study conducted by Oliver in 2007 [21]
racial and ethnic groups [17]. This is reflected in data not only reported that African-American men were less likely to iden-
for African-American men, but also for Caribbeans, and Black tify early symptoms of prostate cancer correctly than Cauca-
men in Europe, suggesting that they possess a common genetic sian men.
background more prone to the development of the cancer. Of
note, Chu et al [18] reported that incidence rates of prostate
cancer were as much as 40 times higher among African-Amer- Trends
ican men than those in Africa. These differences suggest that
environmental factors also play an important role in the etiol- Temporal trends of prostate cancer incidence and mortality
ogy of the prostate cancer and variations in incidence may be varied significantly internationally during the past years, and
due to underdiagnosis, differences in the screening methods they seem tightly correlated to the adoption of PSA testing for
64 Articles © The authors | Journal compilation © World J Oncol and Elmer Press Inc™ | www.wjon.org
Rawla World J Oncol. 2019;10(2):63-89
Figure 2. Map showing estimated age-standardized mortality rates for prostate cancer worldwide in 2018, in males including all
ages. Created with mapchart.net. Data obtained from Globocan 2018 [2].
early detection of the disease especially in Western countries rica (+120.6%), followed by Latin America and the Caribbean
[22]. (+101.1%) and Asia (100.9%). On the contrary, the lowest in-
Incidence rates in the USA, Australia, and Canada have cidence will be registered in Europe (+30.1%). This increase in
seen an increase between the 1980s and 1990s but now de- the incidence rates appears to be related to an increased life ex-
creasing because of rapid dissemination of PSA testing [22, pectancy. Increasing incidence rate trends in developing coun-
23], while rates in European countries continue to slightly in- tries is likely due to improved access to medical care as well
crease because of increased understanding of PSA screening as increased documentation and reporting of cases. Finally, the
and gradual adoption of PSA testing, but also other factors may fact that incidence rates are increasing in those regions where
be involved, such as exposure to ultraviolet radiation and diet PSA testing is not routinely used suggests that this phenom-
[24]. enon reflects westernization of the lifestyle including obesity,
Interestingly, a trend towards an increase of prostate can- physical inactivity and dietary factors [25].
cer incidence worldwide with 1,017,712 new cases (+79.7% Prostate cancer mortality rates in most western countries
overall change) up to 2040 is estimated (Table 1) [4]. The including North America as well as in Western and North
highest incidence of prostate cancer will be registered in Af- Europe have been steadily declining [22, 25]. Although the
Figure 3. Bar chart showing estimated age-standardized incidence and mortality rates (world) in 2018, prostate, males, all ages.
Data obtained from Globocan 2018 [2].
Articles © The authors | Journal compilation © World J Oncol and Elmer Press Inc™ | www.wjon.org 65
Table 1. Estimated Number of Incident Cases From 2018 to 2040, Prostate Cancer, Males, All Ages
2018 2040
Number Number Demographic change Change in risk Overall change
Africa Males (APC 0%) 80,971 178,634 97,663 (+120.6%) 97,663 (+120.6%) 97,663 (+120.6%)
Latin America and the Caribbean Males (APC 0%) 190,385 382,808 192,423 (+101.1%) 192,423 (+101.1%) 192,423 (+101.1%)
North America Males (APC 0%) 234,278 312,901 78,623 (+33.6%) 78,623 (+33.6%) 78,623 (+33.6%)
Europe Males (APC 0%) 449,761 585,134 135,373 (+30.1%) 135,373 (+30.1%) 135,373 (+30.1%)
Asia Males (APC 0%) 297,215 597,180 299,965 (+100.9%) 299,965 (+100.9%) 299,965 (+100.9%)
reasons are not clear, it may reflect both early detection and mortality despite the lower incidence.
improved treatment [26-28]. However, in the USA, a recent
randomized controlled trial failed to demonstrate benefits of
PSA testing in decreasing prostate cancer deaths, although an- Survival
other research study done in Europe showed benefits of PSA
testing [29, 30]. When ethnicity-specific trends were analyzed, Although prostate cancer incidence rates are high, most pros-
it was observed that the decline in mortality in African-Amer- tate cancer cases are detected when the cancer is confined to
ican men was greater than that in White men between 2001 within the prostate. The 5-year survival rate in the USA for
and 2015 (Fig. 4) [11, 20]. Negoita et al documented that im- men diagnosed with prostate cancer is around 98% [11]. The
proved and newer modalities of detection and treatments and data from the Eurocare project (EUROCARE-5) of patients di-
improved treatment of resistant and metastatic prostate cancer agnosed with prostate cancer from 2003 to 2007 showed that
may justify this trend [20]. 5-year survival rates were 83% [13]. Survival varied from 76%
From 2018 to 2040, it is estimated that mortality will dou- in Eastern countries to 88% in Southern and Central European
ble with 379,005 deaths worldwide [4]. The highest mortality countries. Moreover, survival has increased over time in all
rate is estimated to be in Africa (+124.4%), followed by Asia over Europe with the greatest improvement being observed in
(116.7%), while the lowest incidence will be registered in Eu- the Eastern European countries [31].
rope (+58.3%) (Table 2) [4]. The above finding is not surpris- Despite in the last decades, science has made so much
ing due to the limited resources for screening and detection of progress to unveil molecular mechanisms and risk factors in-
prostate cancer which increases the odds of it being detected volved in the prostate cancer, it still is the second leading cause
during the late stages. Furthermore, considering that medi- of cancer mortality among males in the USA [32]. Finally, the
cal care and assistance is not widely accessible in developing general idea for all types of cancers is that the earlier they are
countries, this may provide a possible explanation for the high caught, the earlier they can be successfully treated remaining
Figure 4. Recent trends of prostate cancer mortality rates in USA in 2000 - 2015 by race/ethnicity. Data source: US Mortality
Files, National Center for Health Statistics, CDC [11].
Table 2. Estimated Number of Deaths From 2018 to 2040, Prostate Cancer, Males, All Ages
2018 2040
Number Number Demographic change Change in risk Overall change
Africa Males (APC 0%) 42,298 94,909 52,611 (+124.4%) 52,611 (+124.4%) 52,611 (+124.4%)
Latin America and the Caribbean Males (APC 0%) 53,798 124,990 71,192 (+132.3%) 71,192 (+132.3%) 71,192 (+132.3%)
North America Males (APC 0%) 32,686 65,766 33,080 (+101.2%) 33,080 (+101.2%) 33,080 (+101.2%)
Europe Males (APC 0%) 107,315 169,865 62,550 (+58.3%) 62,550 (+58.3%) 62,550 (+58.3%)
Asia Males (APC 0%) 4,465 9,179 4,714 (+105.6%) 4,714 (+105.6%) 4,714 (+105.6%)
the patients disease-free. However, because the majority of lander (52.4), followed by White (93.9). The highest incidence
prostate cancer have a slow and often indolent course (defined rate is seen in African-American men (157.6) [11].
as “low-risk” tumor), men can avoid immediate treatment (and This vast disparity has been associated with both socioec-
prospective side effects) while safely undergoing active sur- onomic conditions and biologic factors [42]. For instance, it is
veillance or watchful waiting. believed that African Americans receive lower-quality health-
care and consequently, they are also less likely to undergo PSA
screening [43]. Notably, significantly higher PSA levels were
Etiology and Risk Factors seen in Black men, with or without prostate cancer when com-
pared to White men [44, 45].
The etiology of prostate cancer is the subject of numerous Several studies proposed that genetic predisposition might
studies and remains largely unknown compared to other com- play a role. African-American men have the more common
mon cancers. The well-established prostate cancer risk factors chromosome 8q24 variants, which have been shown to be
are advanced age, ethnicity, genetic factors and family history associated with increased prostate cancer risk [46-49]. Some
[33-35]. Other factors positively associated with prostate can- research studies have also demonstrated that African Ameri-
cer include diet (increased consumption of saturated animal fat cans have a high rate of variations in genes that suppress tu-
and red meat, lower intake of fruits, vegetables, vitamins, and mors such as EphB2 [50] or that regulate cell apoptosis such
coffee), obesity and physical inactivity, inflammation, hyper- as BCL2 [51]. Furthermore, African-American men display a
glycemia, infections, and environmental exposure to chemi- more aggressive form of the disease, which has also been asso-
cals or ionizing radiation [34, 36-40]. ciated with genetic and biologic differences, although lack of
adequate screening and delayed presentation was not excluded
too [42].
Age
Family history and genetic factors

Prostate cancer is the most commonly diagnosed malignancy
among elderly males [1]. Indeed, an increasing number of sen-
ior men are diagnosed with prostate cancer due to increasing It is estimated that about 20% of patients with prostate cancer
life expectancy and the increased use of PSA screening. It was report a family history, which may develop not only because of
observed that the risk increases especially after 50 years of shared genes but also for a similar pattern of exposure to cer-
age in White men who have no family history of the prostate tain environmental carcinogens and common lifestyle habits
cancer, and after 40 years of age in Black men or men with a [52, 53]. Several studies reported that inherited genetic back-
familial history of prostate cancer [14]. ground is associated with increased risk for prostate cancer,
Scardino reported that almost 30% of men over 50 years contributing to about 5% of disease risks [54, 55]. Particularly,
of age, who died for causes other than prostate cancer, were this risk is increased by several folds when high-penetrance
found with histological evidence of prostate cancer at the mo- genetic “risk” alleles are inherited, conversely to more com-
ment of autopsy [41]. Indeed, due to its indolent course, elder- mon low-penetrance loci that increase the risk only modestly.
ly men who have concurrent severe co-morbid disease during Gene linkage studies reveal major susceptibility loci for
their lifetimes are more likely to die from other related health prostate carcinoma on genes in seven different loci. Chromo-
conditions or other diseases rather than from prostate cancer. some 1q24-25 that is referred as HPC1 gene encodes the enzyme
ribonuclease L (RNASEL) [56], which is involved in the innate
immune defense mechanisms and the interferon (IFN)-mediated
Ethnicity signaling [57]. It plays an important role in reducing antiviral
activity and the regulation of apoptotic cell death [58]. Of note,
Prevalence of prostate cancer highly varies among different analysis of human prostate cancer samples from patients with
racial groups. In the USA, the lowest incidence is observed RNASEL mutations showed the presence of retrovirus unveiling
in American Indian/Alaska (46.9) Native and Asian/Pacific Is- the importance of antiviral defenses to prostate cancer develop-
ment [59]. Moreover, detection of retroviral infections in some pid metabolism; and 3) increasing basal metabolism, insulin
cases of prostate cancer also showed the potential connection growth factor and tumor proliferation.
of chronic retroviral infection and consequent tissue inflamma- High-calorie intake of saturated animal fat has shown to
tion with cancer initiation [60, 61]. Another HPC gene (HPC2/ increase the growth of prostate cancer cells by increasing the
ELAC2) was identified on chromosome 17p11 and encodes a circulating levels of androgens [76, 77]. Furthermore, rand-
protein with poorly understood function [62], ELAC2, which omized cross-over studies involving low-fat and high-fat diets
is involved in prostate cancer development by binding SMAD2 showed that the level of androgen is lower post-prandial as
that up-regulate proliferation through activation of TGF-beta well as in vegetarians [78]. Finally, several studies reported
signaling pathway [63]. The third identified HPC gene is mac- that alteration of lipid levels undergoing to a low-fat diet re-
rophage scavenger receptor 1 (MSR1), which resides on chro- duces testosterone levels [79-81].
mosome 8p22 [64]. However, considering the low penetrance of Excessive fat increases oxidative stress and ROS levels
this allele, several studies failed to confirm its association with that attack the cells causing peroxidation and eventually DNA
HPC [65, 66]. Additionally, a subset of HPC was found to oc- damage. A role for lipid metabolism and its metabolite have
cur in men with BRCA1 and 2 mutations that showed a clini- also been observed in mice and found that dietary fat is an
cally aggressive form of prostate cancer [67]. Moreover, BRCA2 important modulator of prostate cancer growth. For example,
mutations were correlated with a higher incidence of prostate while some studies did not find any difference in terms of tu-
cancer, and PALB2, BRCA2-interacting protein, was involved mor growth and survival of mice placed on a Western diet,
in familial prostate cancer [68]. other studies showed a delay in cancer cell growth in mice with
The X chromosome is also believed to have a role in pros- low-fat corn-oil diets, suggesting that the amount and type of
tate cancer inheritance, because it contains the androgen recep- fat are critical [82].
tor (AR) and because small deletions in Xq26.3-q27.3 region Mechanistically, corn-oil may promote cancer growth via
were noted in sporadic and hereditary forms of prostate cancer the linoleic acid, the most abundant omega-6 fat in the oil. Ara-
[69, 70]. More recent studies in 301 hereditary prostate cancer chidonic acid which is a metabolite of linoleic acid gives rise
affected families defined a number of other loci that may con- to the formation of several pro-inflammatory prostaglandins
tribute to hereditary prostate cancer [71]. (PG), including PGE2 that promotes cell proliferation, and
5-hydroxyeicosatetraenoic acid that is produced by the action
of 5-lipoxygenase, which is found to be increasingly expressed
Diet in malignant prostate cancer. Hence, a decrease in omega-6
fatty acid intake can decrease cancer growth. As opposite to
Dietary factors may play an essential role in the development omega-6 fats pro-inflammatory effect, omega-3 fats are found
of prostate cancer as evidenced by several studies on immi- beneficial against cancer growth [83].
grants moving from developing countries (low-risk areas) to
industrialized countries (higher risk), that showed how the
Red meat
change to a “westernized” lifestyle induced a shift towards an
increased prostate cancer incidence. For example, Chu et al
[18] reported that when compared to those in Africa, the inci- Dietary meat intake has been associated with prostate carcino-
dence rate of prostate cancer among African Americans was as genesis by correlating cancer incidence and mortality with per
high as 40 times, while Hsing et al in 2000 [72] showed that capita meat consumption [84]. Rohrmann et al [85] showed
compared to men living in China, the prostate cancer incidence that men consuming five or more servings of processed meat
was 16-fold higher for Chinese men living in the USA, sug- per week had a higher risk of prostate cancer when compared
gesting that environmental factors play an important role. with men who consume one or fewer servings per week. In Af-
There are multiple evidences that certain foods are associ- rican-American men, there was no association observed with
ated at higher risk, while others are even protective. high consumption of red meats and increased prostate risk.
However, there was a 20% increased risk for non-advanced
prostate cancer in those consuming red meat cooked at high
Saturated animal fat temperature [86]. Cooking at higher temperatures (125 - 300
°C) causes the formation of aromatic hydrocarbons and muta-
Multiple ecological studies have shown a positive correlation genic heterocyclic amines [87, 88]. Grilled or barbecued meat
between prostate mortality and per capita intake of meat, fat can result in the formation of N-nitroso compounds that can
and dairy products [73, 74]. A recent case-control study in pa- result in lipid peroxidation and DNA damage by the produc-
tients less than or equal to 60 years found that high intake of tion of free radicals [89, 90].
total fat was associated with a statistically significant increase
in prostate cancer risk [75].
Calcium, milk and dairy products
There are several biological mechanisms that are thought
to be involved between saturated animal fat intake and pros-
tate cancer risk: 1) promoting prostate carcinogenesis via an- Dairy foods have generally been associated with an elevated
drogen; 2) increasing levels of reactive oxygen species (ROS) prostate cancer risk [85, 91-94]. Both calcium from supplements
and increasing leukotrienes and prostaglandins levels from li- and dairy put male at high prostate cancer risk. Greater than
2,000 mg per day of calcium was associated with a greater risk dence of a connection between tomatoes assumption and pros-
of prostate cancer. The Health Professional Follow-Up Study tate cancer risk requires further investigation.
examined the diet of 47,885 men and looked closely at partici-
pants’ consumption of animal food, protein and calcium [95].
Vitamin and mineral supplements
After a 24-year follow-up, prostate cancer was diagnosed in
5,861 men, which was associated with high calcium intake [96].
Vitamin D
Vegetables
An inverse relationship was observed between sunlight, or
UVB exposure, and incidence of prostate cancer [126, 127],
Although conflicting results have been generated regarding suggesting that vitamin D deficiency might increase prostate
dietary fat, a strong relationship was found between intake of cancer risk development [128]. Similarly, discoveries were
Crucifers or Brassica vegetables (broccoli, Brussels sprouts, made by Barnett and Beer [129] who found that people living
cauliflower, cabbage, and turnips) and reduced prostate can- in “sunny” countries were at lower risk of developing second-
cer risk. Crucifers have anticancer properties mediated by ary solid cancer after melanoma compared to people living in
phenyethyl isothiocyanate, sulforaphane, phytochemicals and “less sunny” countries.
indole-3-carbinol [97]. Some studies in the USA on a diet rich The incidence of prostate cancer in African-American
with broccoli have shown evidence for the protective effect men is twice that of Caucasians, suggesting that race might
of Brassica vegetables against prostate cancer [98]. However, play a role. There might be a role for vitamin D deficiency in
some other studies revealed no anticancer capabilities of Bras- this as UV radiation is blocked in darkly pigmented skin due
sica vegetables [99-102]. to high melanin levels and this mechanism inhibits the conver-
sion to vitamin D3 [130].
Dietary soy and green tea Biochemical evidence supports a role for vitamin D in
prostate growth [131, 132]. Cell proliferation and invasion can
be inhibited by vitamin D and its analogs, and stimulate cellular
Prostate cancer incidence is significantly lower in Asia when differentiation and apoptosis in prostate cancer cells as well as
compared to North America, which has prompted research in tumor progression in animal models [132-134]. These find-
interest in the potential chemo-preventive action of soy and ings provide a strong rationale for the use of vitamin D analogs
green tea which are a part of the diet in Asia. Decreased risk as therapeutic agents for prostate cancer in a case that androgen
of prostate and several other cancers has been seen with con- deprivation therapy has failed [135]. Early clinical trials with
sumption of soy and green tea [103-106]. Catechins found in 1α,25(OH)2D3 revealed serious side effect such as hypercal-
green tea and isoflavones in soybeans have anticarcinogenic cemia and hypercalciuria associated with its systemic admin-
properties, and they inhibit different phases of carcinogenesis istration [136, 137]. Screening of several thousand vitamin D
[107, 108] and metastasis [109-111]. Additionally, green tea analogs identified a more potent and less calcemic compound
polyphenols cause a reduction of IGF-1 levels [112-114]. compared to 1α,25(OH)2D3 when was tested in nude mice to
inhibit human prostate cancer cells growth [133, 134]. Further
studies are needed to assess the use of vitamin D analogs as
Tomatoes and lycopene
a chemopreventive or therapeutic approach in prostate cancer.
Tomatoes seem to reduce the risk of prostate cancer. They

contain high levels of lycopene which has potent anti-oxidant Vitamin E
properties as well as cancer-preventive effects [115-119]. Ly-
copene also acts on the androgen receptors and reverses the Vitamin E is a vitamin which is fat soluble. Vegetable oils, egg
effects of dihydrotestosterone and also inhibits insulin growth yolks, and nuts are the important dietary sources of vitamin
factor (IGF-I)-stimulation through Akt and GSK3β and tyros- E. Tocopherols present in vitamin E have both potent cellu-
ine phosphorylation of GSK3 [120]. lar anti-oxidant with anticancer properties [54, 138]. Studies
Tomato product consumption and lycopene intake were investigating the relationship between vitamin E and prostate
both associated with a decreased risk of prostate cancer [121]. cancer risk have shown contradicting results. The ATBC trial
The Health Professional Follow-Up Study showed a decreased showed that in men who smoked supplementing daily vitamin
risk of prostate cancer with 2 - 4 servings of tomato sauce per E was not able to reduce the incidence of prostate cancer [139].
week [95]. Venkateswaran and Klotz [122] demonstrated that In another large clinical trial (SELECT trial), vitamin E sup-
in the Lady transgenic mouse model, lycopene is able to re- plementation did not show any benefit in 31,000 men with in-
duce prostate cancer incidence only in association with sele- cident prostate cancer [140].
nium and vitamin E.
On the other hand, an open phase II study of lycopene in
Selenium
advanced prostate cancer could not demonstrate any clinical
benefit of this agent [123]. Similar results were seen in two
other small epidemiological studies [124, 125]. Thus, the evi- Selenium is an essential micronutrient. It is found in the plants
like tubers, cereals and legumes and animal products like meat, more than three drinks per day between wine, liquors or beer)
eggs, and seafood in the form of selenomethionine and seleno- may be a possible risk factor for prostate cancer and other can-
cysteine. It has been inversely associated with several cancers, cers [159]. However, several cohort studies have suggested a
including prostate cancer. weak correlation between alcohol intake and prostate cancer
Several studies have shown a 50-60% risk reduction of de- mortality [160-163], while others did not find any relation with
veloping prostate cancer when comparing high selenium con- increased risk [164]. As opposite, Dennis et al reported a sig-
sumption to low selenium consumption [141, 142]. The NPC nificant relationship between higher alcohol intake and pros-
trial showed a 50% reduction of incidence of prostate cancer tate cancer risk with a relative risk (RR) ranging from 1.05
among men that were taking selenium supplementation [143]; to 1.21 for one or four alcoholic drinks per day, respectively
however, SELECT trial did not report any beneficial effect of [165, 166].
administering selenium alone or combination of selenium with
vitamin E [140]. The different outcomes could result from the
Coffee
utilization of two different forms of selenium: selenized yeast
in the NPC, whereas selenomethionine in the SELECT. These
forms differ significantly in their biological effects, and it was Coffee consumption has been inversely associated with in-
shown they have different mechanisms of action. Selenom- creased prostate cancer risk. Observational studies and some
ethionine acts on prostate cancer cells and induces cell cycle animal studies have revealed an association between long-term
arrest [144, 145]. It can also act by inducing apoptosis and coffee drinking and improved glucose metabolism as well as
inhibiting angiogenesis [145, 146]. Methylseleninic acid acts insulin secretion [167]. Consistently, a reduced risk of type 2
via a caspase-mediated pathway and induces apoptosis [147]. diabetes was observed in those patients who reported higher
Interestingly, Chan et al [148] emphasized the role of gen- consumption of coffee.
otype with respect to the effectiveness of selenium interven- A large prospective study demonstrated that coffee intake
tion. This study revealed that high selenium might be protec- was weakly inversely associated with overall risk of prostate
tive against an aggressive form of prostate carcinoma in men cancer, while it significantly lowered the risk of lethal and ad-
with the AA genotype of superoxide dismutase (SOD)-2 and vanced prostate cancer when heavy coffee drinkers are com-
increase the chances of having a worse tumor in men with a V pared to the one that drinks less coffee [168]. Considering the
allele. These data unveil the potential risks and benefits associ- effects of coffee consumption on insulin, antioxidants and an-
ated with selenium intervention in prostate cancer and may, in drogens [169-174], the findings of this study are in agreement
part, explain the conflicting results from other studies. with the strongest associations between insulin, antioxidants
and androgens with a lower incidence of prostate cancer in an
advanced disease rather than for overall disease.
Folate and vitamin B12
Low folate and vitamin B12 can lead to altered methylation Obesity, insulin and physical activity
and lead to cancer development as these essential vitamins
participate in DNA methylation, synthesis and repair [149]. In Obesity is linked to advanced and aggressive prostate cancer
vitro [150], in vivo studies [151] and genetic studies [152, 153] [175, 176], and high body mass index (BMI) is associated with
on prostate cancer showed the role of folate in the develop- more aggressive disease too and a worse outcome [121, 177].
ment of an aggressive form of prostate cancer. Furthermore, The possible explanation is that most of the time obese
elevated serum concentration of folate was associated with an men present with alteration of circulating levels of metabolic
increased proliferation of prostate cancer cells in some pros- and sex steroid hormones, which are known to be involved in
tate samples collected from patients who underwent radical prostate development as well as oncogenesis [178].
prostatectomy [154]. Obesity, particularly when combined with physical in-
However, a recent meta-analysis reported that higher activity, leads to the development of insulin resistance with
concentrations of vitamin B12 and folate have a modest 12% reduced glucose uptake. That, in turn, leads to chronically el-
increased risk of prostate cancer [155]. In people who have evated blood levels of insulin. Insulin is a hormone that pro-
prostate cancer, available data do not show an effect of con- motes growth and proliferation, thus is reasonable to add it in
sumption of folate on disease progression [156] or survival the list of risk factors that promote prostate cancer initiation
[157]. In conclusion, the association of folate and vitamin B12 and/or progression [179]. Additionally, adipose cells represent
with prostate cancer is unclear and requires further investiga- a source of inflammation as well as of macrophages in adipose,
tion. which releases inflammatory mediators [180]. Three meta-
analyses reported a modest but consistent association between
obesity and prostate cancer incidence independently of BMI
Alcohol consumption increase [181]. Data from three national surveys in the US
population reported that obesity is associated with more ag-
The relationship between alcohol use and several types of hu- gressive prostate cancer and higher mortality despite its lower
man cancers, including prostate cancer, has been since long incidence [182].
observed [158]. Heavy alcohol abuse (> 15 g ethanol/day, or One of the difficulties in interpreting results for obese men
is that they have greater circulating plasma volume and there- growth was driven by androgens, after observing the benefits
fore a “hemodilution” of PSA [183]. Consequently, they will of castration in prostate cancer patients [192]. Several in vitro
less likely undergo a biopsy, and detect the presence of the data obtained with well-differentiated prostate cancer cell lines
tumor until a more advanced stage [179, 181]. Because obe- showed that they respond to androgen stimulation and undergo
sity is a potential factor leading to lower detection of prostate apoptosis upon androgen withdrawal [193, 194]. Likewise, in
cancer, clinicians should consider BMI when interpreting PSA vivo studies showed that androgens promote tumorigenesis
concentration. Physicians should be aware of these factors to and xenograft growth in animal models, and tumor regression
avoid misdiagnosis among obese men and thus should include is seen upon androgen deprivation [195, 196]. Clinically, ADT
BMI along with other well-established risk factors (race, digi- remains a mainstay in prostate cancer treatment, especially in
tal rectal examination (DRE) and family history) in the exist- advanced disease [197]. Even though preclinical studies sup-
ing prostate cancer risk calculator [182]. ported a role for androgens in prostate cancer pathogenesis,
Exercise is supposedly one of the easiest modifiable risk clinical data are still controversial [198].
factor to manage in a way to obtain many benefits and relative- Several evidences that the androgen pathway is one of
ly few side effects when it comes to prostate cancer prevention. the most important signaling mechanisms involved in pros-
Indeed, Keogh and McLeod found that veterans who exercised tate cancer come from gene linkage analysis, which reveals
had a significantly lower risk of prostate cancer [184]. Prostate a significant association between prostate cancer risk and sin-
cancer patients who are committed to exercise display lower gle nucleotide polymorphisms (SNPs) in the genes encoding
PSA levels and delay in initiating androgen deprivation thera- enzymes involved in the synthesis of testosterone and dihy-
py (ADT) by 2 years compared with less active peers and have drotestosterone (DHT): hydroxysteroid (17-beta) dehydro-
a lower risk of high-grade disease, other than having a greater genase-1, hydroxy-delta-5-steroid dehydrogenase [199-202],
quality of life and less fatigue [184]. 5α-reductase-1 [203] and -2 [204-206], and CYP17, CYP3A4,
CYP19A1 [207]. There is also an association between prostate
cancer and the variants of androgen-responsive genes - kal-
Cigarette smoking likrein family, hK2 and PSA [208-210], and microseminopro-
tein [211-213], as well as genes involved in estrogen receptor
Active and passive exposures to cigarette smoke are consid- signaling - estrogen receptors α [214] and β [215, 216]. Further
ered carcinogenic for many human cancers [185]. studies are needed to understand how those gene variations in-
fluence prostate cancer incidence.
Association of smoking and prostate cancer risk may have
Although the positive role of androgens on prostate cell
either a hormonal or genetic basis. For instance, male smokers
growth has been established, some studies found that in pros-
usually have higher levels of circulating sex hormones, which
tate cancer patients, the testosterone and DHT levels were low,
may increase prostate cancer risk or contribute to cancer pro-
suggesting that non-androgenic hormones, including estro-
gression [186, 187]. On the other hand, functional polymor- gens, insulin and vitamin D may be involved in the prostate
phisms in genes involved in polycyclic aromatic hydrocarbons carcinogenesis. Several studies have demonstrated that estro-
(PAHs) metabolism, one of the carcinogenic chemical of the gen, including the natural hormone E2, induces multiple forms
cigarette smoke [185], may affect cancer onset and progres- of genetic lesions such as chromosomal alterations, DNA dam-
sion [188]. age, gene mutations, and microsatellite instability, strongly in-
Most of the epidemiological studies have not found a dicating that estrogen may serve as a carcinogen in the devel-
relationship between smoking and incidence of prostate can- opment of prostate cancer [217, 218].
cer, while some cohort studies have documented a 2 - 3 times
higher risk in smokers of more than a pack a day compared
with nonsmokers [189, 190]. However, these studies have not Insulin and insulin-like growth factor
demonstrated a convincing dose-response relationship, neither
have they evaluated the influence of possible dietary risk fac- Hyperglycemia has been positively associated with cancers
tors that are confusing [189]. On the other hand, most studies such as breast, pancreatic and colorectal [219]. However, its
examining the relationship between smoking and prostate can- link with prostate carcinogenesis is conflicting. Several studies
cer mortality demonstrated that smoking patients double the found evidence of higher risk of more aggressive or advanced
risk of dying from the disease compared to nonsmokers [189- prostate cancer among men with abnormal glucose levels, with
191]. Moreover, there is a dose-response relationship between the association being not significant in two of the studies [220-
the numbers of cigarettes per year of the smoker 10 years be- 223].
fore diagnosis and the increased mortality risk [191]. Conversely, several other studies reported a protective ef-
fect of hyperglycemia or type II diabetes against high-grade or
more advanced prostate cancer [224-226]. For several decades,
Sex hormones
glucose has been documented as an important source of energy
for rapid tumor cell proliferation [227]. Evidence from clinical
There is a large body of both historical and modern data sup- and genetic studies has also linked the hyperglycemic environ-
porting a role for androgens in prostate cancer pathogenesis ment to carcinogenic processes such as apoptosis, oxidative
and progression, also known as the “androgen hypothesis”. stress, DNA damage and chronic inflammation, which may
In 1941, Huggins and Hodges proposed that prostate cancer drive the aggressiveness and progression of cancer [228-231].
Serum glucose is directly controlled by insulin, thus higher SNPs in genes involved in inflammation, such as cyclooxy-
glucose level induces insulin secretion from pancreatic β cells. genase (COX-2) [248, 249], interleukin-1 (IL-1) [250], IL-6
Lehrer et al showed that patients with high-risk prostate can- [251, 252], IL-8 [250] and IL-10 [250, 253], tumor necrosis
cer had higher insulin levels [171]. In addition, diet-induced factor-α (TNF-α) [254] and Toll-like receptor-4 (TLR4) [253,
hyperinsulinemia was associated with increased tumor growth 255-257] were associated to prostate cancer risk.
in a xenograft model [232]. Finally, the high level of circulat- Prostatitis is the inflammation of the prostate gland that
ing insulin decreases the production of insulin-like growth fac- is hard to diagnose because it is often asymptomatic [258].
tor (IGF-1)-binding proteins, increases the level of IGF-1 and Notably, men with symptoms of prostatitis are more likely to
increases the production of advanced glycation end products, be diagnosed with prostate cancer as a result of the increased
which promote carcinogenesis [233]. prevalence of biopsy [259].
In the past years, several studies have recognized a crucial Lu et al conducted a study including cases and controls
role for the components of IGF system in prostate cancer biol- from Minnesota and found that there was a significant associa-
ogy and its implication in both mitogenic and anti-apoptotic tion between prostatitis and prostate cancer (odds ratio = 1.7;
events in prostate cancer cell lines [234]. The IGF family is 95% confidence interval: 1.1 - 2.6) [260]. A first meta-analysis
composed of two receptors (insulin receptor (INSR), IGF-1 involving 11 studies between1971 and 1996 provided statisti-
receptor (IGF-1R) and mannose 6-phosphate receptor (M6P/ cal evidence that prostatitis is a significant risk factor in pros-
IGF-2R)), three ligands (insulin, IGF-1 and IGF-2) and six tate cancer [261]. This observation was confirmed later with
known types of circulating IGF-binding proteins (IGFBP1-6) another meta-analysis that included studies between 1990 and
that modulate the bioavailability and bioactivity of the IGFs 2012 [262].
[235]. The IGF system regulates many important cellular pro- Development of prostatitis is induced by one or a combi-
cesses critical for normal prostate growth and development, nation of factors including infections, chemical and physical
such as proliferation, differentiation and cellular metabolism. trauma, and diet. Chemical irritation because of urine reflux,
The relevance of the IGF system has been evaluated in several or abnormal flow of urine from the bladder back through the
studies. Increased serum concentration of IGF-1 was correlat- ureters, may cause chronic inflammation in the prostate [263].
ed to higher risk of prostate cancer [236-238]. Non-sexually transmitted pathogens such as E. coli and Pro-
However, preclinical studies [239-241] as well as clini- pionibacterium acnes can cause acute and chronic prostatitis
cal studies [291, 292] showed conflicting results. Therefore, [264, 265]. Also, many sexually transmitted organisms, includ-
whether IGF-1 serum levels can be used as a prognostic tool ing Neisseria gonorrhea [266] and Chlamydia trachomatis
requires further investigation. [267], can induce chronic infection and inflammation, that po-
tentially increase the risk of developing prostate cancer [268].
It appears clear that inflammation is the ubiquitous factor
Chronic inflammation and prostatitis associated with increased risk of prostate cancer, independent-
ly of its source (either pathogens or environmental factors).
There is a strong link between prostate cancer and inflamma- Finally, the several signaling pathways involved in the in-
tion, and in 1863, Rudolf Virchow was the first to identify the flammatory process that modifies prostate microenvironment
high density of leukocytes in neoplastic samples, suggesting a and the complexity of biological events linking inflammation
positive association between inflammation and cancer [242]. to prostate cancer progression and metastatic spread provide
After that, both epidemiological and biological studies pro- a broad range of promising targets for pharmaceutical treat-
vided evidence that inflammation is behind the high-grade or ments.
aggressive prostate tumors and ultimately metastatic spread
[174, 243]. The evidence-based knowledge so far supports
Sexually transmitted disease (STD)
the role of inflammatory responses in the regulation of tumor
microenvironment through the remodeling of the extracellular
matrix (ECM) and initiation of epithelial-mesenchymal transi- Several epidemiologic studies evidenced that factors related
tion (EMT). Indeed, inflammatory cells release growth factors to sexual behavior and STDs may be associated with prostate
and cytokines within the tumor microenvironment to promote cancer [269].
angiogenesis and remodeling of the ECM, while further in- STDs represent a major public health problem world-
flammatory cytokines released within the reactive stroma in- wide. Human papilloma virus (HPV) and herpes simplex virus
duce EMT-mediated responses [244]. (HSV) are common STDs worldwide [270, 271], the former
Patients with elevated PSA often present with intrapro- being also involved in the etiology of cancer of cervix uteri
static inflammation detected with biopsies [245]. Recently, and other anatomical sites [272, 273]. The first claims of an
an inflammatory effector, pentraxin 3, has been identified as etiological role of STDs in the development of prostate cancer
a biomarker for predicting tumor progression due to prostatic date back to the 1950s [274] and several mechanisms were
inflammation in prostate cancer patients [246]. subsequently proposed to explain this association. For gonor-
Chronic inflammation causes proliferative inflammatory rhea and other bacterial infections, prostate inflammation and
atrophy (PIA) [174], which may develop prostatic intraepithe- prostate atrophy are the processes that lead to prostate cancer,
lial neoplasia (PIN) a well-known precursor of prostate cancer whereas for viral infections, the emphasis was placed on the
[247]. Consistently with the tight connection between chronic transforming properties of viruses, in particular, HSV [275].
inflammation and high-grade prostate cancer [243], several A large population-based case-control study among Af-
rican-American and white men, revealed an elevated risk of in prostate cancer incidence after 7 years [287]. Dutasteride
prostate cancer among men with a history of gonorrhea or was studied in the REduction by DUtasteride of Prostate Can-
syphilis [268]. HPV, which occurs in human prostate cancer cer Events (REDUCE) trial, and the results showed that men
and benign prostatic tissue [276], has been shown to transform treated with dutasteride had a 23% reduction in prostate cancer
human prostate cells in vitro. Furthermore, seropositivity for incidence after 4 years [288]. However, the results of these
HPV-18 and HPV-16 has been associated with subsequent two trials were largely criticized for many aspects, including
prostate cancer in a Finnish cohort study [277, 278], but a results from biopsies performed towards the end of the study
small case-control study of HPV-16 and HPV-11 [279], and a as opposed to biopsies that are done when patients have el-
large population-based case-control study [268] showed little evated PSA or DRE abnormalities, the capability to prevent
evidence of risk. Finally, a recently published meta-analysis only low-grade cancers that will unlikely lead to death. Most
showed a weak association between HPV-16 and prostate can- importantly, Food and Drug Administration (FDA) Oncology
cer and no association for HPV-18 [280]. Drugs Advisory Committee (ODAC) re-analyzed the data
To our knowledge, only three studies have been published from PCPT and REDUCE trials and confirmed that the results
so far investigating the association between Trichomonas vagi- do not strongly support any preventive effect on high-grade
nalis infection, a common cause of vaginitis in women, and prostate cancer and therefore their use in therapy as chemo-
prostate cancer risk. Trichomonas vaginalis can also infect preventive agents is not recognized yet.
men, where it may cause asymptomatic urethritis and pros- The Reduction by Dutasteride of Clinical Progression
tatitis. In particular, its frequent asymptomatic presentation Events in Expectant Management of Prostate Cancer (RE-
may make it possible to persist untreated and ascend to the DEEM) study reported that dutasteride may provide a useful
prostate, where it can establish foci of chronic inflammation adjunct to “active surveillance” for management of prostate
that may eventually lead to prostate cancer [275]. Mechanis- cancer, because it delayed the time to prostate cancer progres-
tically, Trichomonas vaginalis infection causes adherence of sion, increased the percent of men with no detectable tumor
the protozoan to epithelial cells by decreasing the expression and improved cancer-related anxiety [289].
of anti-apoptotic genes; it also alters the production of IL-6 However, whether the effectiveness of 5-AR inhibitor
and monocyte chemotaxis proteins. Whereas an association therapy is influenced by certain patients’ features, like specific
between Trichomonas vaginalis serostatus and increased risk clinical conditions or genetic variations, was not evaluated yet.
of prostate cancer was found, the same connection between Therefore, identification of these subgroup of patients who
seropositivity for this pathogen and progression to death from may then undergo clinical trials with 5-AR inhibitors would
prostate cancer was not demonstrated [281]. address this intriguing question.
Medications Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin

(ASA)
Despite the knowledge gained over the years about the eti-
opathogenesis of prostate cancer and the known high risk for There is rapidly growing evidence for the impact of NSAIDs
men to be diagnosed with the disease during their lifetime, ef- on cancer [290]. At the cellular level, NSAIDs target cy-
fective chemo-preventive agent that can safely be administered clooxygenase (COX), particularly, the isoform 2 (COX-2) is
to impact the lives of men is still missing positively. The role expressed in inflammatory cells of the prostate and in PIA, a
of testosterone and pro-inflammatory pathways in the patho- precursor of prostate cancer [174, 243]. A recent meta-analysis
genesis of prostate cancer provided some clues about the pos- that included 20 observation studies with a total of 25,768 indi-
sibility to use inhibitors of testosterone endogenous production viduals evaluated the efficacy of NSAIDs in reducing prostate
and inflammation. cancer risk [291]. The clinical data indicated that there was a
statistically significant protective effect as revealed by the risk
reduction at 5% for ASA and 8% for other NSAIDs. In addi-
5-α reductase (5-AR) inhibitors
tion, another study revealed that they were only effective for
patients > 60 years of age [292].
By far the most promising and well-studied chemo-preventive Several experimental studies have documented that COX-
agents are finasteride and dutasteride, which are inhibitors of 2 overexpression in prostate cancer can be effectively targeted
5-AR enzyme that converts testosterone into dihydrotestoster- by COX-2 selective inhibitors such as celecoxib [291].
one, the most prevalent and potent androgen in prostate tissue, Several epidemiological and experimental evidence has
which is responsible for embryologic development [282] and demonstrated an inverse relationship between ASA use and
growth of the prostate as well as promotion of prostate cancer prostate cancer, particularly after 5 or more years of use in
[283]. men with metastatic disease [293]. A population-based case-
Finasteride and dutasteride are effectively used for the control study of 1,900 men reported that the RR of prostate
treatment of benign prostatic hyperplasia [284-286] and were cancer was significantly reduced of 18%, 21% and 24% in men
studied in clinical trials as potential chemopreventive agents. who reported the use of ASA, or currently used ASA, or are
Finasteride was studied in the prostate cancer prevention long-term users of ASA, respectively [294]. Surprisingly, low
trial (PCPT) and its use was associated with a 25% reduction dose of ASA was associated with the highest risk [294]. Fi-
nally, a multicenter study of over 90,000 documented a direct the exposed veterans of the Vietnam War compared with no-
protective effect in patients ingesting six ASAs daily [295]. exposed veterans [305]. They presented with earlier diagnostic
Altogether, the results of these studies have shown that the use ages, high-grade tumor, independently of other modifiable risk
of NSAID and ASA have a beneficial effect on the prevention factors. It suggests that AO is the most predictive factor not
of prostate cancer. only of developing prostate cancer but also of a higher histo-
logical grade and a greater probability of metastatic disease
at diagnosis. These data were later confirmed by the study of
Statin Ansbaugh et al that demonstrated a high correlation between
AO exposure and risk of high-grade prostate cancer among Vi-
Statin medications are inhibitors of the synthesis of lipids, par- etnam War veterans [304].
ticularly cholesterol and recently they showed to reduce PSA
levels [296, 297], and the risk of advanced or aggressive pros-
Chlordecone
tate cancer [298]. They are also associated with improved out-
comes after radiation therapy [299] and radical prostatectomy
[300], although data for the latter are conflicting [301]. Chlordecone (also known as Kepone) is an organochlorine
The use of statins as a preventive agent may offer the ad- insecticide with well-defined estrogenic properties [306, 307]
vantage to reduce cholesterol levels and the risk of cardiac extensively used for decades in the French West Indies, to con-
disease other than being safe. Statins effect as a secondary pre- trol the banana root borer. It is a carcinogenic agent with a
ventive agent was recently tested in two studies. One trial en- long biologic half-life, and among its long-term effects, cancer
rolled patients and randomly assigned them to simvastatin or is not excluded. Indeed, it was shown that chlordecone causes
placebo treatment before radical prostatectomy and examined hepatic tumors in laboratory mice and rats [308] and it has
changes in benign and malignant tissue in the prostate speci- been associated with increased risk of prostate cancer too.
men [302]. From this study, no significative beneficial action The prostate cancer risk associated with chlordecone ex-
of simvastatin was observed and its use was associated to seri- posure was higher in those men with a family history of pros-
ous adverse events (+55% vs. 18.75% of placebo group). The tate cancer, and similar findings were reported for pesticide
second trial is a phase II study evaluating the effect of atorvas- exposure in the Agricultural Health Study [309-312]. There
tatin and celecoxib on the levels of prostate cancer biomarkers, are two possible explanation: 1) Study subjects and their
including PSA, in those patients with rising PSA levels after first-degree relatives may have similar patterns of exposure,
definitive local therapy [303]. which consequently lead to a statistical interaction between
In conclusion, more clinical evidence is called to prove the chlordecone exposure and family history of prostate cancer; 2)
effective advantage of using statins for prostate cancer preven- Genetic variations, such as inheritance of polymorphism in a
tion. metabolic enzyme that alters the balance between chlordecone
bioactivation and detoxification in the body. In line with the
latter hypothesis, previous studies have shown differences in
Environmental carcinogens the inter-individual liver activity of chlordecone reductase be-
tween White and Japanese men [313, 314].
The slow process of prostate carcinogenesis is also influenced
by exposure to certain environmental factors that increase the
risk of developing cancer. These include insecticides, herbi- Bisphenol A (BPA)
cides and other organic compounds.
Another harmful compound associated with a high risk of
prostate cancer is BPA.
Agent orange (AO) BPA has been used to harden plastic since the 1950s in the
manufacture of polycarbonate plastic and epoxy resins that ap-
Herbicides are active chemical compounds that are used to pear in thousands of consumer products since then [315]. BPA
fight plant pests. Agent orange (AO) is a mixture of two her- is also used as a cross-linking compound in many food prod-
bicides that were used as a defoliant between 1962 and 1971 uct containers [316]. BPA leaching from these containers may
in the Vietnam War and was contaminated with the toxin contaminate food and beverage, which constitutes the main
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a putative car- source of exposure of humans via a route of ingestion [317].
cinogen. Dioxins remain an area of important interest as these Approximately 90% of BPA exposure in humans is from
environmental toxins continue to be produced through chemi- the intake of BPA contaminated food and beverage during pro-
cal processing and municipal waste incineration. These chemi- cessing and storage [318]. In addition to ingestion, intake of
cals can then enter the food chain through soil contamination BPA from the routes of inhalation or absorption via direct con-
[304]. tact cannot be ignored [317, 319].
In 1998, the National Academy of Science of the US rec- The first evidence on the direct link between BPA expo-
ognized a positive association between herbicide exposure sure and human prostate cancer was reported in 2014 by two
and many human cancers. In a review published in 2008, the US research teams based on in vitro and in vivo experimental
authors found twice as many cases of prostate cancer among studies [320, 321]. Abnormalities of centrosome (a hallmark of
malignant transformation) induced by a low level of BPA and for prostate cancer development [330, 333]. More frequent
its analogs were underlined as the potential mechanism in pro- ejaculation may alter the function of peripheral-zone epithelial
moting the formation of prostate cancer [320, 322]. Tse et al cells, which start to oxidate citrate rather than secrete it. This
published epidemiological evidence that cumulative exposure metabolic switch is known to occur early in prostate tumori-
to BPA was associated with an excess risk of prostate cancer in genesis [334]. Finally, the higher ejaculatory frequency may
the Chinese population [323]. The authors found a positive as- reduce the development of prostatic intraluminal crystalloids,
sociation of prostate cancer with intake of deep-fried food and which have been associated with a higher risk of prostate can-
pickled vegetable that were independent of other risk factors cer [335, 336]. More frequent ejaculation is thought to help
[324-326]. Deep fried foods (e.g. meats and potato) at high- to lower psychological tension and favors central sympathetic
heat cooking process generate a high amount of heterocyclic nervous system suppression, which could dampen the stimula-
amines and other mutagens and carcinogens (e.g. acrylamide tion of prostate epithelial cell division [337].
and polycyclic aromatic hydrocarbons) that may be carcino-
genic to prostate cells [325].
Diagnostic radiologic procedure and ultraviolet light expo-
sure
Vasectomy
The radiation generated from X-ray, CT and nuclear imag-
Vasectomy is the most frequent male contraception in the ing is ionizing radiation that penetrates the tissue to reveal
USA, with approximately 500,000 procedures performed an- the body’s internal organs. However, ionizing radiation can
nually. Its association with prostate cancer risk was explored in damage DNA, and although cells repair most of the damage,
case-control and cohort studies with conflicting results. Some sometimes small area may remain altered (“misrepair” area)
authors found an increased risk of up to 70% with a vasectomy, consequently leading to DNA mutations that may contribute to
while others found a lesser risk [189, 327, 328]. However, stud- cancer development years down the road. The first study inves-
ies showing small RRs are not convincing as they have some tigating the connection between low-dose ionization radiation
potential bias and methodological shortcoming [329]. On the from diagnostic X-ray procedures and risk for prostate cancer
other hand, in a very well-designed study in New Zealand, the reported that exposure to a hip/pelvic X-ray significantly in-
country with the highest global prevalence of vasectomy, the creased prostate cancer risk independently of other known risk
authors found no relationship with these subgroups [327]. factors such as family history of cancer [338]. However, unless
Biological studies that show underlying mechanism/s that men were exposed to high doses of radiation during cancer
might explain an association between vasectomy and prostate treatment in youth, any increase in the risk for cancer due to
cancer are still lacking. medical radiation appears to be slight. Considering that the in-
crease in high-dose imaging has occurred only since 1980 and
the effects of radiation damage typically take many years to
Ejaculatory frequency appear, this may explain the weak association between ioniz-
ing radiation and prostate cancer risk observed thus far.
Over the years, there has been growing evidence of a link be- Finally, exposure to solar UV radiation is inversely associ-
tween ejaculation and lower chances of prostate cancer. ated with both the incidence and mortality of prostate cancer
In 2004, the Health Professionals Follow-Up Study [128]. The biological explanation of this fact is based on the syn-
(HPFS) cohort reported a significant positive relation between thesis and physiological actions of vitamin D [126, 127, 129].
monthly ejaculation frequency and prostate cancer risk based
on 8 years of follow-up [330].
A major study of 2016 that involved almost 32,000 men Prevention
revealed that men who ejaculated ≥ 21 times per month (EPM)
had about a 20% lower chance of low-grade prostate cancer, An effective prevention strategy for prostate cancer would pro-
compared with those who had ≤ 4 - 7 EPM based on 18 years vide many benefits to men with a substantial positive impact
follow-up [331]. A year later, a case-control study sampling on public health, including the potential to reduce the high
a smaller group of men (2,141) from age 20 to 50 found only lifetime risks of prostate cancer development, the morbidities
weak evidence of an inverse association between ejaculatory associated with cancer treatment, especially in those newly
frequency in the fourth decade of life and advanced prostate diagnosed patients with biological indolent prostate cancer
cancer, which was not significantly modified by a number of that still undergo curative-intent therapy rather than active sur-
new sexual partners [332]. In the same study, no relationship veillance and finally the inability to eradicate life-threatening
was found for ejaculatory frequency in the third and fifth dec- metastatic prostate cancer.
ades of life. Epidemiological data indicate a dominant role for lifestyle
The ejaculatory frequency may influence prostate cancer factors in prostate cancer development. Considering that pros-
development through several mechanisms. One biological tatic carcinogenesis takes many decades, lifestyle modification
mechanism is described as “prostate stagnation hypothesis”, may represent a feasible and cost-effective approach to retard
which involves the prostatic accumulation of potentially car- prostate cancer development.
cinogenic secretions that may create a favorable environment Although the data about the role of specific lifestyle fac-
tors fostering prostate cancer development have often been PSA testing. However, a challenge for the future will be the
conflicting, most of the studies clearly evidence a diet rich in translation of preclinical data into clinically useful strategies,
fruits, vegetables and anti-oxidant micronutrients, and poor in which will require very large trials with thousands of partici-
saturated fats and “well-done” red meats, may significantly re- pants, like those of the SELECT studies [180].
duce risks of prostate cancer development, as well as the risk Furthermore, studies that can fill the knowledge gap re-
of diseases typical of the industrialized world. garding the higher prostate cancer incidence and mortality
The better understanding of prostate cancer etiology rep- in African-American men compared to White men are also
resents the key to open to new opportunities for prostate can- needed. Recently, the “Research on Prostate Cancer in Men
cer prevention. Several nutrients and pharmaceutical agents of African Ancestry: Defining the Roles of Genetics, Tumor
have been studied as potential chemoprevention candidates. Markers, and Social Stress” (RESPOND) study which was
Vitamin E and selenium showed promise [138, 141]. How- funded by the National Institute of Health and Prostate Cancer
ever, these were definitively evaluated in the SELECT, and Foundation was carried out. The primary goals of this study
neither agent reduced prostate cancer risk [140]. Vitamin D were to understand how social and genetic variants contrib-
analogs, NSAIDs and toremifene (a selective estrogen receptor ute to the development of aggressive prostate cancer, and how
modulator) have all been evaluated in laboratory and/or ob- those factors interact with each other. Hopefully, the increased
servational studies [134, 339, 340]. However, vitamin D has knowledge gained within this study will provide new insights
not been formally tested in primary prevention trials, while the to develop positive screening and chemo-preventive strategies.
NSAID rofecoxib, a COX-2 selective inhibitor, could not be Finally, classical prognostic factors such as PSA testing,
successfully tested because the trial was closed when the drug Gleason score and clinical cancer staging have demonstrated
was withdrawn from the market after an interim safety analysis not to be always sufficient to lead to a clinically relevant can-
indicated that the drug was associated with increased risk of cer diagnosis. Considering that various genomic aberrations
cardiovascular events within the Adenomatous Polyp Preven- contribute to the variety in prostate cancer risk and outcome as
tion on Vioxx (APPROVe) trial [341]. Toremifene showed a well as drug responses and progression between patients, the
modest risk reduction in a phase II trial [342], but no signifi- identification of novel genetic biomarkers is highly required.
cant risk reduction in a phase III trial [343]. This will undoubtedly improve cancer diagnosis, subtype
Besides identification of molecular targets, other prin- identification and risk stratification. Most importantly, as we
ciples of prevention include personalized risk assessment, are moving toward personalized medicine, oncogenetic test-
identification of sensitive and accurate surrogate molecular ing and biomarker profiling will facilitate the optimal thera-
markers to serve as intermediate endpoints and identification peutic intervention based on the alterations observed in single
of biomarkers that predict sensitivity to preventive agents. Fur- patients [344, 345]. Clinical trials have already shown high
thermore, it should also emphasize personalized molecularly success rate for drugs that are developed using biomarkers in
targeted approaches for the selection and treatment of patients patients with non-small cell lung cancer, therefore it is desir-
with prostate cancer that result in a positive outcome and ef- able that same results may also be achieved for the treatment
fective therapy. of prostate cancer.
Future Directions Conclusion
The high global incidence of prostate cancer makes a call to Prostate cancer is the most common malignancy in men, rank-
strengthen the current tools available to identify trends and ing second after lung cancer [1]. The identification of biomark-
prevention strategies to reduce the public health impact of this ers such as PSA that are positively correlated with the diag-
disease in the future. nosis of prostate cancer revolutionized the epidemiology of
First, prostate cancer registries play an important role in this disease. Indeed, since the introduction of PSA testing and
the advancement of prostate cancer research and care. Indeed, subsequent biopsies, USA registered double of prostate cancer
they represent an essential source to collect information about incidence starting from the late 1980s [23]. A similar increase
incidence and mortality, disease characteristics at presentation, was also reported in other countries, particularly in the western
trends and risk factors, quality of care, disparities in access type. Unfortunately, although it turned effective in reducing
to treatment, long-term data related to oncologic and health- prostate cancer-specific mortality, the relevant overdiagnosis
related quality of life outcomes and costs associated with man- and the severe side effects of treatments advised against the
agement of the disease. Therefore, improvements in the quality introduction of PSA as a screening program.
of data, collection of tissue samples and the availability of data Perhaps, the most dramatic statistic when it comes to pros-
feedback to health care providers will increase the relevance of tate cancer incidence and mortality is the way that prevalence
epidemiological studies especially when it comes to the evalu- varies among different racial groups, with the highest preva-
ation of data collected from undeveloped countries. lence in African-American men [14]. Both biologic and so-
Chemo-preventive strategies have been explored in sev- cioeconomic factors may explain this discrepancy, but which
eral preclinical and small clinical studies to mitigate the global genes may be involved and how they may interact with the en-
burden of prostate cancer and the overtreatment of indolent vironment is still unknown and is a subject of studies. In 2018,
disease that has been associated with the broad utilization of a study called “Research on Prostate Cancer in Men of Afri-
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Review World J Oncol.

Epidemiology of Prostate Cancer

Manuscript submitted February 20, 2019, accepted March 15, 2019

Family history and genetic factors

Tomatoes seem to reduce the risk of prostate cancer. They

Medications Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin

Future Directions Conclusion

can Ancestry: Defining the Roles of Genetics, Tumor Markers, References

at known prostate cancer susceptibility loci in African 2006;25(41):5591-5600.

present, and future. Cancer. 2007;110(9):1889-1899. 2008;98(9):1574-1581.

Oncol. 1995;1(5):195-198. prostate cancer cells. BJU Int. 2012;109(5):788-795.

adenocarcinoma of mouse prostate model. Cancer Res. cussion 970-961.

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