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Review World J Oncol. 2019;10(2):63-89
Epidemiology of Prostate Cancer
Prashanth Rawla
Abstract
Prostate cancer is the second most frequent cancer diagnosis made in
men and the fth leading cause of death worldwide. Prostate cancer
may be asymptomatic at the early stage and often has an indolent
course that may require only active surveillance. Based on GLOBO-
CAN 2018 estimates, 1,276,106 new cases of prostate cancer were
reported worldwide in 2018, with higher prevalence in the developed
countries. Dierences in the incidence rates worldwide reect dier-
ences in the use of diagnostic testing. Prostate cancer incidence and
mortality rates are strongly related to the age with the highest inci-
dence being seen in elderly men (> 65 years of age). African-Amer-
ican men have the highest incidence rates and more aggressive type
of prostate cancer compared to White men. There is no evidence yet
on how to prevent prostate cancer; however, it is possible to lower
the risk by limiting high-fat foods, increasing the intake of vegeta-
bles and fruits and performing more exercise. Screening is highly
recommended at age 45 for men with familial history and African-
American men. Up-to-date statistics on prostate cancer occurrence
and outcomes along with a better understanding of the etiology and
causative risk factors are essential for the primary prevention of this
disease.
Keywords: Prostate cancer; Epidemiology; Incidence; Mortality;
Trends; Survival; Etiology; Risk factors; Prevention
Introduction
Prostate cancer is the second most frequent malignancy (after
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
prostate cancer worldwide correlate with increasing age with
the average age at the time of diagnosis being 66 years. Of
note, for African-American men, the incidence rates are higher
when compared to the White men, with 158.3 new cases diag-
nosed per 100,000 men and their mortality is approximately
twice as White men [3]. Reasons for this disparity have been
hypothesized to dierences in social, environmental and ge-
netic factors. Although 2,293,818 new cases are estimated un-
til 2040, a small variation in mortality will be observed (an
increase of 1.05%) [4].
Prostate cancer may be asymptomatic at the early stage
and often has an indolent course, and may require minimal or
even no treatment. However, the most frequent complaint is
diculty with urination, increased frequency, and nocturia,
all symptoms that may also arise from prostatic hypertrophy.
More advanced stage of the disease may present with urinary
retention and back pain, as axis skeleton is the most common
site of bony metastatic disease.
Many prostate cancers are detected on the basis of ele-
vated plasmatic levels of prostate-specic antigen (PSA > 4
ng/mL), a glycoprotein normally expressed by prostate tissue.
However, because men without cancer have also been found
with elevated PSA, a tissue biopsy is the standard of care to
conrm cancer’s presence.
Diet and physical activity play an important role in pros-
tate cancer development and progression. Dietary factors are
mainly associated with the observed worldwide and ethnic dif-
ferences in the incidence rates of prostate cancer [5-9].
Most studies are devoted not only into identifying genes
involved in the inherited form of prostate cancer but also the
mutations occurring in the acquired form. Therefore, a de-
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
prostate cancer will provide ways to identify at-risk males and
support the development of eective screening and prevention
methods.
Epidemiology
Based on GLOBOCAN 2018 estimates, we have evaluated
worldwide prostate cancer incidence and mortality rates, as
well as analyzed incidence and mortality, temporal trends and
survival rates.
Incidence
The incidence rate of prostate cancer varies across the regions
and populations (Fig. 1) [2]. In 2018, 1,276,106 new cases of
prostate cancer were registered worldwide, representing 7.1%
of all cancers in men [1]. Prostate cancer incidence rates are
highly variable worldwide. The age-standardized rate (ASR)
Manuscript submitted February 20, 2019, accepted March 15, 2019
Hospitalist, Department of Internal Medicine, SOVAH Health, Martinsville,
VA 24112, USA. Email: rawlap@gmail.com
doi: https://doi.org/10.14740/wjon1191
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64
Epidemiology of Prostate Cancer World J Oncol. 2019;10(2):63-89
was highest in Oceania (79.1 per 100,000 people) and North
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]. Dier-
ences in incidence rates were 190-fold between the popula-
tions at the highest rate (France, Guadeloupe, 189.1), and the
populations with the lowest rate (Bhutan, 1.0).
Prostate cancer incidence increases with age [2]. Although
only 1 in 350 men under the age of 50 years will be diagnosed
with prostate cancer [10], the incidence rate increases up to 1
in every 52 men for ages 50 to 59 years. The incidence rate is
nearly 60% in men over the age of 65 years [11].
The reason for these dierences among the countries is not
entirely clear. The worldwide variations in prostate cancer in-
cidence might be attributed to PSA testing [12]. For example,
in Europe, prostate cancer is the most frequently diagnosed
cancer among men, accounting for 24% of all new cancers
in 2018, with around 450,000 new prostate cancer cases esti-
mated in 2018 [13]. While in the USA, prostate cancer is the
second most common cancer accounting for 9.5% of all new
cancer cases (164,690 new cases of prostate cancer) registered
in 2018 [14]. According to recently conducted research stud-
ies, around 20-40% of the prostate cancer cases in the USA and
Europe could be due to overdiagnosis through extensive PSA
testing [12, 15, 16].
Research has shown that African-American men have
the highest incidence of prostate cancer worldwide and more
likely to develop disease earlier in life when compared to other
racial and ethnic groups [17]. This is reected in data not only
for African-American men, but also for Caribbeans, and Black
men in Europe, suggesting that they possess a common genetic
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-
ican men than those in Africa. These dierences suggest that
environmental factors also play an important role in the etiol-
ogy of the prostate cancer and variations in incidence may be
due to underdiagnosis, dierences in the screening methods
and disparities in healthcare access.
Mortality
International mortality rates for prostate cancer vary consid-
erably worldwide (Fig. 2) [2]. In 2018, the highest mortal-
ity rates were recorded in Central America (10.7 per 100,000
people), followed by Australia and New Zealand (10.2) and
Western Europe (10.1) [2]. The lowest rate was reported in
the countries of Asia (South-Central, 3.3; Eastern, 4.7 and
South-Eastern, 5.4) and Northern Africa (5.8) (Fig. 3) [2].
One-third of the deaths for prostate cancer occurred in Asia
(33.0%, 118,427 of deaths), followed by Europe (29.9%,
107,315 of deaths). The mortality rate of prostate cancer rises
with age, and almost 55% of all deaths occur after 65 years
of age [2].
US Preventive Task Force (USPSTF, 2018) has reported
that there is a potential benet of decreasing deaths from pros-
tate cancer in men aged 55 - 69 years with PSA screening [19].
However, for men above 70 years of age for all races, the data
are less convincing [20].
African-American men have the highest prostate cancer
incidence and mortality rates. This suggests not only that Af-
rican-American men may possess some specic genes that are
more susceptible to mutations in prostate cancer, but mainly
that these mutations are associated with a more aggressive type
of cancer. However, a study conducted by Oliver in 2007 [21]
reported that African-American men were less likely to iden-
tify early symptoms of prostate cancer correctly than Cauca-
sian men.
Trends
Temporal trends of prostate cancer incidence and mortality
varied signicantly internationally during the past years, and
they seem tightly correlated to the adoption of PSA testing for
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].
Articles © The authors | Journal compilation © World J Oncol and Elmer Press Inc™ | www.wjon.org 65
Rawla World J Oncol. 2019;10(2):63-89
early detection of the disease especially in Western countries
[22].
Incidence rates in the USA, Australia, and Canada have
seen an increase between the 1980s and 1990s but now de-
creasing because of rapid dissemination of PSA testing [22,
23], while rates in European countries continue to slightly in-
crease because of increased understanding of PSA screening
and gradual adoption of PSA testing, but also other factors may
be involved, such as exposure to ultraviolet radiation and diet
[24].
Interestingly, a trend towards an increase of prostate can-
cer incidence worldwide with 1,017,712 new cases (+79.7%
overall change) up to 2040 is estimated (Table 1) [4]. The
highest incidence of prostate cancer will be registered in Af-
rica (+120.6%), followed by Latin America and the Caribbean
(+101.1%) and Asia (100.9%). On the contrary, the lowest in-
cidence will be registered in Europe (+30.1%). This increase in
the incidence rates appears to be related to an increased life ex-
pectancy. Increasing incidence rate trends in developing coun-
tries is likely due to improved access to medical care as well
as increased documentation and reporting of cases. Finally, the
fact that incidence rates are increasing in those regions where
PSA testing is not routinely used suggests that this phenom-
enon reects westernization of the lifestyle including obesity,
physical inactivity and dietary factors [25].
Prostate cancer mortality rates in most western countries
including North America as well as in Western and North
Europe have been steadily declining [22, 25]. Although the
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].
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].
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66
Epidemiology of Prostate Cancer World J Oncol. 2019;10(2):63-89
reasons are not clear, it may reect both early detection and
improved treatment [26-28]. However, in the USA, a recent
randomized controlled trial failed to demonstrate benets of
PSA testing in decreasing prostate cancer deaths, although an-
other research study done in Europe showed benets of PSA
testing [29, 30]. When ethnicity-specic trends were analyzed,
it was observed that the decline in mortality in African-Amer-
ican men was greater than that in White men between 2001
and 2015 (Fig. 4) [11, 20]. Negoita et al documented that im-
proved and newer modalities of detection and treatments and
improved treatment of resistant and metastatic prostate cancer
may justify this trend [20].
From 2018 to 2040, it is estimated that mortality will dou-
ble with 379,005 deaths worldwide [4]. The highest mortality
rate is estimated to be in Africa (+124.4%), followed by Asia
(116.7%), while the lowest incidence will be registered in Eu-
rope (+58.3%) (Table 2) [4]. The above nding is not surpris-
ing due to the limited resources for screening and detection of
prostate cancer which increases the odds of it being detected
during the late stages. Furthermore, considering that medi-
cal care and assistance is not widely accessible in developing
countries, this may provide a possible explanation for the high
mortality despite the lower incidence.
Survival
Although prostate cancer incidence rates are high, most pros-
tate cancer cases are detected when the cancer is conned to
within the prostate. The 5-year survival rate in the USA for
men diagnosed with prostate cancer is around 98% [11]. The
data from the Eurocare project (EUROCARE-5) of patients di-
agnosed with prostate cancer from 2003 to 2007 showed that
5-year survival rates were 83% [13]. Survival varied from 76%
in Eastern countries to 88% in Southern and Central European
countries. Moreover, survival has increased over time in all
over Europe with the greatest improvement being observed in
the Eastern European countries [31].
Despite in the last decades, science has made so much
progress to unveil molecular mechanisms and risk factors in-
volved in the prostate cancer, it still is the second leading cause
of cancer mortality among males in the USA [32]. Finally, the
general idea for all types of cancers is that the earlier they are
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 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%)
Data obtained from Globocan 2018 [4].
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Rawla World J Oncol. 2019;10(2):63-89
the patients disease-free. However, because the majority of
prostate cancer have a slow and often indolent course (dened
as “low-risk” tumor), men can avoid immediate treatment (and
prospective side eects) while safely undergoing active sur-
veillance or watchful waiting.
Etiology and Risk Factors
The etiology of prostate cancer is the subject of numerous
studies and remains largely unknown compared to other com-
mon cancers. The well-established prostate cancer risk factors
are advanced age, ethnicity, genetic factors and family history
[33-35]. Other factors positively associated with prostate can-
cer include diet (increased consumption of saturated animal fat
and red meat, lower intake of fruits, vegetables, vitamins, and
coee), obesity and physical inactivity, inammation, hyper-
glycemia, infections, and environmental exposure to chemi-
cals or ionizing radiation [34, 36-40].
Age
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
life expectancy and the increased use of PSA screening. It was
observed that the risk increases especially after 50 years of
age in White men who have no family history of the prostate
cancer, and after 40 years of age in Black men or men with a
familial history of prostate cancer [14].
Scardino reported that almost 30% of men over 50 years
of age, who died for causes other than prostate cancer, were
found with histological evidence of prostate cancer at the mo-
ment of autopsy [41]. Indeed, due to its indolent course, elder-
ly men who have concurrent severe co-morbid disease during
their lifetimes are more likely to die from other related health
conditions or other diseases rather than from prostate cancer.
Ethnicity
Prevalence of prostate cancer highly varies among dierent
racial groups. In the USA, the lowest incidence is observed
in American Indian/Alaska (46.9) Native and Asian/Pacic Is-
lander (52.4), followed by White (93.9). The highest incidence
rate is seen in African-American men (157.6) [11].
This vast disparity has been associated with both socioec-
onomic conditions and biologic factors [42]. For instance, it is
believed that African Americans receive lower-quality health-
care and consequently, they are also less likely to undergo PSA
screening [43]. Notably, signicantly higher PSA levels were
seen in Black men, with or without prostate cancer when com-
pared to White men [44, 45].
Several studies proposed that genetic predisposition might
play a role. African-American men have the more common
chromosome 8q24 variants, which have been shown to be
associated with increased prostate cancer risk [46-49]. Some
research studies have also demonstrated that African Ameri-
cans have a high rate of variations in genes that suppress tu-
mors such as EphB2 [50] or that regulate cell apoptosis such
as BCL2 [51]. Furthermore, African-American men display a
more aggressive form of the disease, which has also been asso-
ciated with genetic and biologic dierences, although lack of
adequate screening and delayed presentation was not excluded
too [42].
Family history and genetic factors
It is estimated that about 20% of patients with prostate cancer
report a family history, which may develop not only because of
shared genes but also for a similar pattern of exposure to cer-
tain environmental carcinogens and common lifestyle habits
[52, 53]. Several studies reported that inherited genetic back-
ground is associated with increased risk for prostate cancer,
contributing to about 5% of disease risks [54, 55]. Particularly,
this risk is increased by several folds when high-penetrance
genetic “risk” alleles are inherited, conversely to more com-
mon low-penetrance loci that increase the risk only modestly.
Gene linkage studies reveal major susceptibility loci for
prostate carcinoma on genes in seven dierent loci. Chromo-
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
signaling [57]. It plays an important role in reducing antiviral
activity and the regulation of apoptotic cell death [58]. Of note,
analysis of human prostate cancer samples from patients with
RNASEL mutations showed the presence of retrovirus unveiling
the importance of antiviral defenses to prostate cancer develop-
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%)
Data obtained from Globocan 2018 [4].
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Epidemiology of Prostate Cancer World J Oncol. 2019;10(2):63-89
ment [59]. Moreover, detection of retroviral infections in some
cases of prostate cancer also showed the potential connection
of chronic retroviral infection and consequent tissue inamma-
tion with cancer initiation [60, 61]. Another HPC gene (HPC2/
ELAC2) was identied on chromosome 17p11 and encodes a
protein with poorly understood function [62], ELAC2, which
is involved in prostate cancer development by binding SMAD2
that up-regulate proliferation through activation of TGF-beta
signaling pathway [63]. The third identied HPC gene is mac-
rophage scavenger receptor 1 (MSR1), which resides on chro-
mosome 8p22 [64]. However, considering the low penetrance of
this allele, several studies failed to conrm its association with
HPC [65, 66]. Additionally, a subset of HPC was found to oc-
cur in men with BRCA1 and 2 mutations that showed a clini-
cally aggressive form of prostate cancer [67]. Moreover, BRCA2
mutations were correlated with a higher incidence of prostate
cancer, and PALB2, BRCA2-interacting protein, was involved
in familial prostate cancer [68].
The X chromosome is also believed to have a role in pros-
tate cancer inheritance, because it contains the androgen recep-
tor (AR) and because small deletions in Xq26.3-q27.3 region
were noted in sporadic and hereditary forms of prostate cancer
[69, 70]. More recent studies in 301 hereditary prostate cancer
aected families dened a number of other loci that may con-
tribute to hereditary prostate cancer [71].
Diet
Dietary factors may play an essential role in the development
of prostate cancer as evidenced by several studies on immi-
grants moving from developing countries (low-risk areas) to
industrialized countries (higher risk), that showed how the
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-
dence rate of prostate cancer among African Americans was as
high as 40 times, while Hsing et al in 2000 [72] showed that
compared to men living in China, the prostate cancer incidence
was 16-fold higher for Chinese men living in the USA, sug-
gesting that environmental factors play an important role.
There are multiple evidences that certain foods are associ-
ated at higher risk, while others are even protective.
Saturated animal fat
Multiple ecological studies have shown a positive correlation
between prostate mortality and per capita intake of meat, fat
and dairy products [73, 74]. A recent case-control study in pa-
tients less than or equal to 60 years found that high intake of
total fat was associated with a statistically signicant increase
in prostate cancer risk [75].
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-
drogen; 2) increasing levels of reactive oxygen species (ROS)
and increasing leukotrienes and prostaglandins levels from li-
pid metabolism; and 3) increasing basal metabolism, insulin
growth factor and tumor proliferation.
High-calorie intake of saturated animal fat has shown to
increase the growth of prostate cancer cells by increasing the
circulating levels of androgens [76, 77]. Furthermore, rand-
omized cross-over studies involving low-fat and high-fat diets
showed that the level of androgen is lower post-prandial as
well as in vegetarians [78]. Finally, several studies reported
that alteration of lipid levels undergoing to a low-fat diet re-
duces testosterone levels [79-81].
Excessive fat increases oxidative stress and ROS levels
that attack the cells causing peroxidation and eventually DNA
damage. A role for lipid metabolism and its metabolite have
also been observed in mice and found that dietary fat is an
important modulator of prostate cancer growth. For example,
while some studies did not nd any dierence in terms of tu-
mor growth and survival of mice placed on a Western diet,
other studies showed a delay in cancer cell growth in mice with
low-fat corn-oil diets, suggesting that the amount and type of
fat are critical [82].
Mechanistically, corn-oil may promote cancer growth via
the linoleic acid, the most abundant omega-6 fat in the oil. Ara-
chidonic acid which is a metabolite of linoleic acid gives rise
to the formation of several pro-inammatory prostaglandins
(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
in malignant prostate cancer. Hence, a decrease in omega-6
fatty acid intake can decrease cancer growth. As opposite to
omega-6 fats pro-inammatory eect, omega-3 fats are found
benecial against cancer growth [83].
Red meat
Dietary meat intake has been associated with prostate carcino-
genesis by correlating cancer incidence and mortality with per
capita meat consumption [84]. Rohrmann et al [85] showed
that men consuming ve or more servings of processed meat
per week had a higher risk of prostate cancer when compared
with men who consume one or fewer servings per week. In Af-
rican-American men, there was no association observed with
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
temperature [86]. Cooking at higher temperatures (125 - 300
°C) causes the formation of aromatic hydrocarbons and muta-
genic heterocyclic amines [87, 88]. Grilled or barbecued meat
can result in the formation of N-nitroso compounds that can
result in lipid peroxidation and DNA damage by the produc-
tion of free radicals [89, 90].
Calcium, milk and dairy products
Dairy foods have generally been associated with an elevated
prostate cancer risk [85, 91-94]. Both calcium from supplements
and dairy put male at high prostate cancer risk. Greater than
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Rawla World J Oncol. 2019;10(2):63-89
2,000 mg per day of calcium was associated with a greater risk
of prostate cancer. The Health Professional Follow-Up Study
examined the diet of 47,885 men and looked closely at partici-
pants’ consumption of animal food, protein and calcium [95].
After a 24-year follow-up, prostate cancer was diagnosed in
5,861 men, which was associated with high calcium intake [96].
Vegetables
Although conicting results have been generated regarding
dietary fat, a strong relationship was found between intake of
Crucifers or Brassica vegetables (broccoli, Brussels sprouts,
cauliower, cabbage, and turnips) and reduced prostate can-
cer risk. Crucifers have anticancer properties mediated by
phenyethyl isothiocyanate, sulforaphane, phytochemicals and
indole-3-carbinol [97]. Some studies in the USA on a diet rich
with broccoli have shown evidence for the protective eect
of Brassica vegetables against prostate cancer [98]. However,
some other studies revealed no anticancer capabilities of Bras-
sica vegetables [99-102].
Dietary soy and green tea
Prostate cancer incidence is signicantly lower in Asia when
compared to North America, which has prompted research
interest in the potential chemo-preventive action of soy and
green tea which are a part of the diet in Asia. Decreased risk
of prostate and several other cancers has been seen with con-
sumption of soy and green tea [103-106]. Catechins found in
green tea and isoavones in soybeans have anticarcinogenic
properties, and they inhibit dierent phases of carcinogenesis
[107, 108] and metastasis [109-111]. Additionally, green tea
polyphenols cause a reduction of IGF-1 levels [112-114].
Tomatoes and lycopene
Tomatoes seem to reduce the risk of prostate cancer. They
contain high levels of lycopene which has potent anti-oxidant
properties as well as cancer-preventive eects [115-119]. Ly-
copene also acts on the androgen receptors and reverses the
eects of dihydrotestosterone and also inhibits insulin growth
factor (IGF-I)-stimulation through Akt and GSK3β and tyros-
ine phosphorylation of GSK3 [120].
Tomato product consumption and lycopene intake were
both associated with a decreased risk of prostate cancer [121].
The Health Professional Follow-Up Study showed a decreased
risk of prostate cancer with 2 - 4 servings of tomato sauce per
week [95]. Venkateswaran and Klotz [122] demonstrated that
in the Lady transgenic mouse model, lycopene is able to re-
duce prostate cancer incidence only in association with sele-
nium and vitamin E.
On the other hand, an open phase II study of lycopene in
advanced prostate cancer could not demonstrate any clinical
benet of this agent [123]. Similar results were seen in two
other small epidemiological studies [124, 125]. Thus, the evi-
dence of a connection between tomatoes assumption and pros-
tate cancer risk requires further investigation.
Vitamin and mineral supplements
Vitamin D
An inverse relationship was observed between sunlight, or
UVB exposure, and incidence of prostate cancer [126, 127],
suggesting that vitamin D deciency might increase prostate
cancer risk development [128]. Similarly, discoveries were
made by Barnett and Beer [129] who found that people living
in “sunny” countries were at lower risk of developing second-
ary solid cancer after melanoma compared to people living in
“less sunny” countries.
The incidence of prostate cancer in African-American
men is twice that of Caucasians, suggesting that race might
play a role. There might be a role for vitamin D deciency in
this as UV radiation is blocked in darkly pigmented skin due
to high melanin levels and this mechanism inhibits the conver-
sion to vitamin D3 [130].
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
dierentiation and apoptosis in prostate cancer cells as well as
in tumor progression in animal models [132-134]. These nd-
ings provide a strong rationale for the use of vitamin D analogs
as therapeutic agents for prostate cancer in a case that androgen
deprivation therapy has failed [135]. Early clinical trials with
1α,25(OH)2D3 revealed serious side eect such as hypercal-
cemia and hypercalciuria associated with its systemic admin-
istration [136, 137]. Screening of several thousand vitamin D
analogs identied a more potent and less calcemic compound
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
a chemopreventive or therapeutic approach in prostate cancer.
Vitamin E
Vitamin E is a vitamin which is fat soluble. Vegetable oils, egg
yolks, and nuts are the important dietary sources of vitamin
E. Tocopherols present in vitamin E have both potent cellu-
lar anti-oxidant with anticancer properties [54, 138]. Studies
investigating the relationship between vitamin E and prostate
cancer risk have shown contradicting results. The ATBC trial
showed that in men who smoked supplementing daily vitamin
E was not able to reduce the incidence of prostate cancer [139].
In another large clinical trial (SELECT trial), vitamin E sup-
plementation did not show any benet in 31,000 men with in-
cident prostate cancer [140].
Selenium
Selenium is an essential micronutrient. It is found in the plants
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like tubers, cereals and legumes and animal products like meat,
eggs, and seafood in the form of selenomethionine and seleno-
cysteine. It has been inversely associated with several cancers,
including prostate cancer.
Several studies have shown a 50-60% risk reduction of de-
veloping prostate cancer when comparing high selenium con-
sumption to low selenium consumption [141, 142]. The NPC
trial showed a 50% reduction of incidence of prostate cancer
among men that were taking selenium supplementation [143];
however, SELECT trial did not report any benecial eect of
administering selenium alone or combination of selenium with
vitamin E [140]. The dierent outcomes could result from the
utilization of two dierent forms of selenium: selenized yeast
in the NPC, whereas selenomethionine in the SELECT. These
forms dier signicantly in their biological eects, and it was
shown they have dierent mechanisms of action. Selenom-
ethionine acts on prostate cancer cells and induces cell cycle
arrest [144, 145]. It can also act by inducing apoptosis and
inhibiting angiogenesis [145, 146]. Methylseleninic acid acts
via a caspase-mediated pathway and induces apoptosis [147].
Interestingly, Chan et al [148] emphasized the role of gen-
otype with respect to the eectiveness of selenium interven-
tion. This study revealed that high selenium might be protec-
tive against an aggressive form of prostate carcinoma in men
with the AA genotype of superoxide dismutase (SOD)-2 and
increase the chances of having a worse tumor in men with a V
allele. These data unveil the potential risks and benets associ-
ated with selenium intervention in prostate cancer and may, in
part, explain the conicting results from other studies.
Folate and vitamin B12
Low folate and vitamin B12 can lead to altered methylation
and lead to cancer development as these essential vitamins
participate in DNA methylation, synthesis and repair [149]. In
vitro [150], in vivo studies [151] and genetic studies [152, 153]
on prostate cancer showed the role of folate in the develop-
ment of an aggressive form of prostate cancer. Furthermore,
elevated serum concentration of folate was associated with an
increased proliferation of prostate cancer cells in some pros-
tate samples collected from patients who underwent radical
prostatectomy [154].
However, a recent meta-analysis reported that higher
concentrations of vitamin B12 and folate have a modest 12%
increased risk of prostate cancer [155]. In people who have
prostate cancer, available data do not show an eect of con-
sumption of folate on disease progression [156] or survival
[157]. In conclusion, the association of folate and vitamin B12
with prostate cancer is unclear and requires further investiga-
tion.
Alcohol consumption
The relationship between alcohol use and several types of hu-
man cancers, including prostate cancer, has been since long
observed [158]. Heavy alcohol abuse (> 15 g ethanol/day, or
more than three drinks per day between wine, liquors or beer)
may be a possible risk factor for prostate cancer and other can-
cers [159]. However, several cohort studies have suggested a
weak correlation between alcohol intake and prostate cancer
mortality [160-163], while others did not nd any relation with
increased risk [164]. As opposite, Dennis et al reported a sig-
nicant relationship between higher alcohol intake and pros-
tate cancer risk with a relative risk (RR) ranging from 1.05
to 1.21 for one or four alcoholic drinks per day, respectively
[165, 166].
Coee
Coee consumption has been inversely associated with in-
creased prostate cancer risk. Observational studies and some
animal studies have revealed an association between long-term
coee drinking and improved glucose metabolism as well as
insulin secretion [167]. Consistently, a reduced risk of type 2
diabetes was observed in those patients who reported higher
consumption of coee.
A large prospective study demonstrated that coee intake
was weakly inversely associated with overall risk of prostate
cancer, while it signicantly lowered the risk of lethal and ad-
vanced prostate cancer when heavy coee drinkers are com-
pared to the one that drinks less coee [168]. Considering the
eects of coee consumption on insulin, antioxidants and an-
drogens [169-174], the ndings of this study are in agreement
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.
Obesity, insulin and physical activity
Obesity is linked to advanced and aggressive prostate cancer
[175, 176], and high body mass index (BMI) is associated with
more aggressive disease too and a worse outcome [121, 177].
The possible explanation is that most of the time obese
men present with alteration of circulating levels of metabolic
and sex steroid hormones, which are known to be involved in
prostate development as well as oncogenesis [178].
Obesity, particularly when combined with physical in-
activity, leads to the development of insulin resistance with
reduced glucose uptake. That, in turn, leads to chronically el-
evated blood levels of insulin. Insulin is a hormone that pro-
motes growth and proliferation, thus is reasonable to add it in
the list of risk factors that promote prostate cancer initiation
and/or progression [179]. Additionally, adipose cells represent
a source of inammation as well as of macrophages in adipose,
which releases inammatory mediators [180]. Three meta-
analyses reported a modest but consistent association between
obesity and prostate cancer incidence independently of BMI
increase [181]. Data from three national surveys in the US
population reported that obesity is associated with more ag-
gressive prostate cancer and higher mortality despite its lower
incidence [182].
One of the diculties in interpreting results for obese men
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is that they have greater circulating plasma volume and there-
fore a “hemodilution” of PSA [183]. Consequently, they will
less likely undergo a biopsy, and detect the presence of the
tumor until a more advanced stage [179, 181]. Because obe-
sity is a potential factor leading to lower detection of prostate
cancer, clinicians should consider BMI when interpreting PSA
concentration. Physicians should be aware of these factors to
avoid misdiagnosis among obese men and thus should include
BMI along with other well-established risk factors (race, digi-
tal rectal examination (DRE) and family history) in the exist-
ing prostate cancer risk calculator [182].
Exercise is supposedly one of the easiest modiable risk
factor to manage in a way to obtain many benets and relative-
ly few side eects when it comes to prostate cancer prevention.
Indeed, Keogh and McLeod found that veterans who exercised
had a signicantly lower risk of prostate cancer [184]. Prostate
cancer patients who are committed to exercise display lower
PSA levels and delay in initiating androgen deprivation thera-
py (ADT) by 2 years compared with less active peers and have
a lower risk of high-grade disease, other than having a greater
quality of life and less fatigue [184].
Cigarette smoking
Active and passive exposures to cigarette smoke are consid-
ered carcinogenic for many human cancers [185].
Association of smoking and prostate cancer risk may have
either a hormonal or genetic basis. For instance, male smokers
usually have higher levels of circulating sex hormones, which
may increase prostate cancer risk or contribute to cancer pro-
gression [186, 187]. On the other hand, functional polymor-
phisms in genes involved in polycyclic aromatic hydrocarbons
(PAHs) metabolism, one of the carcinogenic chemical of the
cigarette smoke [185], may aect cancer onset and progres-
sion [188].
Most of the epidemiological studies have not found a
relationship between smoking and incidence of prostate can-
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
demonstrated a convincing dose-response relationship, neither
have they evaluated the inuence of possible dietary risk fac-
tors that are confusing [189]. On the other hand, most studies
examining the relationship between smoking and prostate can-
cer mortality demonstrated that smoking patients double the
risk of dying from the disease compared to nonsmokers [189-
191]. Moreover, there is a dose-response relationship between
the numbers of cigarettes per year of the smoker 10 years be-
fore diagnosis and the increased mortality risk [191].
Sex hormones
There is a large body of both historical and modern data sup-
porting a role for androgens in prostate cancer pathogenesis
and progression, also known as the “androgen hypothesis”.
In 1941, Huggins and Hodges proposed that prostate cancer
growth was driven by androgens, after observing the benets
of castration in prostate cancer patients [192]. Several in vitro
data obtained with well-dierentiated prostate cancer cell lines
showed that they respond to androgen stimulation and undergo
apoptosis upon androgen withdrawal [193, 194]. Likewise, in
vivo studies showed that androgens promote tumorigenesis
and xenograft growth in animal models, and tumor regression
is seen upon androgen deprivation [195, 196]. Clinically, ADT
remains a mainstay in prostate cancer treatment, especially in
advanced disease [197]. Even though preclinical studies sup-
ported a role for androgens in prostate cancer pathogenesis,
clinical data are still controversial [198].
Several evidences that the androgen pathway is one of
the most important signaling mechanisms involved in pros-
tate cancer come from gene linkage analysis, which reveals
a signicant association between prostate cancer risk and sin-
gle nucleotide polymorphisms (SNPs) in the genes encoding
enzymes involved in the synthesis of testosterone and dihy-
drotestosterone (DHT): hydroxysteroid (17-beta) dehydro-
genase-1, hydroxy-delta-5-steroid dehydrogenase [199-202],
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-
likrein family, hK2 and PSA [208-210], and microseminopro-
tein [211-213], as well as genes involved in estrogen receptor
signaling - estrogen receptors α [214] and β [215, 216]. Further
studies are needed to understand how those gene variations in-
uence prostate cancer incidence.
Although the positive role of androgens on prostate cell
growth has been established, some studies found that in pros-
tate cancer patients, the testosterone and DHT levels were low,
suggesting that non-androgenic hormones, including estro-
gens, insulin and vitamin D may be involved in the prostate
carcinogenesis. Several studies have demonstrated that estro-
gen, including the natural hormone E2, induces multiple forms
of genetic lesions such as chromosomal alterations, DNA dam-
age, gene mutations, and microsatellite instability, strongly in-
dicating that estrogen may serve as a carcinogen in the devel-
opment of prostate cancer [217, 218].
Insulin and insulin-like growth factor
Hyperglycemia has been positively associated with cancers
such as breast, pancreatic and colorectal [219]. However, its
link with prostate carcinogenesis is conicting. Several studies
found evidence of higher risk of more aggressive or advanced
prostate cancer among men with abnormal glucose levels, with
the association being not signicant in two of the studies [220-
223].
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,
glucose has been documented as an important source of energy
for rapid tumor cell proliferation [227]. Evidence from clinical
and genetic studies has also linked the hyperglycemic environ-
ment to carcinogenic processes such as apoptosis, oxidative
stress, DNA damage and chronic inammation, which may
drive the aggressiveness and progression of cancer [228-231].
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Serum glucose is directly controlled by insulin, thus higher
glucose level induces insulin secretion from pancreatic β cells.
Lehrer et al showed that patients with high-risk prostate can-
cer had higher insulin levels [171]. In addition, diet-induced
hyperinsulinemia was associated with increased tumor growth
in a xenograft model [232]. Finally, the high level of circulat-
ing insulin decreases the production of insulin-like growth fac-
tor (IGF-1)-binding proteins, increases the level of IGF-1 and
increases the production of advanced glycation end products,
which promote carcinogenesis [233].
In the past years, several studies have recognized a crucial
role for the components of IGF system in prostate cancer biol-
ogy and its implication in both mitogenic and anti-apoptotic
events in prostate cancer cell lines [234]. The IGF family is
composed of two receptors (insulin receptor (INSR), IGF-1
receptor (IGF-1R) and mannose 6-phosphate receptor (M6P/
IGF-2R)), three ligands (insulin, IGF-1 and IGF-2) and six
known types of circulating IGF-binding proteins (IGFBP1-6)
that modulate the bioavailability and bioactivity of the IGFs
[235]. The IGF system regulates many important cellular pro-
cesses critical for normal prostate growth and development,
such as proliferation, dierentiation and cellular metabolism.
The relevance of the IGF system has been evaluated in several
studies. Increased serum concentration of IGF-1 was correlat-
ed to higher risk of prostate cancer [236-238].
However, preclinical studies [239-241] as well as clini-
cal studies [291, 292] showed conicting results. Therefore,
whether IGF-1 serum levels can be used as a prognostic tool
requires further investigation.
Chronic inammation and prostatitis
There is a strong link between prostate cancer and inamma-
tion, and in 1863, Rudolf Virchow was the rst to identify the
high density of leukocytes in neoplastic samples, suggesting a
positive association between inammation and cancer [242].
After that, both epidemiological and biological studies pro-
vided evidence that inammation is behind the high-grade or
aggressive prostate tumors and ultimately metastatic spread
[174, 243]. The evidence-based knowledge so far supports
the role of inammatory responses in the regulation of tumor
microenvironment through the remodeling of the extracellular
matrix (ECM) and initiation of epithelial-mesenchymal transi-
tion (EMT). Indeed, inammatory cells release growth factors
and cytokines within the tumor microenvironment to promote
angiogenesis and remodeling of the ECM, while further in-
ammatory cytokines released within the reactive stroma in-
duce EMT-mediated responses [244].
Patients with elevated PSA often present with intrapro-
static inammation detected with biopsies [245]. Recently,
an inammatory eector, pentraxin 3, has been identied as
a biomarker for predicting tumor progression due to prostatic
inammation in prostate cancer patients [246].
Chronic inammation causes proliferative inammatory
atrophy (PIA) [174], which may develop prostatic intraepithe-
lial neoplasia (PIN) a well-known precursor of prostate cancer
[247]. Consistently with the tight connection between chronic
inammation and high-grade prostate cancer [243], several
SNPs in genes involved in inammation, such as cyclooxy-
genase (COX-2) [248, 249], interleukin-1 (IL-1) [250], IL-6
[251, 252], IL-8 [250] and IL-10 [250, 253], tumor necrosis
factor-α (TNF-α) [254] and Toll-like receptor-4 (TLR4) [253,
255-257] were associated to prostate cancer risk.
Prostatitis is the inammation of the prostate gland that
is hard to diagnose because it is often asymptomatic [258].
Notably, men with symptoms of prostatitis are more likely to
be diagnosed with prostate cancer as a result of the increased
prevalence of biopsy [259].
Lu et al conducted a study including cases and controls
from Minnesota and found that there was a signicant associa-
tion between prostatitis and prostate cancer (odds ratio = 1.7;
95% condence interval: 1.1 - 2.6) [260]. A rst meta-analysis
involving 11 studies between1971 and 1996 provided statisti-
cal evidence that prostatitis is a signicant risk factor in pros-
tate cancer [261]. This observation was conrmed later with
another meta-analysis that included studies between 1990 and
2012 [262].
Development of prostatitis is induced by one or a combi-
nation of factors including infections, chemical and physical
trauma, and diet. Chemical irritation because of urine reux,
or abnormal ow of urine from the bladder back through the
ureters, may cause chronic inammation in the prostate [263].
Non-sexually transmitted pathogens such as E. coli and Pro-
pionibacterium acnes can cause acute and chronic prostatitis
[264, 265]. Also, many sexually transmitted organisms, includ-
ing Neisseria gonorrhea [266] and Chlamydia trachomatis
[267], can induce chronic infection and inammation, that po-
tentially increase the risk of developing prostate cancer [268].
It appears clear that inammation is the ubiquitous factor
associated with increased risk of prostate cancer, independent-
ly of its source (either pathogens or environmental factors).
Finally, the several signaling pathways involved in the in-
ammatory process that modies prostate microenvironment
and the complexity of biological events linking inammation
to prostate cancer progression and metastatic spread provide
a broad range of promising targets for pharmaceutical treat-
ments.
Sexually transmitted disease (STD)
Several epidemiologic studies evidenced that factors related
to sexual behavior and STDs may be associated with prostate
cancer [269].
STDs represent a major public health problem world-
wide. Human papilloma virus (HPV) and herpes simplex virus
(HSV) are common STDs worldwide [270, 271], the former
being also involved in the etiology of cancer of cervix uteri
and other anatomical sites [272, 273]. The rst claims of an
etiological role of STDs in the development of prostate cancer
date back to the 1950s [274] and several mechanisms were
subsequently proposed to explain this association. For gonor-
rhea and other bacterial infections, prostate inammation and
prostate atrophy are the processes that lead to prostate cancer,
whereas for viral infections, the emphasis was placed on the
transforming properties of viruses, in particular, HSV [275].
A large population-based case-control study among Af-
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rican-American and white men, revealed an elevated risk of
prostate cancer among men with a history of gonorrhea or
syphilis [268]. HPV, which occurs in human prostate cancer
and benign prostatic tissue [276], has been shown to transform
human prostate cells in vitro. Furthermore, seropositivity for
HPV-18 and HPV-16 has been associated with subsequent
prostate cancer in a Finnish cohort study [277, 278], but a
small case-control study of HPV-16 and HPV-11 [279], and a
large population-based case-control study [268] showed little
evidence of risk. Finally, a recently published meta-analysis
showed a weak association between HPV-16 and prostate can-
cer and no association for HPV-18 [280].
To our knowledge, only three studies have been published
so far investigating the association between Trichomonas vagi-
nalis infection, a common cause of vaginitis in women, and
prostate cancer risk. Trichomonas vaginalis can also infect
men, where it may cause asymptomatic urethritis and pros-
tatitis. In particular, its frequent asymptomatic presentation
may make it possible to persist untreated and ascend to the
prostate, where it can establish foci of chronic inammation
that may eventually lead to prostate cancer [275]. Mechanis-
tically, Trichomonas vaginalis infection causes adherence of
the protozoan to epithelial cells by decreasing the expression
of anti-apoptotic genes; it also alters the production of IL-6
and monocyte chemotaxis proteins. Whereas an association
between Trichomonas vaginalis serostatus and increased risk
of prostate cancer was found, the same connection between
seropositivity for this pathogen and progression to death from
prostate cancer was not demonstrated [281].
Medications
Despite the knowledge gained over the years about the eti-
opathogenesis of prostate cancer and the known high risk for
men to be diagnosed with the disease during their lifetime, ef-
fective chemo-preventive agent that can safely be administered
to impact the lives of men is still missing positively. The role
of testosterone and pro-inammatory pathways in the patho-
genesis of prostate cancer provided some clues about the pos-
sibility to use inhibitors of testosterone endogenous production
and inammation.
5-α reductase (5-AR) inhibitors
By far the most promising and well-studied chemo-preventive
agents are nasteride and dutasteride, which are inhibitors of
5-AR enzyme that converts testosterone into dihydrotestoster-
one, the most prevalent and potent androgen in prostate tissue,
which is responsible for embryologic development [282] and
growth of the prostate as well as promotion of prostate cancer
[283].
Finasteride and dutasteride are eectively used for the
treatment of benign prostatic hyperplasia [284-286] and were
studied in clinical trials as potential chemopreventive agents.
Finasteride was studied in the prostate cancer prevention
trial (PCPT) and its use was associated with a 25% reduction
in prostate cancer incidence after 7 years [287]. Dutasteride
was studied in the REduction by DUtasteride of Prostate Can-
cer Events (REDUCE) trial, and the results showed that men
treated with dutasteride had a 23% reduction in prostate cancer
incidence after 4 years [288]. However, the results of these
two trials were largely criticized for many aspects, including
results from biopsies performed towards the end of the study
as opposed to biopsies that are done when patients have el-
evated PSA or DRE abnormalities, the capability to prevent
only low-grade cancers that will unlikely lead to death. Most
importantly, Food and Drug Administration (FDA) Oncology
Drugs Advisory Committee (ODAC) re-analyzed the data
from PCPT and REDUCE trials and conrmed that the results
do not strongly support any preventive eect on high-grade
prostate cancer and therefore their use in therapy as chemo-
preventive agents is not recognized yet.
The Reduction by Dutasteride of Clinical Progression
Events in Expectant Management of Prostate Cancer (RE-
DEEM) study reported that dutasteride may provide a useful
adjunct to “active surveillance” for management of prostate
cancer, because it delayed the time to prostate cancer progres-
sion, increased the percent of men with no detectable tumor
and improved cancer-related anxiety [289].
However, whether the eectiveness of 5-AR inhibitor
therapy is inuenced by certain patients’ features, like specic
clinical conditions or genetic variations, was not evaluated yet.
Therefore, identication of these subgroup of patients who
may then undergo clinical trials with 5-AR inhibitors would
address this intriguing question.
Nonsteroidal anti-inammatory drugs (NSAIDs) and aspirin
(ASA)
There is rapidly growing evidence for the impact of NSAIDs
on cancer [290]. At the cellular level, NSAIDs target cy-
clooxygenase (COX), particularly, the isoform 2 (COX-2) is
expressed in inammatory cells of the prostate and in PIA, a
precursor of prostate cancer [174, 243]. A recent meta-analysis
that included 20 observation studies with a total of 25,768 indi-
viduals evaluated the ecacy of NSAIDs in reducing prostate
cancer risk [291]. The clinical data indicated that there was a
statistically signicant protective eect as revealed by the risk
reduction at 5% for ASA and 8% for other NSAIDs. In addi-
tion, another study revealed that they were only eective for
patients > 60 years of age [292].
Several experimental studies have documented that COX-
2 overexpression in prostate cancer can be eectively targeted
by COX-2 selective inhibitors such as celecoxib [291].
Several epidemiological and experimental evidence has
demonstrated an inverse relationship between ASA use and
prostate cancer, particularly after 5 or more years of use in
men with metastatic disease [293]. A population-based case-
control study of 1,900 men reported that the RR of prostate
cancer was signicantly reduced of 18%, 21% and 24% in men
who reported the use of ASA, or currently used ASA, or are
long-term users of ASA, respectively [294]. Surprisingly, low
dose of ASA was associated with the highest risk [294]. Fi-
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nally, a multicenter study of over 90,000 documented a direct
protective eect in patients ingesting six ASAs daily [295].
Altogether, the results of these studies have shown that the use
of NSAID and ASA have a benecial eect on the prevention
of prostate cancer.
Statin
Statin medications are inhibitors of the synthesis of lipids, par-
ticularly cholesterol and recently they showed to reduce PSA
levels [296, 297], and the risk of advanced or aggressive pros-
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 conicting [301].
The use of statins as a preventive agent may oer the ad-
vantage to reduce cholesterol levels and the risk of cardiac
disease other than being safe. Statins eect as a secondary pre-
ventive agent was recently tested in two studies. One trial en-
rolled patients and randomly assigned them to simvastatin or
placebo treatment before radical prostatectomy and examined
changes in benign and malignant tissue in the prostate speci-
men [302]. From this study, no signicative benecial action
of simvastatin was observed and its use was associated to seri-
ous adverse events (+55% vs. 18.75% of placebo group). The
second trial is a phase II study evaluating the eect of atorvas-
tatin and celecoxib on the levels of prostate cancer biomarkers,
including PSA, in those patients with rising PSA levels after
denitive local therapy [303].
In conclusion, more clinical evidence is called to prove the
eective advantage of using statins for prostate cancer preven-
tion.
Environmental carcinogens
The slow process of prostate carcinogenesis is also inuenced
by exposure to certain environmental factors that increase the
risk of developing cancer. These include insecticides, herbi-
cides and other organic compounds.
Agent orange (AO)
Herbicides are active chemical compounds that are used to
ght plant pests. Agent orange (AO) is a mixture of two her-
bicides that were used as a defoliant between 1962 and 1971
in the Vietnam War and was contaminated with the toxin
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a putative car-
cinogen. Dioxins remain an area of important interest as these
environmental toxins continue to be produced through chemi-
cal processing and municipal waste incineration. These chemi-
cals can then enter the food chain through soil contamination
[304].
In 1998, the National Academy of Science of the US rec-
ognized a positive association between herbicide exposure
and many human cancers. In a review published in 2008, the
authors found twice as many cases of prostate cancer among
the exposed veterans of the Vietnam War compared with no-
exposed veterans [305]. They presented with earlier diagnostic
ages, high-grade tumor, independently of other modiable risk
factors. It suggests that AO is the most predictive factor not
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 conrmed by the study of
Ansbaugh et al that demonstrated a high correlation between
AO exposure and risk of high-grade prostate cancer among Vi-
etnam War veterans [304].
Chlordecone
Chlordecone (also known as Kepone) is an organochlorine
insecticide with well-dened estrogenic properties [306, 307]
extensively used for decades in the French West Indies, to con-
trol the banana root borer. It is a carcinogenic agent with a
long biologic half-life, and among its long-term eects, cancer
is not excluded. Indeed, it was shown that chlordecone causes
hepatic tumors in laboratory mice and rats [308] and it has
been associated with increased risk of prostate cancer too.
The prostate cancer risk associated with chlordecone ex-
posure was higher in those men with a family history of pros-
tate cancer, and similar ndings were reported for pesticide
exposure in the Agricultural Health Study [309-312]. There
are two possible explanation: 1) Study subjects and their
rst-degree relatives may have similar patterns of exposure,
which consequently lead to a statistical interaction between
chlordecone exposure and family history of prostate cancer; 2)
Genetic variations, such as inheritance of polymorphism in a
metabolic enzyme that alters the balance between chlordecone
bioactivation and detoxication in the body. In line with the
latter hypothesis, previous studies have shown dierences in
the inter-individual liver activity of chlordecone reductase be-
tween White and Japanese men [313, 314].
Bisphenol A (BPA)
Another harmful compound associated with a high risk of
prostate cancer is BPA.
BPA has been used to harden plastic since the 1950s in the
manufacture of polycarbonate plastic and epoxy resins that ap-
pear in thousands of consumer products since then [315]. BPA
is also used as a cross-linking compound in many food prod-
uct containers [316]. BPA leaching from these containers may
contaminate food and beverage, which constitutes the main
source of exposure of humans via a route of ingestion [317].
Approximately 90% of BPA exposure in humans is from
the intake of BPA contaminated food and beverage during pro-
cessing and storage [318]. In addition to ingestion, intake of
BPA from the routes of inhalation or absorption via direct con-
tact cannot be ignored [317, 319].
The rst evidence on the direct link between BPA expo-
sure and human prostate cancer was reported in 2014 by two
US research teams based on in vitro and in vivo experimental
studies [320, 321]. Abnormalities of centrosome (a hallmark of
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malignant transformation) induced by a low level of BPA and
its analogs were underlined as the potential mechanism in pro-
moting the formation of prostate cancer [320, 322]. Tse et al
published epidemiological evidence that cumulative exposure
to BPA was associated with an excess risk of prostate cancer in
the Chinese population [323]. The authors found a positive as-
sociation of prostate cancer with intake of deep-fried food and
pickled vegetable that were independent of other risk factors
[324-326]. Deep fried foods (e.g. meats and potato) at high-
heat cooking process generate a high amount of heterocyclic
amines and other mutagens and carcinogens (e.g. acrylamide
and polycyclic aromatic hydrocarbons) that may be carcino-
genic to prostate cells [325].
Vasectomy
Vasectomy is the most frequent male contraception in the
USA, with approximately 500,000 procedures performed an-
nually. Its association with prostate cancer risk was explored in
case-control and cohort studies with conicting results. Some
authors found an increased risk of up to 70% with a vasectomy,
while others found a lesser risk [189, 327, 328]. However, stud-
ies showing small RRs are not convincing as they have some
potential bias and methodological shortcoming [329]. On the
other hand, in a very well-designed study in New Zealand, the
country with the highest global prevalence of vasectomy, the
authors found no relationship with these subgroups [327].
Biological studies that show underlying mechanism/s that
might explain an association between vasectomy and prostate
cancer are still lacking.
Ejaculatory frequency
Over the years, there has been growing evidence of a link be-
tween ejaculation and lower chances of prostate cancer.
In 2004, the Health Professionals Follow-Up Study
(HPFS) cohort reported a signicant positive relation between
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
revealed that men who ejaculated ≥ 21 times per month (EPM)
had about a 20% lower chance of low-grade prostate cancer,
compared with those who had ≤ 4 - 7 EPM based on 18 years
follow-up [331]. A year later, a case-control study sampling
a smaller group of men (2,141) from age 20 to 50 found only
weak evidence of an inverse association between ejaculatory
frequency in the fourth decade of life and advanced prostate
cancer, which was not signicantly modied by a number of
new sexual partners [332]. In the same study, no relationship
was found for ejaculatory frequency in the third and fth dec-
ades of life.
The ejaculatory frequency may inuence prostate cancer
development through several mechanisms. One biological
mechanism is described as “prostate stagnation hypothesis”,
which involves the prostatic accumulation of potentially car-
cinogenic secretions that may create a favorable environment
for prostate cancer development [330, 333]. More frequent
ejaculation may alter the function of peripheral-zone epithelial
cells, which start to oxidate citrate rather than secrete it. This
metabolic switch is known to occur early in prostate tumori-
genesis [334]. Finally, the higher ejaculatory frequency may
reduce the development of prostatic intraluminal crystalloids,
which have been associated with a higher risk of prostate can-
cer [335, 336]. More frequent ejaculation is thought to help
to lower psychological tension and favors central sympathetic
nervous system suppression, which could dampen the stimula-
tion of prostate epithelial cell division [337].
Diagnostic radiologic procedure and ultraviolet light expo-
sure
The radiation generated from X-ray, CT and nuclear imag-
ing is ionizing radiation that penetrates the tissue to reveal
the body’s internal organs. However, ionizing radiation can
damage DNA, and although cells repair most of the damage,
sometimes small area may remain altered (“misrepair” area)
consequently leading to DNA mutations that may contribute to
cancer development years down the road. The rst study inves-
tigating the connection between low-dose ionization radiation
from diagnostic X-ray procedures and risk for prostate cancer
reported that exposure to a hip/pelvic X-ray signicantly in-
creased prostate cancer risk independently of other known risk
factors such as family history of cancer [338]. However, unless
men were exposed to high doses of radiation during cancer
treatment in youth, any increase in the risk for cancer due to
medical radiation appears to be slight. Considering that the in-
crease in high-dose imaging has occurred only since 1980 and
the eects of radiation damage typically take many years to
appear, this may explain the weak association between ioniz-
ing radiation and prostate cancer risk observed thus far.
Finally, exposure to solar UV radiation is inversely associ-
ated with both the incidence and mortality of prostate cancer
[128]. The biological explanation of this fact is based on the syn-
thesis and physiological actions of vitamin D [126, 127, 129].
Prevention
An eective prevention strategy for prostate cancer would pro-
vide many benets to men with a substantial positive impact
on public health, including the potential to reduce the high
lifetime risks of prostate cancer development, the morbidities
associated with cancer treatment, especially in those newly
diagnosed patients with biological indolent prostate cancer
that still undergo curative-intent therapy rather than active sur-
veillance and nally the inability to eradicate life-threatening
metastatic prostate cancer.
Epidemiological data indicate a dominant role for lifestyle
factors in prostate cancer development. Considering that pros-
tatic carcinogenesis takes many decades, lifestyle modication
may represent a feasible and cost-eective approach to retard
prostate cancer development.
Although the data about the role of specic lifestyle fac-
Articles © The authors | Journal compilation © World J Oncol and Elmer Press Inc™ | www.wjon.org
76
Epidemiology of Prostate Cancer World J Oncol. 2019;10(2):63-89
tors fostering prostate cancer development have often been
conicting, most of the studies clearly evidence a diet rich in
fruits, vegetables and anti-oxidant micronutrients, and poor in
saturated fats and “well-done” red meats, may signicantly re-
duce risks of prostate cancer development, as well as the risk
of diseases typical of the industrialized world.
The better understanding of prostate cancer etiology rep-
resents the key to open to new opportunities for prostate can-
cer prevention. Several nutrients and pharmaceutical agents
have been studied as potential chemoprevention candidates.
Vitamin E and selenium showed promise [138, 141]. How-
ever, these were denitively evaluated in the SELECT, and
neither agent reduced prostate cancer risk [140]. Vitamin D
analogs, NSAIDs and toremifene (a selective estrogen receptor
modulator) have all been evaluated in laboratory and/or ob-
servational studies [134, 339, 340]. However, vitamin D has
not been formally tested in primary prevention trials, while the
NSAID rofecoxib, a COX-2 selective inhibitor, could not be
successfully tested because the trial was closed when the drug
was withdrawn from the market after an interim safety analysis
indicated that the drug was associated with increased risk of
cardiovascular events within the Adenomatous Polyp Preven-
tion on Vioxx (APPROVe) trial [341]. Toremifene showed a
modest risk reduction in a phase II trial [342], but no signi-
cant risk reduction in a phase III trial [343].
Besides identication of molecular targets, other prin-
ciples of prevention include personalized risk assessment,
identication of sensitive and accurate surrogate molecular
markers to serve as intermediate endpoints and identication
of biomarkers that predict sensitivity to preventive agents. Fur-
thermore, it should also emphasize personalized molecularly
targeted approaches for the selection and treatment of patients
with prostate cancer that result in a positive outcome and ef-
fective therapy.
Future Directions
The high global incidence of prostate cancer makes a call to
strengthen the current tools available to identify trends and
prevention strategies to reduce the public health impact of this
disease in the future.
First, prostate cancer registries play an important role in
the advancement of prostate cancer research and care. Indeed,
they represent an essential source to collect information about
incidence and mortality, disease characteristics at presentation,
trends and risk factors, quality of care, disparities in access
to treatment, long-term data related to oncologic and health-
related quality of life outcomes and costs associated with man-
agement of the disease. Therefore, improvements in the quality
of data, collection of tissue samples and the availability of data
feedback to health care providers will increase the relevance of
epidemiological studies especially when it comes to the evalu-
ation of data collected from undeveloped countries.
Chemo-preventive strategies have been explored in sev-
eral preclinical and small clinical studies to mitigate the global
burden of prostate cancer and the overtreatment of indolent
disease that has been associated with the broad utilization of
PSA testing. However, a challenge for the future will be the
translation of preclinical data into clinically useful strategies,
which will require very large trials with thousands of partici-
pants, like those of the SELECT studies [180].
Furthermore, studies that can ll the knowledge gap re-
garding the higher prostate cancer incidence and mortality
in African-American men compared to White men are also
needed. Recently, the “Research on Prostate Cancer in Men
of African Ancestry: Dening the Roles of Genetics, Tumor
Markers, and Social Stress” (RESPOND) study which was
funded by the National Institute of Health and Prostate Cancer
Foundation was carried out. The primary goals of this study
were to understand how social and genetic variants contrib-
ute to the development of aggressive prostate cancer, and how
those factors interact with each other. Hopefully, the increased
knowledge gained within this study will provide new insights
to develop positive screening and chemo-preventive strategies.
Finally, classical prognostic factors such as PSA testing,
Gleason score and clinical cancer staging have demonstrated
not to be always sucient to lead to a clinically relevant can-
cer diagnosis. Considering that various genomic aberrations
contribute to the variety in prostate cancer risk and outcome as
well as drug responses and progression between patients, the
identication of novel genetic biomarkers is highly required.
This will undoubtedly improve cancer diagnosis, subtype
identication and risk stratication. Most importantly, as we
are moving toward personalized medicine, oncogenetic test-
ing and biomarker proling will facilitate the optimal thera-
peutic intervention based on the alterations observed in single
patients [344, 345]. Clinical trials have already shown high
success rate for drugs that are developed using biomarkers in
patients with non-small cell lung cancer, therefore it is desir-
able that same results may also be achieved for the treatment
of prostate cancer.
Conclusion
Prostate cancer is the most common malignancy in men, rank-
ing second after lung cancer [1]. The identication of biomark-
ers such as PSA that are positively correlated with the diag-
nosis of prostate cancer revolutionized the epidemiology of
this disease. Indeed, since the introduction of PSA testing and
subsequent biopsies, USA registered double of prostate cancer
incidence starting from the late 1980s [23]. A similar increase
was also reported in other countries, particularly in the western
type. Unfortunately, although it turned eective in reducing
prostate cancer-specic mortality, the relevant overdiagnosis
and the severe side eects of treatments advised against the
introduction of PSA as a screening program.
Perhaps, the most dramatic statistic when it comes to pros-
tate cancer incidence and mortality is the way that prevalence
varies among dierent racial groups, with the highest preva-
lence in African-American men [14]. Both biologic and so-
cioeconomic factors may explain this discrepancy, but which
genes may be involved and how they may interact with the en-
vironment is still unknown and is a subject of studies. In 2018,
a study called “Research on Prostate Cancer in Men of Afri-
Articles © The authors | Journal compilation © World J Oncol and Elmer Press Inc™ | www.wjon.org 77
Rawla World J Oncol. 2019;10(2):63-89
can Ancestry: Dening the Roles of Genetics, Tumor Markers,
and Social Stress” (RESPOND) was nanced by the National
Cancer Institute, the National Institute on Minority Health and
Health Disparities and the Prostate Cancer Foundation with
the purpose of addressing those questions.
In recent years, the development of novel genetic tech-
nologies allowed for the rst time a comprehensive analysis
of genetic and epigenetic changes in human prostate cancer.
This information, combined with targeted functional studies,
helped to identify critical signaling pathways that are casually
involved in prostate cancer initiation and progression. This in-
formation will provide an opportunity for the development of
novel targeted approaches for therapeutic interventions. More
research to identify genes associated with an increased risk of
prostate cancer is ongoing, and researchers are collecting more
insights about the impact that specic genetic changes have on
prostate cancer development.
Although there are no studies that can suciently demon-
strate the direct correlation between diet and nutrition with risk
or prevention of prostate cancer development, many preclini-
cal studies that look at links between certain eating behaviors
and cancer suggest there may be a connection. Moreover, these
studies allowed identifying the underlying biological mecha-
nisms that may explain this link. Therefore, well-designed tri-
als that replicate preclinical ndings are warranted to validate
the impact of dietary agents in prostate cancer. Finally, future
chemoprevention studies should include not only early inter-
vention but should also emphasize personalized molecularly
targeted approaches for the selection and treatment of patients
with prostate cancer that result in a positive outcome and ef-
fective therapy.
Acknowledgments
None.
Conict of Interest
None of the authors have conict of interest.
Ethics Approval
No ethics approval needed.
Funding
No funding to disclose.
Author Contributions
Conception and design: PR. Analysis and interpretation, draft-
ing and critical revision of the article: PR. Final approval of
the article: PR.
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