Prostate cancer risk factors

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Prostate cancer Microchapters
Home
Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Prostate Cancer from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms
Physical Examination
Staging
Laboratory Findings
X Ray
CT
MRI
Ultrasound
Other Imaging Findings
Other Diagnostic Studies
Biopsy
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Alternative Therapy
Case Studies
Case #1
Prostate cancer risk factors On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Prostate cancer risk factors All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Prostate cancer risk factors
CDC on Prostate cancer risk factors
Prostate cancer risk factors in the news
Blogs on Prostate cancer risk factors
Directions to Hospitals Treating Prostate cancer
Risk calculators and risk factors for Prostate cancer risk factors

Overview

Common risk factors in the development of prostate cancer are family history, African American men, dietary factors, obesity, elevated blood levels of testosterone, inherited gene mutation, inflammation of the prostate, tall adult height, exposure to pesticides, and occupational exposures.

Risk Factors

Common risk factors in the development of prostate cancer include:

• Positive family history
• African American men
• Dietary factors

• A diet high in fat
• A diet high in red or processed meats

• Obesity
• Elevated blood levels of testosterone
• Inherited gene mutation

• Men who inherit mutations of the BRCA2 gene may have a higher risk of developing prostate cancer. This gene mutation also increases a woman’s risk of developing breast or ovarian cancer.

• Inflammation of the prostate
• Tall adult height
• Exposure to pesticides
• Occupational exposures

• Cadmium
• Chemicals in rubber manufacturing

AGE

• Prostate cancer has strongest relationships between age and any human malignancy.
• Prostate cancer rarely occurs before the age of 40.
• The incidence rises rapidly and data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program, the annual incidence of new cases of prostate cancer in white men in 1995 was approximately 0.1, 0.6, and 1 percent in men in their 50s, 60s, and 70s, respectively.

• The widespread prevalence of occult prostate cancer in older men and the dramatic increase with age are illustrated by a review of autopsy studies conducted in multiple countries :

●20 to 30 years, 2 to 8 percent of men with occult cancer

●31 to 40 years, 9 to 31 percent

●41 to 50 years, 3 to 43 percent

●51 to 60 years, 5 to 46 percent

●61 to 70 years, 14 to 70 percent

●71 to 80 years, 31 to 83 percent

●81 to 90 years, 40 to 73 percent

ETHNICITY

• Prostate cancer is more common in black than white or Hispanic men.
• Many studies have found that African American men also have higher serum PSA levels, worse Gleason scores, and more advanced stage of disease at the time of diagnosis.

DIET

• The association between intake of nutrients and the risk of prostate cancer are available [20,21].
  • Animal fat — A diet high in animal fat may be an important factor in the development of prostate cancer [22-26]. In particular, intake of large amounts of alpha-linolenic acid and low amounts of linoleic acid appear to be associated with increased risk; this combination is common in red meat and some dairy products [25-27].
  • Vegetables — A diet low in vegetables may be another risk factor for prostate cancer [23,28,29]. A case-control study found a higher prostate cancer risk in men who consume fewer than 14 servings of vegetables weekly, compared with 28 or more servings (adjusted odds ratio 1.54) [28].

There was no association between fruit and/or vegetable consumption and the risk of prostate cancer among 29,361 men in the screening arm of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, 1338 of whom developed prostate cancer [30]

• • Lycopene and tomato based products — Tomato-based products are rich in lycopene, which has potent anti-oxidant properties.

There is only limited evidence to support an association between tomato consumption and reduced prostate cancer risk [34]. recently, an analysis of a prospective cohort of 51,529 men from the Health Professionals Follow-up Study has suggested that dietary intake of lycopene is associated with a lower incidence of prostate cancer and a decreased risk of lethal prostate cancer [35].

• • Soy intake — Phytoestrogens (flavones, isoflavones, lignans) are naturally occurring plant compounds that have estrogen-like activity.

phytoestrogens such as those found in soy foods may reduce prostate cancer risk either via their inherent estrogenic properties (which favorably alters the hormonal milieu), or by inhibition of the enzyme 5-AR, which decreases concentrations of the more prostate-active androgen dihydrotestosterone. The higher intake of soy products among Asian men has been hypothesized to be one reason for the lower incidence of prostate cancer among these men.

• • Omega-3 fatty acids and fish oil — Case-control analyses of serum samples from two large trials (Prostate Cancer Prevention Trial [PCPT], Selenium and Vitamin E Cancer Prevention Trial [SELECT]) found that high levels of omega-3 fatty acids, such as those found in fish oil, were associated with an increased risk of clinically significant, high grade prostate cancer [40,41].
  • Coffee — Increasing consumption of coffee appears to be associated with a decreased risk of lethal prostate cancer (defined as fatal or metastatic). [44]. The decrease in risk of lethal prostate cancer was inversely proportional to increases in coffee consumption (RR 0.44, 95% CI 0.22-0.75, for those drinking six or more cups of coffee per day), and the decreased risk was present after controlling for other known prostate cancer risk factors.
  • Vitamin and mineral supplements- The regular use of multivitamins does not appear to affect the risk of early or localized prostate cancer [45].Two reports have observed an increased risk of advanced or fatal prostate cancer in men using relatively large amounts of multivitamins [45,46].
  • Folic acid and B12 — High serum folic acid and B12 levels may be associated with a small increase in the risk of prostate cancer. Data supporting a possible causal relationship come from cohort studies and from a secondary analysis of a randomized trial.
  • Selenium and vitamin E — The relationship between prostate cancer, and selenium intake and level is complex.In the subset of cases where selenium levels were measured in the blood, the selenium level was not associated with a difference in the risk of prostate cancer (odds ratio 1.01, 95% CI 0.83-1.23). However, high blood levels were associated with lower risk of aggressive disease (advanced-stage disease and/or prostate cancer death).
  • Zinc — At least two studies have suggested an association between zinc supplement use and an increased risk of prostate cancer [50,51]. In the Health Professionals Follow-Up Study, which included 46,974 American men, 2901 cases of prostate cancer were diagnosed over a 14 year period [50]. Compared with nonusers, men who consumed over 100 mg of supplemental zinc daily had a 2.29-fold increased risk of prostate cancer; the RR was 2.37 in those who took zinc for 10 or more years.
  • Calcium and vitamin D — A link between intake of dairy products and calcium and a higher risk of prostate cancer risk has been suggested in many [52-56]

[63]. There was no statistically significant trend in overall prostate cancer risk associated with the serum vitamin D levels, although higher levels of vitamin D were associated with increased aggressiveness in those men diagnosed with prostate cancer, as manifested by Gleason score ≥7 or stage III or IV disease at diagnosis.

CIGARETTE SMOKING

• Cigarette smoking may have an effect on both the risk of developing prostate cancer and its prognosis once a diagnosis is established.

while most case-control studies have found either an increased risk for prostate cancer or more frequent high-grade prostate cancer and advanced stages in smokers [73-78]

There are consistent data on the association of smoking at the time of diagnosis with risk of a cancer recurrence and cancer-related mortality [79-86] Men with prostate cancer should be strongly encouraged to stop smoking.

HORMONE LEVELS AND OBESITY

• Serum concentrations of androgens and insulin-like growth factor 1 (IGF-1) have been studied as possible risk factors for prostate cancer.
• The most definitive data regarding the relationship between serum sex hormone levels and prostate cancer come from a pooled analysis of 18 prospective trials, which included 3886 men with prostate cancer and 6438 controls [87]. Serum concentrations of testosterone, dihydrotestosterone (DHT), and other active androgen derivatives obtained prior to diagnosis were NOT associated with an increased risk of subsequent prostate cancer. In addition, no association was seen with prediagnosis serum levels of estrogens (estradiol, free estradiol).
• In addition, testosterone supplementation as a treatment for hypogonadism does not appear to be associated with an increased risk of prostate cancer, although monitoring for prostate abnormalities is recommended.
• A meta-analysis based upon individual patient data from 3700 men with prostate cancer and 5200 controls found a modest increased risk of prostate cancer in those men with the highest circulating levels of IGF-1 (odds ratio 1.38, 95% CI 1.19-1.60, [88]. The association appeared strongest for low-grade, rather than high-grade, prostate cancers.

Obesity

• meta-analyses have consistently demonstrated a small but statistically significant association between obesity and prostate cancer incidence [94-97].
• there is a clear relationship between obesity and disease aggressiveness, with an increase in both biochemical recurrence rate following treatment and prostate cancer-specific mortality [99,100].

Physical activity

• There was no association overall between prostate cancer incidence and total, vigorous or non-vigorous physical activity in the entire population. However, men over the age of 65 who were in the highest category of vigorous activity (more than three hours per week of vigorous activity) had a significantly lower risk of advanced (relative risk [RR] 0.33, 95% CI 0.17-0.62) or fatal (RR 0.26, 95% CI 0.11-0.66) prostate cancer. Younger men derived no benefit. However, in all age groups, men with high levels of physical activity (more than 29 metabolic equivalent hours versus none) were less likely to be diagnosed with high-grade (Gleason score ≥7) prostate cancers.
• In contrast to these data, another report from the same investigators suggests that young lean men who are more physically active have an increased risk of developing metastatic disease and fatal prostate cancer if they had a high energy intake [103].

5-alpha reductase inhibitors

• 5-alpha reductase inhibitors lower the prostate-specific antigen (PSA), they potentially increase the risk of high-grade prostate cancer.

Prostatitis

• The available data from case-control studies, cohort studies, and meta-analyses suggest a significant but modest increase (approximately 1.5- to 2-fold) in the risk of prostate cancer in men with prostatitis, but the data are generally of low quality and the relationship between prostatitis and prostate cancer remains unclear in African Americans [104-108]. Despite a significant body of work relating inflammation to cancer, a cause and effect relationship has not been established between prostate cancer and prostatitis

Trichomonas vaginalis infection

• Case-control series from the Health Professionals Follow-up Study and the Physician's Health Study both have shown an increased incidence of seropositivity for antibodies against trichomonas vaginalis in men who subsequently are diagnosed with prostate cancer [109,110].
• This association was more pronounced in those with more advanced or higher Gleason grade tumors.

Environmental carcinogens

Agent Orange — Exposure to Agent Orange, an herbicide defoliant sprayed extensively in Vietnam between 1965 and 1971 that contained dioxins, appears to be associated with an increased incidence of prostate cancer. The cases of prostate cancer arising in those exposed to Agent Orange appear to be more aggressive [111-113].

The initial studies that analyzed a possible relationship between exposure to Agent Orange and the subsequent development of prostate cancer yielded conflicting results [111,114-116]. These studies were limited by relatively limited numbers of patients, the young age of the cohorts involved, and potential biases of recall about Agent Orange exposure.

The most extensive study analyzed the history of Agent Orange exposure in a cohort of 13,124 Vietnam veterans from the Veterans Administration electronic medical record database [117]. Prostate cancer developed significantly more frequently in those exposed to Agent Orange (239 of 6214 men exposed [3.8 percent] versus 124 of 6930 unexposed [2.0 percent]). Among those with prostate cancer, a Gleason score of 8 to 10 was significantly more frequent in those exposed to Agent Orange, as was the likelihood of having metastatic disease at presentation (21.8 versus 10.5 and 13.4 versus 4 percent, respectively). There was no difference in the history of PSA screening in those with and without Agent Orange exposure, and a history of Agent Orange exposure was established prior to the diagnosis of prostate cancer in all cases. Implications for Agent Orange exposure for United States veterans can be significant with regards to designation of service-connected illnesses.

Chlordecone — Chlordecone is an organochlorine insecticide with estrogenic properties, which was widely used in the West Indies from 1973 to 1993. Chlordecone has been shown to be carcinogenic in laboratory animal models. A case-control series compared plasma levels of chlordecone and exposure history in 623 men with prostate cancer with 671 controls [118]. There was a statistically significant increase in the incidence of prostate cancer, which was related to the measured level of this agent as well as exposure history. The mechanisms underlying these observations require further study.

Bisphenol A — Exposure to abnormal concentrations of estrogen early in life may initiate changes in prostate stem cells. These changes have been postulated to persist into later life and potentially contribute to the development of prostate cancer [119].

Bisphenol A is widely used in the manufacture of a variety of products such as plastics and resins that are widely present in the environment. In vitro studies and animal models have demonstrated that bisphenol A has significant estrogenic effects on human prostate stem cells, at concentrations consistent with its presence in the environment [120]. The potential contribution of exposure to bisphenol early in life to the subsequent development of prostate cancer remains uncertain.

Use of NSAIDs — Intake of aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) has been associated with a decreased risk of some cancers, particularly colorectal cancer. (See "NSAIDs (including aspirin): Role in prevention of colorectal cancer".)

An inverse association between long-term NSAID use and prostate cancer risk has also been suggested, although the magnitude of the risk reduction is unclear [121-124].

●The largest cohort study examined the association between NSAID use and prostate cancer incidence among 70,144 men in the American Cancer Society Cancer Prevention Study II Nutrition Cohort [121]. Information on use of NSAID was obtained from questionnaires completed at study entry and five to six years later. Over a nine-year follow-up period, 4853 cases of incident prostate cancer were diagnosed. Long duration regular use (30 or more pills per month for five or more years) of either NSAIDs (relative risk [RR] 0.82, 95% CI 0.71-0.94) or adult-strength aspirin (RR 0.85, 95% CI 0.73-0.99) was associated with a significantly reduced incidence of prostate cancer.

●A meta-analysis that looked specifically at the potential effects of aspirin analyzed data from 24 observational studies [125]. There was a decreased risk for the overall incidence of prostate cancer and for advanced prostate cancer (RRs 0.86, 95% CI 0.81-0.92, and 0.83, 95% CI 0.75-0.91, respectively).

●Additional data on the effects of aspirin come from the Physician's Health Study, in which 22,071 men were randomly assigned to aspirin, carotene, both, or placebo in 1981 to 1982 [126]. The aspirin component of the trial was terminated in 1988, but most men continued to take aspirin in an open-label fashion because of its cardiovascular benefits. By 2009, 509 men had died of lethal prostate cancer, and there was a decreased risk of lethal prostate cancer among regular aspirin users (≥3 tablets per week, hazard ratio [HR] 0.68, 95% CI 0.52-0.89).

Statins — Although multiple epidemiologic studies have yielded equivocal results regarding the impact of statins on the incidence of prostate cancer, the epidemiologic evidence suggests that statin use may have a beneficial impact on prostate cancer progression and mortality. (See "Investigational approaches for the treatment of advanced prostate cancer", section on 'Statins'.)

Vasectomy — Whether a prior vasectomy also increases a man's risk of getting prostate cancer is controversial, with some, but not all, studies showing a weak association. This is illustrated by three large contemporary studies and a meta-analysis:

●In the Cancer Prevention Study II, 7451 of 363,726 men died from prostate cancer between 1982 and 2012 [127]. There was no association between vasectomy and prostate cancer mortality (HR 1.01, 95% CI 0.93-1.10). The incidence of prostate cancer was investigated in a subset of 66,542 men; there was no association with either overall prostate cancer incidence (HR 1.02, 95% CI 0.96-1.08) or high-grade prostate cancer (HR 0.91, 95% CI 0.78-1.07).

●In a European Prospective Investigation into Cancer and Nutrition (EPIC) study, 84,753 men were followed for an average of 15 years. In this series, 4377 men were diagnosed with prostate cancer, including 641 who had a prior vasectomy [128]. There was no statistically significant association between prior vasectomy and prostate cancer incidence or death.

●In a cohort study of almost 50,000 men in the Health Professionals Follow-up Study, 6023 men developed prostate cancer [129]. On multivariable analysis incorporating a range of potentially confounding factors, vasectomy was associated with a statistically significant increase in the risk of high-grade (Gleason 8 to 10), lethal (death or the development of metastatic disease), or advanced (T3b or higher, or lethal) prostate cancer (RRs 1.22, 1.19, and 1.20, respectively). (See "Vasectomy", section on 'Prostate cancer'.)

●A meta-analysis that incorporated data from 16 cohort studies, 33 case-control series, and 4 cross-sectional studies concluded that there was at most a weak association between vasectomy and prostate cancer, and that there was no association with high-grade, advanced, or fatal disease [130].

Ejaculatory frequency — An association between ejaculatory frequency and a lower risk of prostate cancer has been suggested in two case-control studies:

●In a study which compared men under the age of 70 who had prostate cancer with age-matched controls, men who had five or more ejaculations per week while in their 20s (but not their 30s or 40s) had a significantly lower risk of prostate cancer (odds ratio 0.66) than those who had fewer ejaculations [131].

●A report from the Health Professionals Follow-up Study compared men who developed prostate cancer (n = 3839) with controls of a similar age group who had similar ejaculatory frequency but no prostate cancer [132]. On multivariable analysis, the incidence of prostate cancer was significantly reduced for men having more than 21 ejaculations per month compared with those with 4 to 7 ejaculations per month between ages 20 and 29 years (HR 0.81, 95% CI 0.72-0.92). The HR for those reporting more than 21 versus 4 to 7 ejaculations per month between ages 40 and 49 years was 0.78 (95% CI 0.69-0.89).

The validity of this relationship has been called into question because of the lack of association of prostate cancer with ejaculation frequency in older men and the fact that other studies have failed to show a protective effect from being married or having more sexual partners [133]. Moreover, the problem of recall bias also casts doubt on the interpretation of studies that use this methodology.

Ultraviolet light exposure — In one case-control study exposure to ultraviolet (UV) light had a protective effect on the development of prostate cancer [134]. Furthermore, cases with low UV exposure developed at a younger median age (68 versus 72 years old). A similar associated has been reported by others [135-137]. It is not clear that any exposure pattern can successfully reduce the risk of prostate cancer without increasing the risk for basal cell skin cancer [137]. (See "Epidemiology, pathogenesis, and clinical features of basal cell carcinoma", section on 'UV radiation'.)

Although the mechanism underlying this association is unclear, involvement of vitamin D and/or its receptor has been hypothesized [137]. (See 'Calcium and vitamin D' above.)

Diagnostic radiologic procedures — A possible increase in risk of prostate cancer due to diagnostic radiologic procedures was suggested in a case-control series of 431 men diagnosed at age 60 years or less and 409 matched controls [138]. Procedures associated with an increased risk included barium enema and hip or pelvis radiographs at least five years prior to the diagnosis of prostate cancer.

EBRT for rectal cancer — Although external beam radiation therapy (EBRT) for prostate cancer is associated with an increased risk of rectal cancer, RT for rectal cancer has not been associated with an increased risk of subsequent prostate cancer. (See "Colorectal cancer: Epidemiology, risk factors, and protective factors", section on 'Other risk factors'.)

In a study based upon the Surveillance, Epidemiology, and End Results (SEER) database, the risk of prostate cancer was decreased by 72 percent in 1572 men who had previously received EBRT as a component of their treatment for rectal cancer [139]. In contrast, the incidence or prostate cancer among 3114 men with rectal cancer and 24,578 with colon cancer who were treated without RT was similar to that expected in the general population.

In contrast to the findings from the SEER study, a decrease in the incidence of prostate cancer was not observed in two Swedish studies of men receiving EBRT for rectal cancer [140]. A possible explanation for the discrepant findings is that substantially lower doses of EBRT were used in the Swedish studies (25 Gy in five fractions versus typical regimens of 45 to 54 Gy in 1.8 to 2 Gy fractions in the United States).

At least two mechanisms could contribute to a reduction in the apparent risk of prostate cancer following EBRT for pelvic cancer. Incidental RT to the prostate may have a biologic effect, reducing or sterilizing subclinical areas of disease. Alternatively inadvertent irradiation of the prostate can decrease the serum PSA, which would diminish the diagnosis of prostate cancer without affecting its incidence [141,142].

Depression — The antecedent diagnosis of a depressive disorder adversely affects the choice of therapy. In a cohort study of 41,275 men with clinically localized prostate cancer from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, 1894 (4.6 percent) had been diagnosed with a depression in the two years prior to diagnosis of prostate cancer [143]. These men were significantly less likely to receive definitive treatment (radical prostatectomy or RT) and more likely to be managed with androgen deprivation therapy alone, active surveillance, or watchful waiting compared with those without such a history.