3. EPIDEMIOLOGY AND AETIOLOGY
3.1 Epidemiology
Prostate cancer (PCa) is the second most commonly diagnosed cancer in men, with an estimated 1.4 million diagnoses and 375,000 deaths worldwide in 2020 [5,6]. In more than half of the countries of the world it is the most frequently diagnosed cancer in men and PCa is the leading cause of death among men in a quarter of all countries [7]. In Europe, it is the most frequently diagnosed cancer in men and the third cancer-related cause of death in men [8].
A SR of autopsy studies reported a prevalence of PCa at age < 30 years of 5% (95% confidence interval [CI]: 3–8%), increasing with age, to a prevalence of 59% (48–71%) by age > 79 years [9]. There is variation in the frequency of autopsy-detected PCa between men with different ethnical backgrounds and geographical areas (e.g., 83% in white US males vs. 41% in Japan at age 71–80) [10].
Regarding incidence of PCa diagnosis, the variation is even more pronounced between different geographical areas, partly driven by rate of prostate-specific antigen (PSA) testing and influenced by (inter)national organisations recommendations on screening (see section 5.1) [11]. It is highest in Australia/New Zealand and Northern America (age-standardised rates [ASR] per 100,000 of 111.6 and 97.2, respectively), and in Western and Northern Europe (ASRs of 94.9 and 85, respectively) [12]. The incidence is low in Eastern and South-Central Asia (ASRs of 10.5 and 4.5, respectively), but rising [13]. Rates in Eastern and Southern Europe were low but have also shown a steady increase [6,10]. Other reasons for variation in PCa incidence include the age of the population, ethnicity and dietary factors [7].
There is relatively less variation in mortality rates worldwide, although rates are generally high in populations of African descent (e.g., Caribbean: ASR of 29 and Sub-Saharan Africa: ASRs ranging between 14 and 19), intermediate in the USA and very low in Asia (South-Central Asia: ASR of 2.9) [6,7]. Mortality due to PCa has decreased in most Western nations but the magnitude of the reduction varies between countries [5].
3.2. Aetiology and risk factors for prostate cancer
A wide variety of endogenous and exogenous/environmental factors have been discussed as being associated with the risk of developing PCa, or as being aetiologically important for the progression from latent to clinical PCa [14]. As previously discussed, there is likely a racial factor involved, but Asians who immigrated to the USA have approximately half the risk of PCa when compared to their US born Asian-descendant counterparts, implying a role for environmental and/or dietary factors [15]. These guidelines divide the risk factors into hereditary, such as ethnicity, family history and known genetic mutations, in which direct heritance of the risk factor is more obvious and direct, and non-hereditary, such as dietary and medical factors as well as metabolic syndrome and obesity, in which there may well be hereditary components, but they are more indirect.
3.2.1. Hereditary risk factors for PCa
There are basically three inherited risk factors that are consistently associated with PCa: ethnicity/family history, rare germline mutations in several candidate genes, and common genetic single nucleotide polymorphism (SNPs).
3.2.1.1. Ethnicity and Family history
Ethnic background and family history are both associated with varying PCa incidence, suggesting a genetic predisposition [7]. Men of African ancestry in the Western world demonstrate more unfavourable outcomes that may be due to biological, environmental, social, and/or health care factors [16]. They have been reported to be at increased risk of being diagnosed with more advanced disease [17] and more likely to be upgraded after prostatectomy than White men [18], but the question is more intricate than that. In a population, race is categorised based on a combination of e.g. ancestry, skin colour and geographical origin, and within any race there are hundreds of areas of geographical origins [7]. Indeed, a multi-ancestry polygenic risk score of 278 risk variants showed a strong association with PCa risk in men with African ancestry, especially sub-Saharan, and might be used to identify susceptibility in this high-risk population [19]. There is also data suggesting no difference in overall survival (OS) or prostate cancer specific mortality (PCSM) between White, Black or Hispanic men with metastatic PCa [20]. Racial disparities in development of, prevention of, and therapies for PCa may exist. It should be kept in mind that very few PCa treatment trials report on race, education and socioeconomics [21]. Moreover, participation in a clinical trial is precluded by a selection process, whereby in itself, decrease PCSM drastically and most PCa studies include either small percentages of non-White men, or focus on highly specific other groups [22,23]. A recent SR also found that Black men without PCa seem to have higher baseline levels of PSA which could lead to over-detection, and further affect described differences [24].
A small subpopulation of all men with PCa, regardless of ethnicity, have true hereditary PCa (HPCA), defined as ≥ 3 cases in the same family, PCa in three successive generations, or ≥ 2 cases in the same family diagnosed < 55 yrs. In a Swedish population-based study, the probability of high-risk PCa at age 65 was 11.4% (vs. a population risk of 1.4%), and for any PCa 43.9% (vs. 4.8%) if the father as well as two brothers were affected [25]. HPCa was also, in a large USA population database, reported by 2.18% of participants, and showed a relative risk (RR) of 2.30 for diagnosis of any PCa, 3.93 for early-onset PCa, 2.21 for lethal PCa, and 2.32 for clinically significant PCa (csPCa) [26]. On the other hand, recent data from the UK even suggest an inverse association between PCSM and a stronger family history, likely attributed to higher awareness of the risks and adherence to screening [27]. For familial PCa, defined as ≥ 2 first- or second-degree relatives with PCa on the same side of the pedigree, or familial syndromes such as hereditary breast and ovarian cancer and Lynch syndrome, the risk is lower [25].
Table 3.1: Definition of familial and hereditary PCa
| Type | Definition |
| Familial | 2 first-degree relatives diagnosed with PCa at any age or 1 first-degree relative and ≥ 2 second-degree relatives diagnosed at any age. |
| Hereditary | ≥ 3 cases in the same family, PCa in three successive generations, or ≥ 2 cases in the same family diagnosed < 55 yrs. |
3.2.1.2. Germline mutations
Pathogenic germline mutations in the BRCA2 and HOXB13 genes, but also in the genes CHEK2, BRCA1, ATM, NBS1, and genes involved in Lynch syndrome, have been suggested to increase the risk of PCa [7]. Data from UK, on over 21,000 men without a PCa diagnosis, suggest that 1.6 % carry a pathogenic mutation in at least one of the genes BRCA2, HOXB13 or CHEK2. Even though germline mutations leading to PCa are relatively rare (1/300), the impact on PCa risk is quite strong, and the prevalence in patients with advanced PCa is high [28]. In a study on 3,607 unselected patients with PCa diagnosis as many as 17.2% contained a pathogenic mutation [29]. In men with PCa undergoing multigene testing across the USA, it was found that 15.6% of men with PCa have pathogenic variants identified in genes tested ([Breast Cancer genes] BRCA1, BRCA2, HOXB13, MLH1, MSH2, PMS2, MSH6, EPCAM, ATM, CHEK2, NBN, and TP53), and 10.9% of men have germline pathogenic variants in DNA repair genes (Table 3.2) [30]. Pathogenic variants were most commonly identified in BRCA2 (4.5%), CHEK2 (2.2%), ATM (1.8%), and BRCA1 (1.1%) [30].
Among men with metastatic PCa, an incidence of 11.8% was found for germline mutations in genes mediating DNA-repair processes [31], and for patients diagnosed with metastatic castrate-resistant PCa (mCRPC) the incidence was 16.2% [32]. Targeted genomic analysis of genes associated with an increased risk of PCa could offer options to identify families at high risk [33,34].
A prospective cohort study of male BRCA1 and BRCA2 carriers confirmed BRCA2 association with aggressive PCa [35]. An analysis of the outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers, and 1,940 non-carriers) showed that PCa with germline BRCA1/2 mutations were more frequently associated with ISUP grade group (GG) ≥ 4, stage T3/T4, nodal involvement, and metastases at diagnosis, than PCa in non-carriers [36]. BRCA-susceptibility gene mutation carriers were also reported to have worse outcome when compared to non-carriers after local therapy [37]. In a retrospective study of 313 patients who died of PCa and 486 patients with low-risk localised PCa, the combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients (6.1%) than in localised PCa patients (1.4%) [38]. The rate of PCa among BRCA1 carriers was more than twice as high (8.6% vs. 3.8%) compared to the general population, in contrast to findings of the prospective IMPACT study (Identification of Men with a Genetic Predisposition to Prostate Cancer) [39].
Table 3.2: Germline mutations in DNA repair genes associated with increased risk of PCa
| Gene | Location | PCa risk | Findings |
| BRCA2 | 13q12.3 | - PCa at 55 years or | |
| HOXB13 | 17q21.2 | OR 3.4–7.9 [33,45] |
|
| CHEK2 | 22q12.1 | OR 3.3 [40,41] |
|
| BRCA1 | 17q21 | RR: 1.8–3.8 at 65 years or under [47,48] | |
| ATM | 11q22.3 | RR: 6.3 for metastatic PCa [31] | |
MMR genes MLH1 MSH2 MSH6 PMS2 | 3p21.3 2p21 2p16 7p22.2 | RR: 3.7 [49] |
BBRCA2 = breast cancer gene 2; HOXB13 = homeobox B13; CHEK2 = checkpoint kinase 2; BRCA1 = breast cancer gene 1; ATM = ataxia telangiectasia mutated; GS = Gleason score; MMR = mismatch repair; MLH1 = mutL homolog 1; MSH2 = mutS homolog 2; MSH6 = mutS homolog 6; OR = odds ratio; PMS2 = post-meiotic segregation increased 2; PCa = prostate cancer; RP = radical prostatectomy; RR = relative risk; PSA = prostate-specific antigen.
3.2.1.3. Genetic single nucleotide polymorphism (SNPs)
If germline genetic mutations are relatively rare, but with quite high impact on PCa risk, SNPs are very common, but each SNP has low impact on the risk of developing PCa [7]. Two hundard and sixty nine individual SNPs have been identified to be associated with PCa risk [52]. Although each individual SNP has a low impact on PCa risk, the additive effects of multiple alleles can cause substantial increased risk of developing PCa and are likely causative of a large proportion of hereditary PCa [53]. The additive effect of of the different SNPs can be summed into polygenic risk scores (PRSs), which are directly associated with the absolute risk of developing PCa [19,54]. However, so far there seems to be no additive prognostic value in the PRSs when added to PSA and PRSs can therefore not be used for risk stratification [53].
3.2.2. Non-hereditary risk factors for PCa
There are a number of risk factors for PCa, that are less determined by ethnicity and/or heredity, of which age is the most obvious [9]. Despite this, currently there are no known effective preventative dietary or pharmacological interventions.
3.2.2.1. Metabolic syndrome
The association between metabolic syndrome and PCa is not clear, with mixed results in various studies. There seems to be a weak association overall, but a slightly stronger in the sub-group of men with more aggressive disease [7]. The single components of metabolic syndrome (MetS) that have been strongest associated with a significantly greater risk of PCa are hypertension (p = 0.035) and waist circumference ≥ 102 cm (p = 0.007) [55].
3.2.2.1.1. Obesity
Within the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study, obesity was associated with lower risk of low-grade PCa (OR: 0.79, p = 0.01), and a higher risk of high-grade PCa (OR: 1.28, p = 0.042), in multivariable analyses [56]. This effect seems mainly explained by environmental determinants of height/body mass index (BMI) rather than genetically elevated height or BMI [57]. A SR showed an association between obesity and increased PC-specific mortality [58].
3.2.2.1.2. Diabetes/metformin
A SR from 2021 could not identify any association between diabetes type 2 and PCa [59]. The association between metformin use and PCa is controversial. At population level, metformin users (but not other oral hypoglycaemic agents) were found to be at a decreased risk of PCa diagnosis compared with never users (adjusted OR: 0.84; 95% CI: 0.74–0.96) [60]. In 540 diabetic participants of the REDUCE study, metformin use was not significantly associated with PCa and therefore not advised as a preventive measure (OR: 1.19, p = 0.50).
3.2.2.1.3. Cholesterol/statins
A meta-analysis of fourteen large prospective studies did not show any association between blood total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol levels and the risk of developing either overall PCa or high-grade PCa [51]. Two meta-analysis suggested a lower risk of PCa overall (OR: 0.94) as well as advanced PCa in statin users [61,62]. Pooled estimates indicated that the effect seemed to be exclusive to lipophilic statins [61].
3.2.2.2. Dietary factors
The association between a wide variety of dietary factors and PCa have been studied, but there is a paucity of quality evidence (Table 3.3). To date, the current body of evidence will not support a causal relationship between specific (dietary and otherwise) factors and the development of PCa. Consequently, no effective preventative strategies can be suggested.
Table 3.3: Main dietary factors that have been associated with PCa
| Main dietary factors that have been associated with PCa | |
| Alcohol | High alcohol intake, but also total abstention from alcohol has been associated with a higher risk of PCa and PCa-specific mortality [63]. A meta-analysis suggests a weak relationship with PCa [64]. |
| Coffee/Tea | Coffee consumption may be associated with a reduced risk of PCa; with a pooled RR of 0.91 for the highest category of coffee consumption [65]. No clear association was found between tea consumption and PCa risk [7]. |
| Dairy/Calcium | A SR suggests a correlation between high intake of protein from dairy products and the risk of PCa was found, but many of the included studies were affected by PSA screening bias [66]. |
| Fat | No association between intake of long-chain omega-3 poly-unsaturated fatty acids and PCa was found [67]. A relation between intake of fried foods and risk of PCa may exist [68]. |
| Tomatoes (lycopenes/carotenes) | A trend towards a favourable effect of tomato intake (mainly cooked) and lycopenes on PCa incidence has been identified in meta-analyses [69,70]. Randomised controlled trials comparing lycopene with placebo did not identify a significant decrease in the incidence of PCa [71]. |
| Plant-based diets | A SR on the association between plant-based diets and PCa suggest a small beneficial impact on PCa risk [72]. Another SR/meta-analysis, including a total of 16 studies and > 1.2 million men, suggested a linear association between higher intake of cruciferous vegetables and a lower risk of PCa [73]. |
| Meat | Meta-analyses show a potential association between red meat, total meat, and processed meat consumption and PCa [74,75]. |
| Fish | A SR/meta-analysis comparing men with high vs. low intake of fish over time could not find an association between fish intake and risk of PCa. However, there was a strong association with high intake of fish and PCSM (RR: 0.55), as well as PCa progression (RR: 0.84) [76]. |
Soy (phytoestrogens [isoflavones/coumestans]) | Phytoestrogen intake was significantly associated with a reduced risk of PCa in a meta-analysis [66]. Total soy food intake has been associated with a reduced risk of PCa [77]. |
| Vitamin D | A U-shaped association has been observed, with both low- and high vitamin-D concentrations being associated with an increased risk of PCa, and more strongly for high-grade disease [69,70]. |
| Vitamin E/Selenium | An inverse association of blood, but mainly nail selenium levels (reflecting long-term exposure) with aggressive PCa have been found [78,79]. Selenium and Vitamin E supplementation were, however, found not to affect PCa incidence [80]. |
3.2.2.3. Hormonally active medication
3.2.2.3.1.5-alpha-reductase inhibitors (5-ARIs)
Although it seems that 5-ARIs have the potential of preventing or delaying the development of PCa (decreasing the risk by 25% but only for ISUP GG 1 cancer), this must be weighed against treatment-related side effects as well as the potential small increased risk of high-grade PCas (although this does not seem to impact PCa mortality) [81-83]. None of the available 5-ARIs have been approved by the European Medicines Agency (EMA) for chemoprevention.
3.2.2.3.2. Testosterone
Hypogonadal men receiving testosterone supplements do not have an increased risk of developing PCa [84]. A pooled analysis showed that men with very low concentrations of free testosterone (lowest 10%) have a below average risk (OR: 0.77) of PCa [85]. Furthermore, although the evidence is limited, men who are managed expectantly for PCa, or who received radical curative therapy, do not have worse outcomes when receiving testosterone supplementation, despite a theoretical higher risk of progression after correction of the hypogonadal situation [86].
3.2.2.4. Other potential risk factors
Taller height, potentially due to higher levels if insulin-like growth factor during puberty, and vertex pattern baldness, has been reported to be associated with an increased risk of PCa [7,87].
A significantly higher rate of ISUP GG ≥ 2 PCa (hazard ratio [HR]: 4.04) was found in men with inflammatory bowel disease (IBD) when compared with the general population [88]. However, in a SR the results on IBD overall were mixed, except for the sub-group of ulcerative colitis, where a clear association could be seen [7].
Occupational exposure may also play a role. Increased occupational physical activity appears to reduce PCa risk while occupational exposure to chemicals and pesticides increases the risk [7]. Plasma concentration of the estrogenic insecticide chlordecone is associated with an increase in the risk of PCa (OR: 1.77 for highest tertile of values above the limit of detection) [89]. Meta-analyses indicate that night-shift work is associated with an increased risk of PCa in a dose-dependent manner [7,90]. There has been reports of an increased risk among firefighters and policemen, but the studies showed great heterogeneity and the results may be hampered by a high rate of PSA testing among the included men. A meta-analysis on Cadmium (Cd) found a positive association (magnitude of risk unknown due to heterogeneity) between high Cd exposure and risk of PCa for occupational exposure, but not for non-occupational exposure, potentially due to higher Cd levels during occupational exposure [91].
Current cigarette smoking was associated with an increased risk of PCa death (RR: 1.24, 95% CI: 1.18–1.31) and with aggressive tumour features and worse prognosis, even after quitting smoking [92,93].
Men positive for human papillomavirus-16 may be at increased risk [94], and gonorrhoea has been significantly associated with an increased incidence of PCa (OR: 1.31; 95% CI: 1.14–1.52) [95].
The use of aspirin or nonsteroidal anti-inflammatory drugs seems to have a protective effect on the risk of PCa [7]. Ultraviolet radiation exposure also decreased the risk of PCa (HR: 0.91, 95% CI: 0.88–0.95) [96], and a review found a small but protective association of circumcision status with PCa [97]. Higher ejaculation frequency (≥ 21 times a month vs. 4 to 7 times) has been associated with a 20% lower risk of PCa [98]. A number of other factors previously linked to an increased risk of PCa have been disproved including vasectomy [99], and self-reported acne [100].
3.2.3. Summary of evidence for epidemiology and aetiology
| Summary of evidence | LE |
| Prostate cancer is a major health concern in men, with incidence mainly dependent on age and extent of PSA testing. | 3 |
| Genetic factors are associated with risk of (aggressive) PCa. | 3 |
| A variety of dietary/exogenous/environmental factors have been associated with PCa incidence and prognosis. | 3 |
| In hypogonadal men, testosterone supplements do not increase the risk of PCa. | 2a |
| No conclusive data exist which could support specific preventive or dietary measures aimed at reducing the risk of developing PCa. | 1a |