Prostate Cancer

3. EPIDEMIOLOGY AND AETIOLOGY

3.1. Epidemiology

Prostate cancer is the second-most diagnosed cancer in men, with an estimated 1.46 million diagnoses and 396,792 deaths worldwide in 2022 [3,4]. In more than half of the countries of the world, PCa is the most frequently diagnosed cancer in men and is the leading cause of death among men in a quarter of all countries [5]. In Europe, PCa is the most frequently diagnosed cancer in men and the third most common cancer-related cause of death in men [6].

An 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 [7]. There is variation in the frequency of autopsy-detected PCa among men with different ethnical backgrounds and geographical areas (e.g. 83% in White US males vs. 41% in Japan at age 71-80) [8].

Regarding incidence of PCa diagnosis, the variation is even more pronounced among geographical areas, partly driven by rate of prostate-specific antigen (PSA) testing and influenced by the recommendation of national/international organisations on screening (see Section 5.1) [9]. PCa diagnosis 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) [10]. Incidence is low in Eastern and South-Central Asia (ASRs of 10.5 and 4.5, respectively) but is rising [11]. Rates in Eastern and Southern Europe were low but have also shown a steady increase [8,12]. Other reasons for variation in PCa incidence include the age of the population, ethnicity and dietary factors [5].

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) [5,12]. Mortality due to PCa has decreased in most Western nations but the magnitude of the reduction varies between countries [3].

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 [13]. As discussed previously, there is likely a racial factor involved, but first-generation Asian immigrants in the USA have approximately half the risk of PCa when compared to their US-born Asian-descendant compatriots, implying a role for environmental and/or dietary factors [14]. 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 nonhereditary - such as dietary and medical factors, as well as metabolic syndrome and obesity - in which hereditary components may well be involved, but they are more indirect.

3.2.1. Hereditary risk factors for PCa

There are three basic inherited risk factors that are consistently associated with PCa: ethnicity/family history, rare germline mutations in various candidate genes and common genetic single-nucleotide polymorphism (SNPs).

3.2.1.a. Ethnicity and Family history

Ethnic background and family history are both associated with varying PCa incidence, suggesting a genetic predisposition [5]. 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 [15]. These men have been reported to be at increased risk of being diagnosed with more advanced disease [16] and more likely to be upgraded after prostatectomy than White men [17], but the question is more intricate than that. In a population, race is categorised based on a combination of factors including ancestry, skin colour and geographical origin, and within any race there are hundreds of areas of geographical origins [5]. Indeed, a multiancestry polygenic risk score of 278 risk variants showed a strong association with PCa risk in men with African ancestry, particularly sub-Saharan, and could potentially be used to identify susceptibility in this high-risk population [18]. 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 [19]. Racial disparities in accessing both screening and therapies for PCa may exist. It should be noted that very few PCa treatment trials report on race, education and socioeconomics [20]. Moreover, participation in a clinical trial is preceded by a selection process and most PCa studies include either small percentages of non-White men, or focus on other, highly specific groups which might affect the applicability of treatments [21,22]. A systematic review also found that Black men without PCa appear to have higher baseline levels of PSA, which could lead to increased detection and further affect described differences [23].

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 years. 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 [24]. In a large USA population database, HPCa was also 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) [25].

Familial PCa is defined as ≥ 2 first- or second-degree relatives with PCa on the same side of the pedigree. In this group and in those with known familial syndromes such as hereditary breast and ovarian cancer and Lynch syndrome, data from the UK suggests higher awareness of the risks and adherence to screening might decrease PCSM [26]. In both groups the more members affected the higher the risk [24].

Table 3.1: Definition of familial and hereditary PCa

3.2.1.b. 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 [5]. Data from the United Kingdom 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. Although 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 [27]. In a study of 3,607 unselected patients with PCa diagnosis, as many as 17.2% had a pathogenic mutation [28]. In men with PCa undergoing multigene testing across the United States, 15.6% of men with PCa were found to have pathogenic variants identified in genes tested (BRCA1, BRCA2, HOXB13, MLH1, MSH2, PMS2, MSH6, EPCAM, ATM, CHEK2, NBN, and TP53), and 10.9% of men were found to have germline pathogenic variants in DNA repair genes (Table 3.2) [29]. Pathogenic variants were most commonly identified in BRCA2 (4.5%), CHEK2 (2.2%), ATM (1.8%) and BRCA1 (1.1%) [29].

Among men with metastatic PCa, an incidence of 11.8% was found for germline mutations in genes mediating DNA-repair processes [30], and for patients diagnosed with metastatic castrate-resistant PCa (mCRPC), the incidence was 16.2% [31]. Targeted genomic analysis of genes associated with an increased risk of PCa could offer options to identify families at high risk [32,33].

A prospective cohort study of male BRCA1 and BRCA2 carriers confirmed BRCA2 association with aggressive PCa [34]. An analysis of the outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers and 1,940 noncarriers) 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 noncarriers [35]. BRCA-susceptibility gene mutation carriers were also reported to have worse outcome when compared to noncarriers after local therapy [36]. 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%) [37].

Table 3.2: Germline mutations in DNA repair genes associated with increased risk of PCa

ATM = ataxia telangiectasia mutated; BRCA1 = breast cancer gene 1; BRCA2 = breast cancer gene 2; CHEK2 = checkpoint kinase 2; GS = Gleason score; HOXB13 = homeobox B13; MLH1 = mutL homolog 1; MMR = mismatch repair; MSH2 = mutS homolog 2; MSH6 = mutS homolog 6; OR = odds ratio; PCa = prostate cancer; PMS2 = post-meiotic segregation increased 2; PSA = prostate-specific antigen; RP = radical prostatectomy; RR = relative risk.

3.2.1.c. Genetic single nucleotide polymorphism (SNPs)

If germline genetic mutations are relatively rare, but with significant impact on PCa risk, SNPs are very common, but each SNP has low impact on the risk of developing PCa [5]. Two hundred and sixty-nine individual SNPs have been identified to be associated with PCa risk [50]. 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 [51]. The additive effect of the different SNPs can be summed into polygenic risk scores (PRSs), which are directly associated with the absolute risk of developing PCa [18,52]. Thus far, however, there appears to be no additive prognostic value in the PRSs when added to PSA and PRSs therefore cannot be used for risk stratification [51].

3.2.2. Non-hereditary risk factors for PCa

There are a number of risk factors for PCa, which are less determined by ethnicity and/or heredity, of which age is the most obvious [7].

3.2.2.a. Metabolic syndrome

The association between metabolic syndrome and PCa is not clear, with mixed results in various studies. There appears to be a weak association overall, but a slightly stronger association in the subgroup of men with more aggressive disease [5]. The single components of metabolic syndrome that have been the most strongly associated with a significantly greater risk of PCa are hypertension (p = 0.035) and waist circumference ≥ 102 cm (p = 0.007) [53]. A SR found a slightly reduced risk of PCa, from anti-hypertension medication with renin-angiotensin inhibitors, while the use of calcium channel blockers was suggested to be associated with a slightly higher risk [54].

3.2.2.a.1. Obesity

Within the 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 [55]. This effect appears mainly to be explained by environmental determinants of height/body mass index (BMI) rather than genetically elevated height or BMI [56]. An SR showed an association between obesity and increased PC-specific incidence and mortality [57,58].

3.2.2.a.2. Diabetes/metformin

An SR from 2021 could not identify any association between diabetes type 2 and PCa [59]. However, another SR including 43 studies and over 3.7 million patients, concluded that diabetes (type not specified) was associated with a reduced risk of PCa [60]. 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) [61], a result that was replicated in a meta-analysis (RR: 0.82, 95% CI: 0.74-0.91) [62]. 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). Moreover, the STAMPEDE trial randomised 1,874 patients with high-risk locally advanced or metastatic PCa to standard of care +/- metformin and did not find any survival benefit from addition of metformin (HR 0·91, 95% CI 0·80-1·03; p=0·15) [63,64].

3.2.2.a.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-analyses suggested a lower risk of PCa overall (OR: 0.94), as well as advanced PCa in statin users [65,66]. Pooled estimates indicated that the effect seemed to be exclusive to lipophilic statins [65].

3.2.2.b. 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

3.2.2.c. Hormonally active medication

3.2.2.c.1. 5-alpha-reductase inhibitors (5-ARIs)

Although it appears 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 appear to impact PCa mortality) [88-90]. None of the available 5-ARIs have been approved by the European Medicines Agency (EMA) for chemoprevention.

3.2.2.c.2. Testosterone

Hypogonadal men receiving testosterone supplements do not have an increased risk of developing PCa [91]. 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 [92]. 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 [93].

3.2.2.d. Other potential risk factors

Taller height, potentially due to higher levels of insulin-like growth factor during puberty, and vertex pattern baldness, has been reported to be associated with an increased risk of PCa [5,94].

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 [95]. However, in an SR, the results on IBD overall were mixed, except for the subgroup of ulcerative colitis, where a clear association could be seen [5].

Increased occupational physical activity appears to be associated with reduce PCa risk while occupational exposure to chemicals and pesticides increases the risk [5]. 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) [96]. Meta-analyses indicate that night-shift work is associated with an increased risk of PCa in a dose-dependent manner [5,97]. There have been reports of an increased risk among firefighters and police officers, but the studies had high 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 between high Cd exposure and risk of PCa (OR 1.11, 95% CI 0.85-1.45) and for the aggressive histopathological type of PCa (OR 1.50, 95% CI 1.08-2.07). In most of the included studies Cd exposure was occupational, but there was a high level of heterogeneity between the studies [98].

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 [99,100].

Men positive for human papillomavirus type 16 may be at increased risk [101], and gonorrhoea has been significantly associated with an increased incidence of PCa (OR: 1.31; 95% CI: 1.14-1.52) [102].

A two-sample Mendelian randomisation study indicated a causal relationship between twelve specific gut microbial taxa and PCa. While these findings may be difficult to use clinically, they may offer new targets for PCa screening and treatment [103].

The use of aspirin or nonsteroidal anti-inflammatory drugs seems to have a protective effect on the risk of PCa [5]. Ultraviolet radiation exposure also decreased the risk of PCa (HR: 0.91, 95% CI: 0.88-0.95) [104], and a review found a small but protective association of circumcision status with PCa [105]. Higher ejaculation frequency (≥ 21 times a month vs. 4 to 7 times) has been associated with a 20% lower risk of PCa [106]. A number of other factors previously linked to an increased risk of PCa have been disproved, including vasectomy [107] and self-reported acne [108].

3.2.3. Summary of evidence for epidemiology and aetiology