Prostate Cancer

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 Europe, it is the most frequently diagnosed cancer in men and the third cancer-related cause of death in men [7].

A SR of autopsy studies reported a prevalence of PCa at age < 30 years of 5% (95% confidence interval [CI]: 3–8%), increasing by an odds ratio (OR) of 1.7 (1.6–1.8) per decade, to a prevalence of 59% (48–71%) by age > 79 years [8]. 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) [9].

Regarding incidence of PCa diagnosis, the variation is even more pronounced between different geographical areas, driven by rate of prostate-specific antigen (PSA) testing and influenced by (inter)national organisations recommendations on screening (see Section 5.1) [10]. 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). The incidence is low in Eastern and South-Central Asia (ASRs of 10.5 and 4.5, respectively), but rising [11]. Rates in Eastern and Southern Europe were low but have also shown a steady increase [6,9]. Besides PSA testing, incidence is also dependent on the age of the population, geography and ethnicity.

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 nineteen and fourteen), intermediate in the USA and very low in Asia (South-Central Asia: ASR of 2.9) [6,12]. Mortality due to PCa has decreased in most Western nations but the magnitude of the reduction varies between countries [5].

3.2. Aetiology

3.2.1. Family history/hereditary prostate cancer

Family history and ethnic background are associated with an increased PCa incidence suggesting a genetic predisposition [13,14]. Men of African ancestry in the Western world demonstrate more unfavourable outcomes due to a combination of biological, environmental, social, and health care factors [15]. They are more likely to be diagnosed with more advanced disease [16] and upgrade after prostatectomy was more frequent as compared to white men (49% vs. 26%) [17]. Indeed, a multi-ancestry polygenic risk score of 278 risk variants published by Chen et. al. showed a strong association with PCa risk in men with African ancestry and might be used to identify susceptibility in this high-risk population [18]. Racial disparities in engagement with healthcare providers, and access to therapies for PCa also exist. Consequently it should be kept in mind that in many PCa studies ethnic minorities are poorly represented which might affect the applicability of results [19].

However, only a small subpopulation of men with PCa have true hereditary disease (≥ 3 cases in the same family, PCa in three successive generations, or ≥ two men diagnosed with PCa < 55 yrs). Hereditary PCa (HPCa) is associated with a six-to-seven-year earlier disease onset but the disease aggressiveness and clinical course does not seem to differ in other ways [13,20]. In a large USA population database, HPCa (reported by 2.18% of participants) 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) [21]. These increased risks with HPCa were higher than for familial PCa (≥two 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. With the father as well as two brothers affected, 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%, in a Swedish population-based study [22].

3.2.1.1. Germline mutations and prostate cancer

Genome-wide association studies have identified more than 100 common susceptibility loci contributing to the risk for (aggressive) PCa [23,24]. The frequency and distribution of positive germline variants in 3,607 unselected PCa patients showed that 620 (17.2%) contained a pathogenic mutation [25]. Whilst in men with PCa disease 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 (see Table 3.1) [26]. Pathogenic variants were most commonly identified in BRCA2 (4.5%), CHEK2 (2.2%), ATM (1.8%), and BRCA1 (1.1%) [26].

Among men with metastatic PCa, an incidence of 11.8% was found for germline mutations in genes mediating DNA-repair processes [27] and 16.2% of patients diagnosed with metastatic castrate-resistant PCa (mCRPC) [28]. Targeted genomic analysis of genes associated with an increased risk of PCa could offer options to identify families at high risk [29,30].

A prospective cohort study of male BRCA1 and BRCA2 carriers confirmed BRCA2 association with aggressive PCa [31]. 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 ≥ 4, T3/T4 stage, nodal involvement, and metastases at diagnosis than PCa in non-carriers [32]. BRCA-susceptibility gene mutation carriers were also reported to have worse outcome when compared to non-carriers after local therapy [33]. 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 (6.07%) than in localised PCa patients (1.44%) [34]. 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 (see Chapter 5) [35].

Table 3.1: Germline mutations in DNA repair genes associated with increased risk of prostate cancer

BRCA2 = breast cancer gene 2; ATM = ataxia telangiectasia mutated; CHEK2 = checkpoint kinase 2; BRCA1 = breast cancer gene 1; GS = Gleason score; HOXB13 = homeobox B13; 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.

3.2.2. Risk factors for prostate cancer

A wide variety of 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 [48]. 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 or dietary factors [49]. However, currently there are no known effective preventative dietary or pharmacological interventions.

3.2.2.1. Metabolic syndrome

The single components of metabolic syndrome (MetS) that have been associated with a significantly greater risk of PCa are hypertension (p = 0.035) and waist circumference ≥ 102 cm (p = 0.007), but in contrast, having
≥ 3 components of MetS is associated with a reduced risk (OR: 0.70, 95% CI: 0.60–0.82) [50,51].

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 [52]. This effect seems mainly explained by environmental determinants of height/body mass index (BMI) rather than genetically elevated height or BMI [53]. A SR showed an association between obesity and increased PC-specific mortality [54].

3.2.2.1.2. Diabetes/metformin

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) [55]. 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]. Results from the REDUCE study did not show a preventive effect of statins on PCa risk, even though a meta-analysis suggested a lower risk of advanced PCa in statin users [50,56].

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 3.2). 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 3.2: Main dietary factors that have been associated with PCa

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 grade group 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) [73,74]. 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 [75]. 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 [76]. 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 [77].

3.2.2.4. Other potential risk factors

A significantly higher rate of ISUP grade group ≥ 2 PCa (hazard ratio [HR]: 4.04) was found in men with inflammatory bowel disease when compared with the general population [78]. Balding was associated with a higher risk of PCa death [79]. Gonorrhoea was significantly associated with an increased incidence of PCa (OR: 1.31, 95% CI: 1.14–1.52) [80]. Occupational exposure may also play a role, based on a meta-analysis which revealed that night-shift work is associated with an increased risk (2.8%, p = 0.030) of PCa [81]. 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 [82,83]. 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 [84]. Men positive for human papillomavirus-16 may be at increased risk [85]. 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) [86]. A number of other factors previously linked to an increased risk of PCa have been disproved including vasectomy [87] and self-reported acne [88]. There are conflicting data about the use of aspirin or nonsteroidal anti-inflammatory drugs and the risk of PCa and mortality [89,90]. Ultraviolet radiation exposure decreased the risk of PCa (HR: 0.91, 95% CI: 0.88–0.95) [91]. A review found a small but protective association of circumcision status with PCa [92]. Higher ejaculation frequency (≥ 21 times a month vs. 4 to 7 times) has been associated with a 20% lower risk of PCa [93].

3.2.3. Summary of evidence for epidemiology and aetiology