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Prostate Cancer Epidemiology and Aetiology Narrative Review Article Part 1 Prof. Dr. Semir. A. Salim. Al Samarrai Prostate cancer is the second most commonly diagnosed cancer in men, with an estimated 1.4 million diagnoses worldwide in 2020 [1,2]. The frequency of autopsy-detected PCa is roughly the same worldwide [3]. A systematic review 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 [4]. The incidence of PCa diagnosis varies widely between different geographical areas, being 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), largely due to the use of prostate-specific antigen (PSA) testing and the aging population. The incidence is low in Eastern and South-Central Asia (ASRs of 10.5 and 4.5, respectively), but rising [5]. Rates in Eastern and Southern Europe were low but have also shown a steady increase [2,3]. Incidence and disease stage distribution patterns follow biological-, genetic-, and/or lifestyle factors [6]. There is relatively less variation in mortality rates worldwide, although rates are generally high in populations of African descent (Caribbean: ASR of 29 and Sub-Saharan Africa: ASRs ranging between 19 and 14), intermediate in the USA and very low in Asia (South-Central Asia: ASR of 2.9) [2]. Family history and ethnic background are associated with an increased PCa incidence suggesting a genetic predisposition [7,8]. Only a small subpopulation of men with PCa have true hereditary disease. 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 [7,9]. In a large USA population database, HPCa (in 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) [10]. These increased risks of HPCa were higher than for familial PCa (> 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 probability of high-risk PCa at age 65 was 11.4% (vs. a population risk of 1.4%) in a Swedish population-based study [11]. The Identification of Men with a Genetic Predisposition to Prostate Cancer (IMPACT) study, which evaluated targeted PCa screening (annually, biopsy recommended if PSA > 3.0 ng/mL) using PSA in men aged 40–69 years with germline BRCA1/2 mutations found that after 3 years of screening, BRCA2 mutation carriers were associated with a higher incidence of PCa, a younger age of diagnosis, and more clinically significant tumours compared with non-carriers [12]. The influence of BRCA1 mutations on PCa remained unclear. No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 non-carriers. Limitations of the IMPACT study include the lack of magnetic resonance imaging (MRI) data and targeted biopsies as it was initiated before that era. 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 [13]. Japanese men have a lower PCa risk compared to men from the Western world. However, as Japanese men move from Japan to California, their risk of PCa increases, approaching that of American men, implying a role of environmental or dietary factors [14]. However, currently there are no known effective preventative dietary or pharmacological interventions. The single components of metabolic syndrome (MetS), hypertension (p = 0.035) and waist circumference > 102 cm (p = 0.007), have been associated with a significantly greater risk of PCa. 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 neverusers (adjusted OR: 0.84, 95% CI: 0.74–0.96) [15]. In 540 diabetic participants of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study, metformin use was not significantly associated with PCa and therefore not advised as a preventive measure (OR: 1.19, p = 0.50) [16]. The ongoing Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial assesses metformin use in advanced PCa (Arm K) [17]. A meta-analysis of 14 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 either overall PCa or high-grade PCa [18]. Results from the REDUCE study also did not show a preventive effect of statins on PCa risk [19]. Within the REDUCE study, obesity was associated with lower risk of low-grade PCa in multivariable analyses (OR: 0.79, p = 0.01), but increased risk of high-grade PCa (OR: 1.28, p = 0.042) [20]. This effect seems mainly explained by environmental determinants of height/body mass index (BMI) rather than genetically elevated height or BMI [21]. The association between a wide variety of dietary factors and PCa have been studied, but there is paucity of quality of evidence (table 3.1) Although it seems that 5-ARIs have the potential of preventing or delaying the development of PCa (~25%, for ISUP grade 1 cancer only), this must be weighed against treatment-related side effects as well as the potential small increased risk of high-grade PCas, although these do not seem to impact PCa mortality [39-42]. None of the available 5-ARIs have been approved by the European Medicines Agency (EMA) for chemoprevention. Hypogonadal men receiving testosterone supplements do not have an increased risk of PCa [43]. A pooled analysis showed that men with very low concentrations of free testosterone (lowest 10%) have a belowaverage risk (OR: 0.77) of PCa [44]. A significantly higher rate of ISUP > 2 PCa (hazard ratio [HR]: 4.04) was found in men with inflammatory bowel disease when compared with