Prostate Cancer

Prostate Cancer Diagnostic Evaluation Comprehensive Review Article Part 3 Prof. Dr. Semir. A. Salim. Al Samarrai Figure 1. Schematic representation of traditional and proposed mpMRI-molecular-biomarker-directed prostate cancer diagnostic pathway. CaP, prostate cancer; PSA, prostate serum antigen; DRE, digital rectal examination; mpMRI, multiparametric magnetic resonance imaging. Text color of FDA/CLIA-approved molecular markers represents tissue of origin: yellow—urine derived; red—blood derived; brown—tissue derived. The diagnostic evaluations are a very important measures in the screening and early detection of prostate cancer in decreasing of cancer-specific mortality by developing early and precise treatment and strategy. Prostate cancer mortality trends range widely from country to country in the industrialised world [1]. Mortality due to PCa has decreased in most Western nations but the magnitude of the reduction varies between countries. The integration of MRI in the biopsy protocol may reduce the number of men that undergo biopsies while detecting more clinically significant and less clinically insignificant PCa [2,3]. Men at elevated risk of having PCa are those > 50 years [4] or at age > 45 years with a family history of PCa (either paternal or maternal) [5] or of African descent [6,7]. Men of African descent are more likely to be diagnosed with more advanced disease [8] and upgrade was more frequent after prostatectomy as compared to Caucasian men (49% vs. 26%) [9]. Germline mutations are associated with an increased risk of the development of aggressive PCa, i.e. BRCA2 [10,11]. Prostate-specific antigen screening in male BRCA1 and 2 carriers detected more significant cancers at a younger age compared to non-mutation carriers [12,13]. Men with a baseline PSA < 1 ng/mL at 40 years and < 2 ng/mL at 60 years are at decreased risk of PCa metastasis or death from PCa several decades later [14,15]. Informed men requesting an early diagnosis should be given a PSA test and undergo a DRE [16]. The use of DRE alone in the primary care setting had a sensitivity and specificity below 60%, possibly due to in experience, and can therefore not be recommended to exclude PCa [17]. Prostate-specific antigen measurement and DRE need to be repeated [18]. This could be every 2 years for those initially at risk, or postponed up to 8 years in those not at risk with an initial PSA < 1 ng/mL at 40 years and a PSA < 2 ng/mL at 60 years of age and a negative family history [19]. Risk calculators, combining clinical data (age, DRE findings, PSA level, etc.) may be useful in helping to determine (on an individual basis) what the potential risk of cancer may be, thereby reducing the number of unnecessary biopsies. Prostate MRI stratifies suspected PCa in lower- and higher risk, based on a 1- to 5- risk scale of having csPCa [PI-RADS v2.1 guidelines 2019]. A recent meta-analysis of this risk assessment tool showed (on a patient level) a significant cancer detection rate of 9% (5–13%) for PI-RADS 2 scores, 16% (7–27%) for PI-RADS 3 scores, 59% (39–78%) for PI-RADS 4 scores, and 85% (73–94%) for PI-RADS 5 scores [20]. Men with PI-RADS assessment scores of 3 to 5 are recommended to undergo biopsy [21]. Prostate MRI and related MRI-directed biopsies have shown to be at least as diagnostically effective as systematic biopsies alone in diagnosing significant cancers [22]. However, if the MRI-directed biopsy decision strategy (without performing systematic biopsies) can reduce the number of unnecessary biopsy procedures, this will be at the expense of missing a small percentage of csPCas [23]. PSA-density (PSA-D) is the strongest predictor in risk calculators. Combinations of PSA-D and MRI have been explored [24-29], showing guidance in biopsy-decisions whilst safely avoiding redundant biopsy testing. Increasing evidence supports the implementation of genetic counselling and germline testing in early detection and PCa management [30]. Several commercial screening panels are now available to assess main PCa risk genes [31]. However, it remains unclear when germline testing should be considered and how this may impact localised and metastatic disease management. Germline BRCA1 and BRCA2 mutations occur in approximately 0.2% to 0.3% of the general population [32]. It is important to understand the difference between somatic testing, which is performed on the tumour, and germline testing, which is performed on blood or saliva and identifies inherited mutations. Genetic counselling is required prior to and after undergoing germline testing. Germline mutations can drive the development of aggressive PCa. Therefore, the following men with a personal or family history of PCa or other cancer types arising from DNA repair gene mutations should be considered for germline testing: • Men with metastatic PCa; • Men with high-risk PCa and a family member diagnosed with PCa at age < 60 years; • Men with multiple family members diagnosed with csPCa at age < 60 years or a family member who died from PCa cancer; • Men with a family history of high-risk germline mutations or a family history of multiple cancers on the same side of the family. Further research in this field (including not so well-known germline mutations) is needed to develop screening, early detection and treatment paradigms for mutation carriers and family members (table 1). Table 1. Germline mutations in DNA repair genes associated with increased risk of prostate cancer By the clinical diagnosis evaluation, prostate cancer is usually suspected on the basis of DRE and/or PSA levels. Definitive diagnosis depends on histopathological verification of adenocarcinoma in prostate biopsy cores. In ~18% of cases, PCa is detected by suspect DRE alone, irrespective of PSA level [50]. A suspect DRE in patients with a PSA level < 2 ng/mL has a positive predictive value (PPV) of 5–30% [51]. The use of PSA as a serum marker has revolutionised PCa diagnosis [52]. Prostate-specific antigen is organ but not cancer specific; therefore, it may be elevated in benign prostatic hypertrophy (BPH), prostatitis and other non-malignant conditions. As an independent variable, PSA is a better predictor of cancer than either DRE or TRUS [53]. There are no agreed standards defined for measuring PSA [54]. It is a continuous parameter,

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Prostate Cancer PART 2

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Prostate Cancer Classification Comprehensive Review Article Part 2 Prof. Dr. Semir. A. Salim. Al Samarrai The objective of a tumour classification system is to combine patients with a similar clinical outcome. This allows for the design of clinical trials on relatively homogeneous patient populations, the comparison of clinical and pathological data obtained from different hospitals across the world, and the development of recommendations for the treatment of these patient populations. Throughout these Guidelines the 2017 Tumour, Node, Metastasis (TNM) classification for staging of PCa (Table 1) [1], Table 1. Clinical Tumour Node Metastatis (TNM) classification of PCa and the EAU risk group classification, which is essentially based on D’Amico’s classification system for PCa, are used (Table 2) [2]. Table 2. EAU risk groups for biochemical recurrence of localized and locally advanced prostate cancer The latter classification is based on the grouping of patients with a similar risk of biochemical recurrence (BCR) after radical prostatectomy (RP) or external beam radiotherapy (EBRT). Magnetic resonance imaging and targeted biopsy may cause a stage shift in risk classification systems [3]. Clinical T stage only refers to digital rectal examination (DRE) findings; local imaging findings are not considered in the TNM classification. Pathological staging (pTNM) is based on histopathological tissue assessment and largely parallels the clinical TNM, except for clinical stage T1 and the T2 substages. Pathological stages pT1a/b/c do not exist and histopathologically confirmed organ-confined PCas after RP arempathological stage pT2. The current Union for International Cancer Control (UICC) no longer recognises pT2 substages [1]. Of note: the EANM recently proposed a ‘miTNM’ (molecular imaging TNM) classification, taking into account prostate-specific membrane antigen positron emission tomography–computed tomography (PSMA PET/CT) findings [4]. The prognosis of the miT, miN and miM substages is likely to be better to their T, N and M counterparts due to the ‘Will Rogers phenomenon’; the extent of this prognosis shift remains to be assessed as well as its practical interest and impact [5]. In the original Gleason grading system, 5 Gleason grades (ranging from 1–5) based on histological tumour architecture were distinguished, but in the 2005 and subsequent 2014 International Society of Urological Pathology (ISUP) Gleason score (GS) modifications Gleason grades 1 and 2 were eliminated [6,7]. The 2005 ISUP modified GS of biopsy-detected PCa comprises the Gleason grade of the most extensive (primary) pattern, plus the second most common (secondary) pattern, if two are present. If one pattern is present, it needs to be doubled to yield the GS. For three grades, the biopsy GS comprises the most common grade plus the highest grade, irrespective of its extent. The grade of intraductal carcinoma should also be incorporated in the GS [8]. In addition to reporting of the carcinoma features for each biopsy, an overall (or global) GS based on the carcinoma-positive biopsies can be provided. The global GS takes into account the extent of each grade from all prostate biopsies. The 2014 ISUP endorsed grading system limits the number of PCa grades, ranging them from 1 to 5 (see Table 2 and table 3) [8,9]. Table 3. International Society of Urological Pathology 2014 grade (group) system Further sub-stratification of the intermediate-risk group can be made and specifically the National Cancer Center Network (NCCN) Guidelines subdivide intermediate-risk disease into favourable intermediate-risk and unfavourable intermediate-risk, with unfavourable features including ISUP grade 3, and/or > 50% positive biopsy cores and/or at least two intermediate-risk factors [10]. The descriptor ‘clinically significant’ is widely used to differentiate PCa that may cause morbidity or death from types of PCa that do not. This distinction is particularly important as insignificant PCa that does not cause harm is so common [11]. Unless this distinction is made, such cancers are at high risk of being overtreated, with the treatment itself risking harmful side effects to patients. The over-treatment of insignificant PCas has been criticised as a major drawback of PSA testing [12]. However, defining what is clinically significant and what is insignificant PCa is difficult. In large studies of RP specimens which showed only ISUP grade 1 disease, extra prostatic extension (EPE) was extremely rare (0.28% of 2,502 cases) and seminal vesicle (SV) invasion or lymph node (LN) metastasis did not occur at all [13,14]. International Society for Urological Pathology grade 1 disease itself can therefore be considered clinically insignificant. Whilst ISUP grade 1 bears the hallmarks of cancer histologically, ISUP grade 1 itself does not behave in a clinically malignant fashion. However, ISUP grade 1 is first diagnosed at biopsy and guides management decisions, not after the prostate has been removed. The current standard practice of MRI-targeted and template biopsies has reduced diagnostic inaccuracy [15], however sampling error may still occur such that higher grade cancer could be missed. This should be especially considered if the prior MRI showed a suspicious lesion, but only ISUP grade 1 was found at biopsy. Another complexity in defining insignificant cancer is that ISUP grade 1 may progress to higher grades over time, becoming clinically significant at a later biopsy [16]. Therefore, although ISUP grade 1 itself can be described as clinically insignificant, it is important to take into account other factors, including imaging prior to biopsy and adequate sampling core number. When combined with low-risk clinical factors (see Table 2), ISUP grade 1 represents low-risk PCa, with its recommendation of preferred management being active surveillance (AS) or watchful waiting (WW). It should be noted, therefore, that defining ISUP grade 1 as insignificant cancer does not mean it should be ignored, but safely observed. Epidemiological and autopsy data also suggest that a proportion of ISUP grade 2 PCas would remain undetectable during a man’s life [17] and therefore may be overtreated. In current guidelines deferred treatment may be offered to select patients with intermediate-risk PCa [10], but evidence is lacking for appropriate selection criteria [18]. Recent papers have defined clinically significant cancer differently, commonly using ISUP grade 2 and above and even ISUP grade 3 and above, demonstrating the lack of consensus and evolution of its definition [19-22]. Some papers

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Prostate Cancer

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Prostate Cancer Epidemiology and Aetiology Comprehensive 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]. Figure 1. Risk Factors of Prostatic Cancer. 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 1). Table 1. Main dietary factors that Have been associated with PCa 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

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