Eve's and Adam's rib for prostate cancer screening

Prostate cancer (PCa) is set to become a much bigger burden for healthcare providers and men in the coming decades and its overall management continues to evolve. Substantial advances in understanding the genomic landscape and biology of PCa have been achieved, anchoring both diagnosis and screening in new scenarios. In this issue of BJUI, Cussenot et al. [1] investigate new strategies to optimize early detection of PCa in men with high genetic risk. A combination of multiparametric MRI with biomarkers (total PSA, PSA density, Prostate Health Index [PHI], PCA3, T2:ERG and SelectMdx) might result in appropriate diagnosis of clinically significant tumours in this subset of patients. The findings of Cussenot et al. suggest that screening of men at high genetic risk for PCa could be based on multiparametric MRI, without pre-screening based on PSA >3 ng/mL, and could avoid missing tumours of International Society of Urological Pathology grade >1 and reduce the number of unnecessary biopsies. Poor levels of genetic PCa risk awareness exist and there is an unmet clinical need to design acceptable and appropriate health promotion interventions and screening in young men with genetic risk of developing PCa. A recent survey has investigated the activity and engagement across multiple social media platforms (Twitter, Facebook and YouTube) regarding BRCA and genetic testing for PCa compared with that in breast cancer in women, which has a long history of public awareness and advocacy and a prominent social media presence [2]. The authors found that there was substantially less activity on social media regarding genetic status and genetic testing for PCa in comparison to breast cancer. More recently, a clinical practice study showed that only 24% of male relatives of women with ovarian/breast cancer and a pathogenic variant in a DNA-repair gene (DRG) accepted predictive testing to find out if they carried the variant [3]. However, once they were discovered to be carriers of a DRG variant with a higher risk of developing PCa, 100% agreed to undergo yearly prostate screening. Those observations, combined with the findings of Cussenot et al., support the urgent need to raise awareness of genetic risk of PCa and to design effective public health promotion policies and personalized screening programmes for men with such a genetic risk. The number of studies exploring screening strategies tailored to men with a family history of PCa or with genetic risk is low. Most of them support the use of targeted screening but methodological differences make it impossible to draw conclusions from these data. The main large study assessing the usefulness of targeted PCa PSA-based screening in men with germline BRCA1/2 variants, the IMPACT study, after 3 years of follow-up, demonstrated that being a BRCA2 variant carrier was associated with a higher incidence of PCa, a younger age of diagnosis, and clinically significant PCa [4]. The IMPACT study (http://impact.icr.ac.uk/) is an international study evaluating targeted PCa screening for men who carry genetic alterations in BRCA1, BRCA2 and Lynch syndrome genes (MSH2, MSH6 and MLH1). IMPACT aims to evaluate the utility of PSA screening in detecting clinically significant PCa using a PSA threshold of >3.0 ng/mL. PCa incidence was higher for carriers of MSH2 and MSH6 pathogenic variants in comparison to age-matched controls not carrying pathogenic variants. The authors support the use of targeted PSA screening for these men to identify those with clinically significant PCa [5]. IMPACT was started before multiparametric MRI was routinely used as a diagnostic tool and therefore it is not able to evaluate the use of MRI in these higher-risk groups. The PCa pathway from screening and diagnosis to treatment has recently been critically questioned in light of Level 1 evidence pointing to pathway-related harms that may outweigh the benefits in the male general population. Innovative intervention focusing on men with high genetic risk might be the answer to counterbalance the shortcomings of the current pathway, with screening targeted at those men who need it the most. The involvement of women in information and the promotion of male awareness and engagement could be critical for dissemination activities about ‘hereditary syndromes’ in general and specific male populations. We could propose two scenarios for selecting men at high genetic risk for screening. The first is an ‘Eve's rib strategy’ that involves searching within a population of the male relatives (son/brother/cousin) of women with variants in higher-risk DRGs such as BRCA1/2. Male relatives of those female patients could be offered genetic counselling and, once agreed, testing for germline variants, and all probands who tested positive for the DRG variant would be offered dedicated PCa screening. The second is an ‘Adam's rib strategy’ that involves searching for germline DRG variant in men with a diagnosis of PCa. Male relatives (brother/cousin/father/uncle) of these patients who test positive will be offered genetic counselling. Probands who were positive for the DRG variant would be offered dedicated PCa screening. Figure 1 summarizes this new approach, suggesting a ‘road map’ for screening men with high genetic risk of PCa. The potential impact of early detection of PCa in high-risk populations, through multidisciplinary collaboration, will be essential for the safe and effective use of new guidelines to be adopted, avoiding underdiagnosis and undertreatment of a lethal PCa. None of the authors have conflicts of interest to disclose.