Prostate cancer risk in men of differing genetic ancestry and approaches to disease screening and management in these groups.

Prostate cancer is the second most common solid tumour in men worldwide and it is also the most common cancer affecting men of African descent. Prostate cancer incidence and mortality vary across regions and populations. Some of this is explained by a large heritable component of this disease. It has been established that men of African and African Caribbean ethnicity are predisposed to prostate cancer (PrCa) that can have an earlier onset and a more aggressive course, thereby leading to poorer outcomes for patients in this group. Literature searches were carried out using the PubMed, EMBASE and Cochrane Library databases to identify studies associated with PrCa risk and its association with ancestry, screening and management of PrCa. In order to be included, studies were required to be published in English in full-text form. An attractive approach is to identify high-risk groups and develop a targeted screening programme for them as the benefits of population-wide screening in PrCa using prostate-specific antigen (PSA) testing in general population screening have shown evidence of benefit; however, the harms are considered to weigh heavier because screening using PSA testing can lead to over-diagnosis and over-treatment. The aim of targeted screening of higher-risk groups identified by genetic risk stratification is to reduce over-diagnosis and treat those who are most likely to benefit.

A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

How can we recruit more men of African or African-Caribbean ancestry into our research? Co-creating a video to raise awareness of prostate cancer risk and the PROFILE study.

BACKGROUND: Men of African ancestry are at increased risk of developing prostate cancer (PrCa) compared to men from other backgrounds. The PROFILE study aims to understand whether genetic information can better target who needs PrCa screening. PROFILE has so far had difficulty reaching men of African or African -Caribbean ancestry to take part. In this involvement project we worked in partnership with a group of such men to co-create a video to raise awareness of PrCa risk amongst this community and promote participation in the study. METHODS: We recruited seven men of African or African-Caribbean ancestry who completed an initial survey on the Cancer Patients' Voice platform. We then held an online discussion panel and maintained contact to encourage dialogue and planning of the video. Utilising a participatory approach, the ideas for the video were decided in collaboration with the panel who held expert knowledge of various communities and understood the messages that would best resonate and engage with other men of the same origins. Once the video had been edited and finalised, two members of the group expressed interest in writing up the project and are listed as co-authors. RESULTS: The video in its entirety was driven by the panel's ideas. The choice of a barber shop setting; leading with a positive case study and highlighting the importance of men's family members rather than a focus on scientific language, statistics or researchers were all features that were discussed and agreed upon by the panel. The men shared the video within their networks. It was placed on websites and promoted as part of a social media campaign during Black History Month. CONCLUSIONS: Groups with the greater healthcare needs and the most to gain from advances in care and treatment can often be the most excluded from research participation. This is pertinent in PrCa research where men of African or African-Caribbean ancestry are at greater risk. The project gave equal power and decision making to the men and provides an example of successful inclusive involvement. The result was a unique approach to making a study video.

METHODS: We engaged seven men of African or African-Caribbean ancestry: three PROFILE study participants and four from the Race, Ethnicity and Cultural Heritage (REACH) staff forums across the Royal Marsden Hospital and the Institute of Cancer Research. They completed a survey, joined an online discussion panel and we continued working together. The group decided on the structure and content of the video; to include a PrCa survivor who had been successfully screened and treated early for his disease, and a daughter of one of the panellists. The men were also involved in the dissemination plans of the finished video, and two agreed to be co-authors of this paper. FINDINGS: Features of the video led by the men included the choice of a barber shop setting; leading with a positive shared story and highlighting the importance of family rather than science, statistics or researchers. DISSEMINATION: The group shared the video within their networks. It was placed on websites and promoted as part of a social media campaign during Black History Month.

This project involved working in partnership with men of African or African-Caribbean ancestry to co-create a video intended to raise awareness of prostate cancer (PrCa) risk and promote participation in a genetic screening study called PROFILE. Men of African or African-Caribbean ancestry are at increased risk of developing PrCa compared to other men. The PROFILE study aims to understand whether genetic information can better target who needs PrCa screening. The study has had problems recruiting men from these communities.

Postgraduate training in Cancer Genetics-a cross-specialty survey exploring experience of clinicians in Ireland.

BACKGROUND: As genomic profiling of constitutional and tumour-derived DNA becomes increasingly critical in cancer risk estimation, prognostication and treatment, there is a growing need for clinicians involved in cancer care to up-skill in Cancer Genetics. In the Republic of Ireland (ROI), this is particularly crucial, given a paucity of vocationally trained Clinical Geneticists per capita compared to other European countries. AIMS: We aimed to assess the self-reported confidence of postgraduate medical/surgical trainees in ROI in requesting, interpreting, and managing genomic data in patients with cancer, and to assess their selfreported experience, and demand for future training in this area. METHODS: A cross-sectional survey of postgraduate trainees in four specialties (Medical and Radiation Oncology, Surgery, and Obstetrics and Gynaecology (O&G)), training in ROI, was undertaken. A bespoke electronic questionnaire was designed to capture data regarding preceding experience, and confidence across several hypothetical clinical scenarios involving genomic testing. The survey was circulated to eligible participants by training programme administrators, after relevant institutional ethical approval. Data was collected anonymously. RESULTS: The study cohort included 62 respondents. A paucity of cancer genetics training at every level was demonstrated, with "hardly any" or "none at all" reported by 47(76%), 62(100%), and 50(81%) during undergraduate, core specialty, and higher specialist training, respectively. A relative lack of confidence in all clinical scenarios was apparent, particularly among Surgery/O&G trainees. Most respondents would value more training in Cancer Genetics. CONCLUSIONS: This study demonstrates an unmet need in dedicated Cancer Genetics training for postgraduate specialty trainees in ROI.

A Case-Based Clinical Approach to the Investigation, Management and Screening of Families with BRCA2 Related Prostate Cancer.

BRCA2 is the most commonly implicated DNA damage repair gene associated with inherited prostate cancer. BRCA2 deficient prostate cancer typically presents at a younger age, is more poorly differentiated, and is associated with worse survival outcomes than non-BRCA2 associated prostate cancer. Despite these unfavourable prognostic implications, poly-ADP ribose polymerase inhibitors and platinum-based chemotherapy have been identified as potent targeted therapeutic agents towards BRCA1/2 deficient cancer cells. This review article explores the literature surrounding BRCA2-related prostate cancer through a familial clinical scenario. The investigation, diagnosis and management of BRCA2 deficient prostate cancer will be explored, alongside the implications of the identification of a germline pathogenic BRCA2 variant within a family, cascade screening and prostate cancer surveillance in unaffected male BRCA2 carriers. A greater understanding of the molecular pathogenesis of DNA damage repair gene deficient prostate cancer, coupled with new treatment paradigms and widened access to both somatic and germline genetic analysis for prostate cancer patients and their families will hopefully enable the robust implementation of high quality evidence-based clinical pathways for both the management and identification of BRCA2 deficient prostate cancer and improved screening, early detection and prevention strategies for individuals at increased genetic risk of prostate cancer.