In the 1990s, it was discovered that inherited loss-of-function pathogenic variants in the BRCA1 and BRCA2 genes (referred to as BRCA1/2 PVs) were linked to an increased familial risk of early-onset breast and ovarian cancers. Studies over the following decades demonstrated the benefits of early detection and preventive measures for female carriers of BRCA1/2 PVs, including significant mortality reduction through the use of PARP inhibitors (PARPi) for certain cancers. Despite these advances, there are challenges in improving genetic testing and ensuring equitable access to these measures. Indeed, male carriers of BRCA1/2 PVs, who are also at increased risk of cancers such as prostate, pancreatic, and breast cancer, have been largely overlooked. Even though they represent half of the BRCA1/2 PV carriers, many men are unaware of their risk and management options due to low rates of genetic testing.
The proposed reading for this month, “BRCA1, BRCA2, and Associated Cancer Risks and Management for Male Patients,” reviews the lack of inclusion in national guidelines for males in regard to cancer prevention, as well as the different treatment techniques which are slowly being used in the context of BRCA1/2 PV related pathologies.
Men who haven’t had cancer might still be eligible for genetic testing if they have a detailed family history of various cancer types and subtypes. Genetic testing is now available for men with pancreatic, breast, or high-risk prostate cancer. However, past data on genetic variants lack diversity, and tumour sequencing can uncover germline mutations that family history might miss. While genetic testing options have expanded, the limited availability of genetic counsellors necessitates new approaches for delivery and personalized workflows for counselling and testing relatives. In conclusion, the review highlights that enhancing the identification and testing of male BRCA1/2 PV carriers is crucial for improving early cancer detection, risk management, and treatment outcomes.
Examining risk management for men with BRCA1/2 PVs reveals that BRCA1 variants increase prostate cancer risk by up to 3.8 times, with a lifetime risk of 15-45%. In contrast, BRCA2 variants raise the risk 4.7-8.6 times, with a 60% lifetime risk. Metastatic prostate cancer is notably more common in these men. For pancreatic cancer, BRCA1 carriers face a 1.9-fold increased risk, while BRCA2 carriers have a 3.0-7.8-fold higher risk. Additionally, BRCA2 carriers have a 7-9% lifetime risk of breast cancer, whereas BRCA1 carriers have up to a 1.2% risk. Recommended screening includes annual clinical breast exams starting at age 35 and considering mammograms at age 50 or younger based on family history.
Furthermore, genetic testing for BRCA1/2 PVs is shown to be crucial due to the expanding treatment options for associated cancers. PARP inhibitors (PARPi), initially approved for BRCA1/2-related ovarian cancer, now extend to prostate, pancreatic, and breast cancers, offering improved survival outcomes. For metastatic castration-resistant prostate cancer with BRCA1/2 PVs, PARPi and combinations with androgen receptor signalling inhibitors are beneficial. Platinum chemotherapy, though historically limited in prostate cancer, is another option for advanced cases with BRCA1/2 deficiency. These new methods, though promising, are not yet part of standard guidelines and should be used in clinical trials to complement existing screening tests.
In summary, male carriers of BRCA1/2 PVs face higher risks of prostate, pancreatic, and breast cancers. Despite the clinical information available, males are less likely to undergo genetic testing, missing chances for health interventions. Increasing the identification of male BRCA1/2 PV carriers can improve early cancer detection, targeted risk management, and treatment for these men, as well as offer preventive measures for their families, ultimately reducing the impact of hereditary cancers.
We at 4bases have introduced the BRaCA panel, allowing germline analysis of hereditary predisposition by identifying mutations in both BRCA1 and BRCA2, based on Next Generation Sequencing (NGS) technologies. Learn more about the product here: https://4bases.ch/oncological-kits/
Cheng HH, Shevach JW, Castro E, et al. BRCA1, BRCA2, and Associated Cancer Risks and Management for Male Patients: A Review. JAMA Oncol. Published online July 25, 2024. doi:10.1001/jamaoncol.2024.2185
