J Urol. 2019 Feb 5. doi: 10.1097/JU.0000000000000137. [Epub ahead of print]
Bringing prostate cancer germline genetics into clinical practice.
Until recently, the role of germline genetics in prostate cancer care was not well defined. While important questions remain, here we review the current understanding of germline genetic alterations related to prostate cancer and discuss the clinical implications for geneticcounselling, genetic testing, early detection, and treatment in men with these mutations.
MATERIALS AND METHODS:
We performed a PubMed search for English Language articles published since 2001 with keywords "germline mutations", or "BRCA", or "family history", or "prostate cancer genetics." Relevant data from websites including Center for Medicaid Services, the National Comprehensive Cancer Network, Bureau of Labor Statistics, and National Society of Genetic Counselors are included as well.
A number of germline mutations in DNA damage repair (BRCA1, BRCA2, CHEK2, ATM, PALB2) and DNA mismatch repair (MLH1, MSH2, MSH6, and PMS2) genes can drive the development of prostate cancer. Careful genetic counseling coupled with multi-panel gene testing can help identify men with these mutations and provide an enhanced understanding of disease risk. Cascade testing of family members can then have an impact extending well beyond the index patient. For men with a pathogenic germline mutation, the optimal early detection paradigm is not well defined. Data from the IMPACT study indicate that cancer detection rates are substantially elevated in BRCA1 and BRCA2 carriers at a PSA >3 ng/ml and help establish the importance of close PSA screening in these men. Additionally, BRCA2 and likely other DNA damage repair mutations are associated with aggressive disease, although it is not clear yet how this impacts localized disease management. There is strong evidence, however, that patients with mCRPC with DNA damage repair defects respond positively to targeting PARP enzymes. There is also evidence for many cancers that patients with increased tumor mutational burden, such as in Lynch syndrome, are particularly sensitive to immune checkpoint inhibitors.
Emerging evidence supports the implementation of germline genetic counselling and testing as a key component of prostate cancer. Further research is needed to elucidate the clinical significance of lesser known germline mutations and to develop optimal screening, early detection, and treatment paradigms in this patient population.