Prostate Cancer Germline Genetics in Clinical Practice

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TAKE-HOME MESSAGE

•To date, germline genetic testing for prostate cancer has not been widely used. In this literature review of prostate cancer genetics, the authors identified mutations in germline DNA repair genes (BRCA1, BRCA2, CHEK2, ATM, and PALB2) that may place men at increased risk for prostate cancer. Likewise, the use of PARP inhibitors may be beneficial in men who have mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2).

•While germline genetic testing may inform men and their relatives about prostate cancer risk, there exist ongoing challenges. Some of these challenges include a lack of genetic counselors, affordability/insurance coverage of testing, and how these results ultimately affect testing and treatment. With increased utilization and interest in genetic risk stratification, more studies are needed on how germline mutations affect systemic therapies in patients with metastatic disease as well as cancer screening in men with germline mutations.

- Michael H. Johnson, MD

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Urology 

Written by Ashley E. Ross MD, PhD

Cancer genetics and molecular-based management of malignancies have come to the forefront of oncological practice in recent years. In this issue of the Journal of Urology, Das and colleagues provide an excellent review of our current understanding of germline genetics in prostate cancer, highlighting multiple points. Guidelines, such as the NCCN guidelines, now suggest consideration of germline genetic testing in men with metastatic disease, where approximately 12% will have mutations in DNA damage response (DDR) genes. These men can serve as sentinels for other family members to be screened, and identification of DDR mutations can have implications for their own treatment (ie, with PARP inhibitors or immunotherapy).

Furthermore, although not mentioned in the review, there is emerging evidence that germline allelic variants in genes regulating androgen metabolism, particularly HSD3B1, may affect clinical outcomes and response to androgen-deprivation therapy. Of note, with the advent of more targeted therapies (eg, AKT inhibitors) and with loss of heterozygosity in DDR genes being common, it becomes increasingly important that men with metastatic disease have their somatic mutational status routinely tested as well. The authors also point out that guidelines currently support consideration of genetic testing in men with Gleason grade group 2 or higher disease and a family history, and that men with a known pathogenic germline mutation initiate screening for prostate cancer at an earlier age.

Although reimbursement issues may remain in some cases, I have not experienced any recent issues in my practice, and this likely results from the guideline endorsements and a decline in the cost of next-generation sequencing. I have found this true both of single-gene testing and multi-gene panel testing, the latter of which, I believe, is preferred. Genetic testing, particularly with multi-gene panels, should be offered by genetic professionals, and strong collaborations between genetic counselors and any practice treating prostate cancer are a must.

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PURPOSE

Until recently the role of germline genetics in prostate cancer care was not well defined. While important questions remain, we reviewed the current understanding of germline genetic alterations related to prostate cancer. We discuss the clinical implications for genetic counseling, genetic testing, early detection and treatment in men with these mutations.

MATERIALS AND METHODS

We searched PubMed® for English language articles published since 2001 with the key words "germline mutations," "BRCA," "family history" or "prostate cancer genetics." We also used relevant data from websites, including the Centers for Medicare and Medicaid Services, National Comprehensive Cancer Network®, Bureau of Labor Statistics and National Society of Genetic Counselors websites.

RESULTS

A number of germline mutations in DNA damage repair genes ( BRCA1, BRCA2, CHEK2, ATM and PALB2) and in DNA mismatch repair genes ( MLH1, MSH2, MSH6 and PMS2) can drive the development of prostate cancer. Careful genetic counseling coupled with multipanel gene testing can help identify men with these mutations and provide enhanced understanding of the disease risk. Cascade testing of family members can then have an impact extending well beyond the index patient. In men with a pathogenic germline mutation the optimal early detection paradigm is not well defined. Data from the IMPACT study ( ClinicalTrials.gov NCT00261456) that the cancer detection rate is substantially elevated in BRCA1 and BRCA2 carriers at prostate specific antigen greater than 3 ng/ml has helped establish the importance of close prostate specific antigen screening in these men. Additionally, BRCA2 and likely other DNA damage repair mutations are associated with aggressive disease, although it is not yet clear how this impacts localized disease management. However, there is strong evidence that patients with metastatic, castration resistant prostate cancer who have DNA damage repair defects respond positively to targeting PARP enzymes. In many cancers there is also evidence that patients with an increased tumor mutational burden, such as in Lynch syndrome, are particularly sensitive to immune checkpoint inhibitors.

CONCLUSIONS

Emerging evidence supports the implementation of germline genetic counseling and testing as a key component of prostate cancer management. Further research is needed to elucidate the clinical significance of lesser known germline mutations and develop optimal screening, early detection and treatment paradigms in this patient population.

The Journal of Urology

Bringing Prostate Cancer Germline Genetics Into Clinical Practice

J Urol 2019 Aug 01;202(2)223-230, S Das, SS Salami, DE Spratt, SD Kaffenberger, MF Jacobs, TM Morgan