- Meets the definition for hereditary prostate cancer (three or more generations of prostate cancer; three or more first-degree relatives (son(s), brother(s), father) with prostate cancer; two or more men with prostate cancer diagnosed at age 55 or younger)
- Two or more close relatives with cancer associated with hereditary breast and ovarian cancer or Lynch syndrome
- Metastatic castration-resistant prostate cancer (mCRPC)
- Somatic pathogenic variants identified via tumor testing
However, these testing guidelines are based on limited evidence. Thus, there was an urgent need to determine a more robust way to identify pathogenic germline variants in men with prostate cancer.
We analyzed 1,812 men with prostate cancer who underwent clinical genetic testing at a commercial genetic testing laboratory and performed stepwise logistic regression of the clinical variables reported on the test requisition forms to determine the most reliable predictors of positive results. Pathogenic variants were found in 12% of men who underwent multigene panel testing who had no prior genetic testing. This result was similar to comparable studies of the yield of multi-gene panel test results in men with prostate cancer.2,3 Predictors of positive results included: increasing Gleason score, personal history of breast or pancreatic cancer, family history of breast, ovarian or pancreatic cancer, and family history of Lynch-syndrome associated cancers.
These results support the 2017 guidelines including testing men with aggressive disease or with a family history of cancers related to hereditary breast and ovarian cancer or Lynch syndrome. Similar to previous studies, we did not find an association between men who met the definition of hereditary prostate cancer and positive test results.1 We were unable to confirm the association between mCRPC and positive results, as this clinical information was missing for 86.9% of the men in this cohort. However, other studies strongly support this association.2,4 Likewise, prior somatic test results were not reported for most men in the study. It is unclear if somatic test results were not reported because most men did not have somatic testing, or if clinicians chose not to include this information on the test requisition form. Increasingly, clinicians will have somatic genetic results available for prostate cancer patients, as somatic testing is recommended for patients with mCRPC by the National Comprehensive Cancer Network guidelines. Somatic testing may identify pathogenic variants that require additional testing to determine if they are of germline origin, and typically providers will want to include somatic test results with the germline test requisition form so that the coverage of the exact alteration identified in the tumor can be confirmed in the germline.
We found that among all men with no prior genetic testing, the pooled frequency of pathogenic variants in therapeutically actionable genes at the time of the study (BRCA1/2 and mismatch repair genes) was 7.4%. Genetic testing is becoming increasingly relevant in this context considering the FDA’s recent approval of olaparib and rucaparib for mCRPC patients with somatic and germline pathogenic variants in certain genes. Among men with prior genetic testing, 15% were found to have pathogenic variants via multi-gene panel testing that may have been missed based on previous test results (immunohistochemistry [IHC], limited germline testing). This included two men with normal IHC results who were found to have a pathogenic variant in a non-mismatch repair gene; one man who was found to have a mismatch repair mutation with discordant IHC results; and three men with previously limited germline testing who were found to have germline pathogenic variants upon expanded testing. These results highlight the importance of genetic testing and the utility of a multi-gene panel testing approach.
Written by: Mary Pritzlaff, MS, Reporting Genetic Counselor, CGC Ambry Genetics
References:
- Giri, Veda N., Karen E. Knudsen, William K. Kelly, Wassim Abida, Gerald L. Andriole, Chris H. Bangma, Justin E. Bekelman et al. "Role of genetic testing for inherited prostate cancer risk: Philadelphia Prostate Cancer Consensus Conference 2017." Journal of Clinical Oncology 36, no. 4 (2018): 414.
- Pritchard, Colin C., Joaquin Mateo, Michael F. Walsh, Navonil De Sarkar, Wassim Abida, Himisha Beltran, Andrea Garofalo et al. "Inherited DNA-repair gene mutations in men with metastatic prostate cancer." N Engl J Med 375 (2016): 443-453.
- Giri VN, Hegarty SE, Hyatt C. et al. "Germline genetic testing for inherited prostate cancer in practice: implications for genetic testing, precision therapy, and cascade testing." The Prostate (2018); 1-7.
- Leongamornlert, D., E. Saunders, T. Dadaev, M. Tymrakiewicz, C. Goh, S. Jugurnauth-Little, I. Kozarewa et al. "Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease." British journal of cancer 110, no. 6 (2014): 1663-1672.