By Veda N. Giri, MD
Germline genetic testing for prostate cancer is undergoing immense expansion. Prostate cancer has long been recognized to have a substantial hereditary component.
Familial clustering of prostate cancer has been recognized for many years, with a working definition of hereditary prostate cancer encompassing generational prostate cancer with multiple cases in a nuclear family, and/or early-onset prostate cancer (Genetics of Prostate Cancer (PDQ) NCI: https://www.cancer.gov/types/prostate/hp/prostate-genetics-pdq; J Urol 1993;150(3):797-802). Furthermore, higher rates of prostate cancer have been observed in families with hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) (Genetics of Prostate Cancer (PDQ) NCI: https://www.cancer.gov/types/prostate/hp/prostate-genetics-pdq; Semin Oncol 2016;43(5):560-565).
Multiple genes have been identified to predispose to inherited prostate cancer, including BRCA1, BRCA2, HOXB13, and the DNA mismatch repair genes (Genetics of Prostate Cancer (PDQ) NCI: https://www.cancer.gov/types/prostate/hp/prostate-genetics-pdq; Semin Oncol 2016;43(5):560-565; J Clin Oncol2018;36(4):414-424). In addition, a substantial rate of germline mutations in DNA repair genes was reported in men with metastatic prostate cancer of approximately 12 percent (N Engl J Med 2016;375:443-453).
Prior to 2017, guidelines were limited regarding genetic testing for men with prostate cancer and were focused only on BRCA1/2 testing for men meeting strict family history criteria or having metastatic disease. Therefore in 2017, an international consensus conference was convened to develop a comprehensive framework for genetic testing for men with prostate cancer encompassing which men to test, which genes to test, and how testing may impact prostate cancer screening, early-stage management, and treatment for metastatic disease (J Clin Oncol 2018;36(4):414-424).
The consensus statement expanded upon consideration of BRCA testing to include testing for other genes on multigene panels such as DNA mismatch repair genes and HOXB13 in specific scenarios (J Clin Oncol 2018;36(4):414-424).
Shortly thereafter, the NCCN Prostate Cancer guideline significantly expanded to include consideration of genetic testing of all men with metastatic prostate cancer and men in the higher disease risk categories (high risk, very high risk, and regional disease) regardless of family history (NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Prostate (Version 4.2018)).
For men with very low-to-unfavorable, intermediate risk disease, consideration of genetic testing was recommended based upon family history of prostate cancer, particularly if men were diagnosed at age less than 60 or had family cancer history suggestive of HBOC or LS. Genes to test in the guideline include BRCA1, BRCA2, ATM, PALB2, DNA mismatch repair genes (particularly with correlating molecular analysis), and FANCA (NCCN Guidelines: Prostate (Version 4.2018)).
In the current era of clinical genetic testing, multiple genes are now available for genetic testing of men with prostate cancer, not only for BRCA1, BRCA2, HOXB13, DNA mismatch repair genes, and ATM, but also for several genes with varying levels of data regarding association to prostate cancer risk and/or aggressiveness, such as CHEK2, PALB2, and NBN (J Clin Oncol 2018;36(4):414-424).
Analyzing Real-World Data
Given the expansion of genetic testing guidelines, prevalence estimates in clinical cohorts of men with prostate cancer undergoing genetic testing are needed to gain an understanding of the burden of potential inherited prostate cancer and implications of germline testing for prostate cancer management, treatment, and cascade genetic testing in families.
Giri et al. published the first analysis of real-world genetic data among men with prostate cancer undergoing germline testing with the goal to estimate prevalence of genetic mutations overall and particularly in DNA repair genes (such as BRCA1, BRCA2, ATM, PALB2, NBN, and the DNA mismatch repair genes) that are informing therapeutic and clinical trial options (Prostate 2019; doi:10.1002/pros.23739). A secondary goal was to identify predictors of germline mutations in DNA repair genes that may help identify which men with prostate cancer in particular should be referred for genetic evaluation.
The study team from Sidney Kimmel Cancer Center at Thomas Jefferson University analyzed de-identified data from 1,328 men with prostate cancer who had undergone germline genetic testing. ICD-10 billing codes were used to identify a personal diagnosis of prostate cancer and family cancer history. Gleason score was extracted manually from information provided on testing forms.
The prevalence of genetic mutations was 15.6 percent overall and 10.9 percent in DNA repair genes. BRCA2 mutations were the most commonly identified (4.5%), followed by mutations in CHEK2 (2.2%), ATM (1.8%), BRCA1 (1.1%), PMS2(0.6%), MSH2 (0.5%), NBN (0.2%), MLH1 (0.2%), and EPCAM (0.1%). Selected additional DNA repair gene mutations included PALB2 (0.5%), RAD50 (0.4%), BRIP1 (0.2%), RAD51C (0.2%), and RAD51D (0.1%).
Furthermore, family history of breast cancer was significantly associated with an approximate two-fold increased risk of germline DNA repair mutations in men with prostate cancer. In addition, Gleason score ≥8 was significantly associated with mutations in DNA repair genes compared to Gleason scores of 6-7. Of note, the rate of variants of uncertain significance (VUS) in this cohort was 37.2 percent.
The findings by Giri et al. have several implications. First, this was the first study to report on the prevalence of germline mutations in men with prostate cancer undergoing clinical genetic testing with an overall mutation rate of 15.6 percent. An even more recent study by Nicolosi et al. conducted also in the same dataset reported a germline variant rate of 17.2 percent (JAMA Oncol 2019; doi:10.1001/jamaoncol.2018.6760), confirming the initial findings by Giri et al. and adding support that men with prostate cancer do indeed have substantial rates of germline mutations in a spectrum of cancer risk genes.
Second, the genetic landscape is coming into clearer view showing that men with prostate cancer may harbor mutations in a spectrum of genes such as BRCA1, BRCA2, CHEK2, ATM, PALB2, DNA mismatch repair genes, and additional genes involved in DNA repair. These genes have potential therapeutic and clinical trial implications for men particularly with metastatic, castration-resistant prostate cancer (mCRPC) (N Engl J Med 2015;373(18):1697-1708, N Engl J Med2015;372:2509-2520).
For example, the FDA has granted olaparib Breakthrough Therapy designation for BRCA1/2- or ATM-positive mCRPC based on phase II data (N Engl J Med 2015;373(18):1697-1708). Recently, rucaparib was also granted Breakthrough Therapy designation for men with BRCA1/2-positive mCRPC following at least one androgen receptor-directed therapy and taxane-based chemotherapy based on phase II data from the TRITON2 study.
Genetically informed clinical trial options are also rapidly expanding for men with mCRPC (JCO Precis Oncol 2018; doi:10.1200/PO.18.00060). Additionally, genetic results will likely increasingly be factored into active surveillance discussions particularly if the genetic mutations inform risk for aggressive disease (NCCN Guidelines: Prostate (Version 4.2018), Eur Urol 2017;71(5):740-747, Eur Urol 2018; doi:10.1016/j.eururo.2018.09.021).
Furthermore, this spectrum of germline mutations is in cancer risk genes that confer additional cancer risks for men with prostate cancer. For example, men with BRCA2 mutations are also at risk for male breast cancer, pancreatic cancer, and melanoma where guidelines-based management exist or may require high-risk consultation (NCCN Guidelines: Genetic/Familial High-risk Assessment: Breast and Ovarian (Version 2.2019)). These recommendations to reduce additional cancer risks are important to impart, particularly for men with early-stage prostate cancer and many of whom will enter survivorship.
Third, family history of breast cancer or higher Gleason may be useful in identification of men with prostate cancer for genetic counseling and genetic testing referral, according to the results published (Prostate 2019; doi:10.1002/pros.23739). While other studies have reported that family history and Gleason score could not fully stratify men with prostate cancer for presence of germline mutations (JAMA Oncol 2019; doi:10.1001/jamaoncol.2018.6760), predictors of germline mutations—particularly in DNA repair genes—can be helpful to streamline efforts to refer appropriate men with prostate cancer for genetic evaluation to inform therapeutic options and cascade testing. Further data are needed in this context.
Fourth, the spectrum of genetic mutations in men with prostate cancer informs cascade genetic testing of male and female blood relatives to determine if they carry the genetic mutation and to guide cancer screening and risk reduction recommendations.
Finally, the report by Giri et al. shows that the rate of VUS is approximately 37 percent, which is important to discuss with men considering genetic testing. While VUS are reported to patients in their clinical results, there are no management changes based upon VUS at the time of report. Over time a small minority of these VUS are reclassified to "mutation" (JAMA 2018;320(12):1266-1274), and therefore men need to understand this potential for reclassification in the future and keep in touch with their ordering provider. Prior work by the Giri research team has shown that a subset of men may misinterpret "VUS" as "mutations" at the time of reporting, raising the need to reinforce understanding of VUS at disclosure of genetic results (Prostate 2019; doi:10.1002/pros.23535).
In summary, genetic evaluation of men with prostate cancer is a rapidly growing field that is capitalizing on advances in genetic sequencing and it is now in need of data-driven genetic testing guidelines for optimal evaluation and management.
The publication by Giri et al. provides the first insights into the real-world landscape of genetic testing for men with prostate cancer with implications for genetic testing referral, precision therapy, and cascade testing in families.
VEDA N. GIRI, MD, is Associate Professor of Medical Oncology, Cancer Biology, and Urology, and Director of Cancer Risk Assessment and Clinical Cancer Genetics at Sidney Kimmel Cancer Center at Jefferson Health, Philadelphia.