Germline genetic testing for inherited prostate cancer in practice: Implications for genetic testing, precision therapy, and cascade testing

Abstract

Background Genetic testing capability and guidelines are rapidly expanding to assess inherited prostate cancer (PCA). Clinical genetic data from multigene testing can provide insights into the germline pathogenic variant (PV) spectrum and correlates in men with PCA unselected for metastatic disease to optimize identification of men for genetic evaluation and management. Methods A retrospective cross‐sectional analysis was conducted of de‐identified clinical genetic testing data from a large commercial genetic testing laboratory in the US. ICD‐10 claims codes were used to identify men with PCA, along with family history data. Gleason score was abstracted from test request forms. Overall PV rate among men with PCA was estimated, along with PVs in DNA repair genes. Family history and Gleason score association to germline DNA repair PVs was assessed using Fisher's exact test with correction for false‐discovery. Results As of August 2017, genetic results were available on 1328 men with PCA. Overall PV rate was 15.6%, with 10.9% of PV in DNA repair genes. PVs were most commonly identified in BRCA2 (4.5%), CHEK2 (2.2%), ATM (1.8%), and BRCA1 (1.1%). Breast cancer family history was significantly associated with germline DNA repair PVs (OR 1.89, [95%CI 1.33, 2.68], P = 0.003). Among men with Gleason score>= 6 (n = 706), Gleason> = 8 was significantly associated with DNA repair PVs (OR 1.85 [95%CI 1.22, 2.80], P = 0.004). Conclusions A substantial proportion of men with PCA unselected for metastatic disease carry germline DNA repair PVs. Breast cancer family history and high Gleason score are important predictors to identify men with PCA who may carry germline DNA repair PVs. Our findings support current NCCN guidelines and have implications for genetic assessment, therapeutic management, and cascade testing for men with PCA and their families.

Prostate Cancer, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology

“…Another study also found that a family history of breast cancer increased the chances of identifying a germline DNA repair gene mutation in men with prostate cancer (odds ratio [OR], 1.89; 95% CI, 1.33-2.68; P5.003). 37 In a study of an unselected cohort of 3,607 patients with a personal history of prostate cancer who had germline genetic testing based on clinician referral, 11.5% had germline mutations in BRCA2, CHEK2, ATM, BRCA1, or PALB2. 38 More than 2% of Ashkenazi Jews carry germline mutations in BRCA1 or BRCA2, and these carriers have a 16% chance (95% CI, 4%-30%) of developing prostate cancer by the age of 70.…”

Validation of a prostate cancer polygenic risk score

“…PrCa risk assessment has been primarily based on family history (FH) and screening of rare pathogenic/likely pathogenic variants (RPVs). Germline RPVs in cancer susceptibility genes have been observed in 8% to 12% of men with localized PrCa, 2 and up to 20% of men with advanced or metastatic disease 3‐6 . In addition to rare RPVs, common genetic variations also contribute to PrCa risk 7 .…”

Rare germline genetic variants and risk of aggressive prostate cancer

“…Although variants that can be classified as P/LP are rare, when considered in the context of commercial multigene testing for prostate cancer susceptibility, it is clear that the number of men to whom this information could be clinically relevant is not inconsequential. For example, Giri et al report that 11% of men undergoing multigene testing for prostate cancer susceptibility (unselected for metastatic disease) had pathogenic variants in DNA repair genes that have implications for therapeutic management and cascade testing 50 …”

“…Recognised gaps in knowledge currently include cost‐effectiveness of genetic testing for PrCa susceptibility and whether the strategies for testing should include breast cancer family history information and/or Gleason score 50 …”