Diagnosing hereditary cancer predisposition in men with prostate cancer

Mary Pritzlaff,Yuan Tian,Patrick Reineke,A.J Stuenkel,Kyle Allen,Stephanie Gutierrez,Michelle Jackson,Jill S Dolinsky,Holly Laduca,Jianfeng Xu,Mary Helen Black,Brian T Helfand

doi:10.1038/s41436-020-0830-5

Mary Pritzlaff, Yuan Tian + Show 10 more

Open Access

https://doi.org/10.1038/s41436-020-0830-5

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Abstract

PurposeWe describe the pathogenic variant spectrum and identify predictors of positive results among men referred for clinical genetic testing for prostate cancer. MethodsOne thousand eight hundred twelve men with prostate cancer underwent clinical multigene panel testing between April 2012 and September 2017. Stepwise logistic regression determined the most reliable predictors of positive results among clinical variables reported on test requisition forms. ResultsA yield of 9.4–12.1% was observed among men with no prior genetic testing. In this group, the positive rate of BRCA1 and BRCA2 was 4.6%; the positive rate for the mismatch repair genes was 2.8%. Increasing Gleason score (odds ratio [OR] 1.19; 95% confidence interval [CI] 0.97–1.45); personal history of breast or pancreatic cancer (OR 3.62; 95% CI 1.37–9.46); family history of breast, ovarian, or pancreatic cancer (OR 2.32 95% CI 1.48–3.65); and family history of Lynch syndrome–associated cancers (OR 1.97; 95% CI 1.23–3.15) were predictors of positive results. ConclusionThese results support multigene panel testing as the primary genetic testing approach for hereditary prostate cancer and are supportive of recommendations for consideration of germline testing in men with prostate cancer. Expanding the criteria for genetic testing should be considered as many pathogenic variants are actionable for treatment of advanced prostate cancer.

Highlights

Germline pathogenic variants (PVs) in cancer predisposition genes are reported in 7.3% to 11.8% of aggressive prostate cancer (PC) cases, including genes associated with homologous repair deficiency (HRD) (e.g., BRCA1, BRCA2, ATM, BRIP1, CHEK2, NBN, BARD1, RAD51C, MRE11A, and PALB2), and mismatch repair (MMR) deficiency (e.g., MLH1, MSH2, MSH6, and PMS2).[1,2] Most of these genes have clear management guidelines for early cancer detection and risk reduction, which may benefit the patient and family members
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 were predictors of positive results
Expanding the criteria for genetic testing should be considered as many pathogenic variants are actionable for treatment of advanced prostate cancer

Summary

Introduction

Germline pathogenic variants (PVs) in cancer predisposition genes are reported in 7.3% to 11.8% of aggressive prostate cancer (PC) cases, including genes associated with homologous repair deficiency (HRD) (e.g., BRCA1, BRCA2, ATM, BRIP1, CHEK2, NBN, BARD1, RAD51C, MRE11A, and PALB2), and mismatch repair (MMR) deficiency (e.g., MLH1, MSH2, MSH6, and PMS2).[1,2] Most of these genes have clear management guidelines for early cancer detection and risk reduction, which may benefit the patient and family members. Men with HRD or MMR-deficient metastatic prostate tumors may benefit from targeted therapeutics, such as pembrolizumab, platinum therapies, or PARP inhibitors.[7,8,9]

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