Clinical Germline Testing Results of Men With Prostate Cancer: Patient-Level Factors and Implications of NCCN Guideline Expansion

Abstract

PURPOSE Germline likely pathogenic or pathogenic variants (PVs) have been identified in up to 17% of men with prostate cancer (PC) and may drive disease severity or be targetable by novel therapies. National Comprehensive Cancer Network (NCCN) guidelines encouraging germline testing in metastatic PC were recently expanded to include all men with high-risk, very high-risk, or regional PC. Our aim was to assess the impact of expanded NCCN guidelines on the detection rate of germline PVs and to determine patient-level factors associated with a PV germline testing result. PATIENTS AND METHODS Men with PC underwent multigene germline genetic testing for PVs from June 2016 to December 2018, and trends were compared. The association of patient-level factors with a PV germline testing result, where ≥ 1 PV was identified, was assessed using analysis of variance and univariate logistic regression. Sensitivity analyses were limited to clinically actionable variants and those associated with disease severity or progression ( BRCA1/2 and ATM). RESULTS Of 408 men undergoing germline testing, 42 (10.3%) men had PVs and 366 (89.7%) men did not have PVs identified. The proportion of men identified with a germline PV remained stable following testing criteria expansion (9.4% v 10.6%, P = .73). No patient-level factors were significantly associated with increased odds of a PV germline testing result, including age at diagnosis, race, pretreatment prostate-specific antigen, Gleason grade group, NCCN risk group, and family history of cancer (breast and/or ovarian, prostate, or any cancer). CONCLUSION This study demonstrated a stable PV detection rate in men with PC using expanded criteria aligned to the updated NCCN testing guidelines. However, we did not find strong evidence to suggest that patient-level factors are associated with PV germline testing results. These findings support the recent expansion of NCCN germline testing guidelines in PC.

Initial outcomes and insights from a novel high‐risk prostate cancer screening clinic

“…28 An interdisciplinary approach to screening individuals at high risk for developing PCa is beneficial, similar to the collaboration between genetics and urologists in implementing germline testing in individuals with PCa. 1 The urologist perspective on PSA results and performing the DRE is key to identifying the need for prostate biopsy.…”

“…An increasing number of individuals benefit from active surveillance for prostate cancer (PCa) due to identified germline pathogenic variants (PVs). [1][2][3][4][5] Consensus guidelines provide PCa screening recommendations in individuals with germline PVs. 6,7 There is universal agreement that individuals with BRCA2 PVs are at increased risk for aggressive PCa.…”

Progress in prostate cancer prevention

“…About 10% of PCa accounts as hereditary form (Greenberg et al , 2021). The cumulative incidence of PCa in documented germline mutation carriers is 43% for men diagnosed <55 years, but only 9% for men >85 years old (Heidegger et al , 2019).…”

Mainstream germline genetic testing in men with metastatic prostate cancer: design and protocol for a multicenter observational study

“…Most patients present with local prostate cancer, whereas at least 7% present with metastatic prostate cancer (mPC) [2,3]. According to different studies, between 3 and 19% of men with mPC harbor a pathogenic germline variant in a cancer predisposition gene [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Pathogenic germline variants are hereditary and therefore family members can have these variants too.…”

“…Pathogenic germline variants are hereditary and therefore family members can have these variants too. These variants are mostly prevalent in breast cancer genes BRCA2, CHEK2 and ATM [4,6,7,10,12,16,18]. Depending on the affected gene, female family members who carry a pathogenic germline variant in one of these genes have a moderate to high risk of developing breast cancer and a moderate risk of developing ovarian cancer [19][20][21].…”