Rethinking germline testing in localized prostate cancer: Prevalence of germline variants and association with Gleason score and NCCN risk grouping.

Abstract

322 Background: Men with prostate cancer who harbor germ-line pathogenic variants have increased likelihood of a more aggressive cancer and/or an increased risk for second primary cancers. However, current National Comprehensive Cancer Network (NCCN) guidelines limit germline genetic testing recommendations to men with prostate cancer who have higher Gleason scores or NCCN Risk Groups, metastatic disease and/or a family history of cancer. We examined the prevalence of pathogenic variants in a real-world cohort of men with localized prostate cancer, stratified by Gleason score and NCCN Risk Group. Methods: Blood was drawn for germline genetic testing at the time of prostate cancer diagnostic biopsy. For patients who had biopsy-confirmed cancer, germline testing was initiated. Those with a benign biopsy were not included in this analysis. A positive result was defined as a pathogenic variant in at least one of the 49 genes tested. Relationships between a positive test result and Gleason score or NCCN Risk Group were assessed using logistic regression. Results: A total of 3995 men completed germline testing and 274 (6.9%) had a positive test result. Gleason scores and NCCN Risk Groups are summarized in Table 1. Positive test rates of 6.3%, 6.0%, 7.8%, and 8.4% were observed for Gleason scores 3+3, 3+4, 4+3, and greater than 7, respectively. Positive test rates by NCCN Risk Group were 6.7%, 5.7%, 5.6%, and 8.4% for low, favorable intermediate, unfavorable intermediate, and high risk NCCN Risk Groups, respectively. There was no statistically significant difference in positive testing rates across Gleason scores (p = 0.17) or NCCN Risk Groups (p = 0.14). Conclusions: A substantial proportion of men with localized prostate cancer harbor pathogenic germline variants. Neither Gleason scores nor NCCN Risk Groups were associated with positive germline test results. These results have the potential to impact the management of prostate cancer and/or screening for other cancers. Our findings suggest that limiting germline testing based on Gleason score or NCCN Risk Group may miss a significant number of patients harbor a pathogenic variant, supporting consideration for broader testing criteria for all men with localized prostate cancer. Distribution of Gleason Score and NCCN Risk Group (N=3995). N (%) Gleason score  3+3 1454 (36.4)  3+4 1056 (26.4)  4+3 640 (16.0)  >7 (8, 9, 10) 620 (15.5)  Unknown 225 (5.6) NCCN Risk Group  Low 1031 (25.8)  Favorable Intermediate 679 (17.0)  Unfavorable Intermediate 663 (16.6)  High 726 (18.2)  Unknown 896 (22.4)