Underdiagnosis of germline genetic prostate cancer: Are genetic testing guidelines an aid or an impediment?

Abstract

10504Background: Pathogenic/likely pathogenic (P/LP) germline genetic variants are estimated to occur in 10-15% of all prostate cancer (PCa) patients. However, genetic testing for PCa patients is underutilized, partially due to complicated and restrictive testing guidelines developed at a time when the cost of testing was high. We conducted a study based in community urology clinics to determine the incidence of P/LP variants in PCa patients who met and did not meet the NCCN 2019 PCa germline genetic testing criteria. Methods: An IRB-approved, multicenter, prospective registry was initiated with 15 community and academic urologists nationwide. Eligibility criteria included patients with a PCa diagnosis unselected for personal or family history, stage or histology who had not been previously tested. Consecutive patients ages 18-90 were consented and underwent an 84-gene germline panel test. HIPAA-compliant electronic case report forms distributed to clinician collected information on patient diagnoses, NCCN testing criteria, and results-based recommendations. Results: To date, 640 enrolled patients have genetic testing results available. Overall, 69 (10.8%) patients had 72 P/LP variants detected, 15% of which were in BRCA1/2. Of the 532 patients for whom we have clinician-reported data, 293 (55%) met NCCN criteria and 239 (45%) did not. Median age was 70 (range 44-90). Overall, 11.1% (59/532) of patients with clinician-reported data had a P/LP variant. 36 (12.3%) of patients who met NCCN criteria and 23 (9.6%) of patients who did not meet criteria had a P/LP variant. The difference in P/LP rate between the two groups was not statistically significant (p=0.33). If only a conservative 12-gene PCa panel was considered, P/LP yield was 5.5% (29/532), with 8 (28%) of these patients missed by guidelines. Stratification by self-reported ethnicity was: 76% White/Caucasian (52 patients w/ P/LP), 18% Black/African American (2 patients w/ P/LP), and <5% each of Hispanic or Asian. Conclusions: There was no statistically significant difference in the yield of P/LP variants between patients who met and those who did not meet NCCN PCa guidelines, reinforcing that a significant number of P/LP variants are missed if NCCN guidelines are required for genetic testing. Expanded panel testing yields more medically actionable P/LP variants than testing BRCA1/2 alone or PCa panels with 12 genes. While 18% of the cohort was Black/African American, there was a lower P/LP rate (2%) relative to other groups, indicating that more research is needed to understand genetic variation in underrepresented populations with PCa.