1391P Tumor-first mutation-specific risk approach to trigger germline testing in castration-resistant prostate cancer

Abstract

The prevalence of hereditary prostate cancer (PCa) in the Netherlands appears lower than previously reported, and routine germline testing is not advocated as standard of care. Current referral strategies are based on a positive family history (FH) for high-risk penetrating cancer predisposition genes, on presence of metastatic disease (DISCOVER-study), or on a tumor-first approach in patients (pts) with castration-resistant PCa (CRPC) with cascade germline testing in those with an alteration in predefined genes. Here we compare referral based on FH with the tumor-first approach. The PROMPT trial (NCT04746300) prospectively studies the impact of routine molecular tumor profiling with broad next-generation sequencing (NGS) in recently diagnosed CRPC pts. All results were discussed within the Radboudumc Molecular Tumor Board to guide precision medicine and for germline testing by geneticists per protocol. FH was taken at screening. The presence of familial and hereditary PCa by Dutch criteria for included pts was retrospectively assessed. High-risk homologous recombination deficiency (HRD) genes studied were BRCA1, BRCA2 and PALB2. Data on ATM and CHEK2 (lower-risk) will also be presented. In the 307 evaluable pts at least one pathogenic HRD alteration was found in 24 pts (8%), in BRCA1 (n=1), BRCA2 (n=21) and PALB2 (n=2) respectively. 17 pts (6%) were referred for germline testing; in 11 pts a germline variant was found. In 7/11 families the genetic predisposition was unknown, with pts not fulfilling Dutch referral criteria. FH was reported in 305 pts. Based on FH 53 pts would have been eligible for referral to clinical genetics and germline testing. In these pts, 48 pts did not have a pathogenic aberration in BRCA1/BRCA2 or PALB2 in tumor DNA. Based on reported FH, 18% of the pts would meet the Dutch criteria for genetic testing. In the majority of them the chance of a germline mutation is estimated to be low based on tumor test results, and 7 families with a germline mutation would have been missed. A tumor-first approach for high risk genes led to referral of 6%, with a germline variant in 53% of pts. Routine tumor-first DNA testing in CRPC efficiently identifies pts eligible for germline testing.