Putative germline findings in tumor-only and liquid biopsy sequencing in veterans with aggressive prostate cancer.

Abstract

179 Background: Tumor-only and/or liquid-biopsy based Next Generation Sequencing (NGS)-based tests, which are routinely performed in metastatic prostate cancer patients, may identify putative germline mutations. The European Society of Medical Oncology (ESMO) made recommendations on findings which should be referred for germline genetic testing; however, it is unknown the burden of genetic testing referrals that may result from implementation of these recommendations. We therefore determined the frequency of putative germline findings in Veterans with metastatic prostate cancer who have undergone NGS-based sequencing of tumor and/or cell-free DNA (cfDNA) on the Foundation Medicine (FMI) platform. Methods: This is a retrospective analysis of Veterans with FMI NGS testing results reported from January 2019-February 2021 who had prostate cancer as the submitted diagnosis and metastatic diagnosis according to a VINCI natural language processing tool. Raw variant data were extracted from FMI reports and harmonized for variant annotation. Variants were annotated using ANNOVAR. Putative germline mutations were defined as 1) likely pathogenic or pathogenic (LP/P) by Clinvar annotation and VAF> 30%. Mutation rates are reported in genes recommended by ESMO to trigger referral for germline testing in all tumor types and all ages of diagnosis and proposed prostate cancer susceptibility genes ( ATM, BARD1, CHEK2). Results: 1,597 Veterans with metastatic prostate cancer underwent FMI NGS testing (63% White, 33% African American, 4% other). Median age was 66 years, with 78.6% of cases from men >60 years. Of 1,597 prostate cancer patients who underwent blood or tumor testing, n=85 (5.3%) had an LP/P mutation in an ESMO-guideline gene. When mutations in ATM, BARD1 and CHEK2 were added, n=133 (8.3%) of patients had an LP/P mutation. The most commonly identified putative germline findings were in BRCA2 (n=49 patients, 3.1%). 18 patients (1.1%) had mutations in other prostate cancer risk genes on the ESMO list ( BRCA1, MLH1, MSH2, MSH6, PMS2). 18 (1.1%) of patients had putative incidental germline findings, which included mutations in PALB2, BRIP1, RAD51C, RAD51D, SDHC. No putative incidental germline mutations were identified in RET, SDHA, SDHB, SDHD, TSC2, VHL. Comparing self-identified White versus self-identified Black patients, putative germline mutation rates were nearly the same in all ESMO-referral genes combined (8.2% vs 8.5%), BRCA2 (2.9% vs 3.0%), and ATM (2.4% vs 2.1%). Conclusions: While guidelines recommend that all veterans with metastatic prostate cancer undergo germline genetic testing, significant patient and system-level barriers continue to limit access to germline genetic testing for many Veterans. Tumor-only NGS testing, with a low rate of putative incidental findings, can help to prioritize which Veterans should be referred for germline genetic testing.