Germline sequencing in men with metastatic castration-resistant prostate cancer from the BARCODE2 study reveals a wide range of pathogenic variants in DNA repair genes

Abstract

<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>The presence of germline mutations plays an increasingly important role in risk assessment and treatment of prostate cancer (PrCa). Screening for high-risk mutations in subsets of patients is becoming routine. We explore the prevalence of germline genetic mutations in men with metastatic castration-resistant prostate cancer (mCRPC) recruited to the BARCODE2 trial.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>The BARCODE2 trial is a two-part study investigating the response to carboplatin chemotherapy in mCRPC patients carrying a germline variant in a DNA repair gene (DRG). We report interim data from Part 1, in which participants are recruited for germline genetic testing using a customised next-generation sequencing panel consisting of 115 genes.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>These interim results (<jats:italic>N</jats:italic> = 220) demonstrate a similar frequency of germline DRG variants in mCRPC patients compared with previously published data (15% detection rate). No significant clinical differences were identified between all carriers and non-carriers, though <jats:italic>BRCA2/ATM</jats:italic> carriers were found to have a shorter time to mCRPC diagnosis.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Germline pathogenic/likely pathogenic (P/LP) variants in <jats:italic>BRCA2 and ATM</jats:italic> genes are associated with a shorter time to progression and rarer P/LP variants in other DRG genes may play a role in mCRPC. This justifies the use of routine screening of men with advanced PrCa for germline variants and supports the need for an expanded panel test.</jats:p> </jats:sec>