Prevalence of homologous recombination deficiency (HRD)-related signatures indicates that a wider range of prostate cancer patients may benefit from PARP-inhibitor therapy

Abstract

Abstract Background Prostate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP-inhibition and platinum-based chemotherapy. Currently targeted sequencing of key HR genes serves as an indicator of homologous recombination deficiency (HRD) in prostate cancer. It is well known, however, that other mechanisms, such as suppression of expression, rare mutations of HR-related genes can also cause HRD. Methods HRD levels can be estimated using various mutational, genomic signatures derived from next-generation sequencing data. We used this approach to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. Whole genome (n = 311) and whole exome sequencing data (n = 498) of both primary and metastatic prostate adenocarcinomas (PRAD) were analyzed. Results Known BRCA-deficient samples showed robust signs of HR-deficiency associated mutational signatures. HRD-patterns were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR-related genes. The signs HRD present low intratumor heterogeneity and in most cases, the metastasis’s HRD-status is similar to the primary tumor’s. Patients with HRD signatures had a significantly worse prognosis than patients without signs of HRD. Conclusions Based on the HRD associated mutational and genomic scar signatures, 5-8 % of prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations). The prioritization of these patients for clinical trials, extending PARP-inhibitor therapy to all cases with HRD associated mutational signatures, even to those without BRCA1/2 mutations, will likely increase the efficacy of this treatment. Legal entity responsible for the study The authors. Funding Research and Technology Innovation Fund (KTIA_NAP_13-2014-0021 to Z.S.); Breast Cancer Research Foundation (BCRF-17-156 to Z.S.) and the Novo Nordisk Foundation Interdisciplinary Synergy Programme Grant (NNF15OC0016584 to Z.S.), Department of Defense through the Prostate Cancer Research Program (award number is W81XWH-18-2-0056) to Z.S. and M.F. The Danish Cancer Society grant (R90-A6213 to MK). Z.S. and J.B. was supported by Velux Foundation 00018310 grant. Disclosure Z. Szallasi: Licensing / Royalties: Inventor on a patent used in the myChoice HRD assay: Myriad. All other authors have declared no conflicts of interest.