Importance
DNA damage response repair (DDR) gene mutations represent actionable alterations that can guide precision medicine strategies in men with advanced prostate cancer (PC). However, acquisition of contemporary tissue samples for molecular testing can be a barrier to deploying precision medicine approaches. We hypothesized that DDR alterations represent truncal events in PC and that primary tissue would reflect mutations found in cell-free circulating tumor (ctDNA) and/or metastatic tissue. OBJECTIVE: To assess concordance in DDR gene alterations between primary PC and metastases or ctDNA specimens.
Methods
Patients were included if a DDR pathway mutation was detected in metastatic tissue or ctDNA and primary tissue sequencing was available for comparison. Sequencing data from three cohorts were analyzed: (1) FoundationOne; (2) University of Washington (UW-OncoPlex or SU2C/PCF International Dream Team sequencing pipelines); and (3) University of Washington rapid autopsy series. Only pathogenic somatic mutations were included and we required 30 days between primary tumor tissue and ctDNA/ metastatic tissue acquisition. Clonal hematopoiesis of indeterminant potential (CHIP) and germline events were adjudicated by an expert molecular pathologist and excluded. DDR gene mutations detected in primary prostate tissue matched with metastatic tissue and/or ctDNA findings.
Results
Paired primary and ctDNA/metastatic samples were sequenced from 72 individuals with known DDR alterations. After excluding ctDNA studies where only CHIP and/or germline events (N=21) were observed, 51 subjects remained and were included in the final analysis. The median time from acquisition of primary tissue to acquisition of ctDNA or tumor tissue was 55 months (range: 5-193 months). Concordance in DDR gene mutation status across samples was 84% (95% CI: 71-92%). Rates of concordance between metastatic-primary and ctDNAprimary pairs were similar when CHIP cases were excluded. BRCA2 reversion mutations associated with resistance to PARP inhibitors and platinum chemotherapy were detected in ctDNA from two subjects.
Discussion
Primary prostate tissue accurately reflected the mutational status of actionable DDR genes in metastatic tissue, consistent with DDR alterations being truncal in most cases. After excluding likely CHIP events, ctDNA profiling accurately captured these DDR mutations, while also detecting reversion alterations that may suggest resistance mechanisms.
