Comprehensive genomic profiling of matched primary prostate cancer tissue and cell-free DNA (cfDNA) to assess ontogeny of BRCA1/BRCA2 mutations.

166 Background: Both olaparib and rucaparib have recently been approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) with BRCA1/2 mutations (BRCAm). In the PROFOUND trial, 36.9% of men had either no tissue or tissue that was inadequate for genomic profiling (PMID: 32343890). A recent report suggests BRCAm may be an early event in the evolution of prostate cancer (PMID: 29662167). This suggests comprehensive genomic profiling (CGP) of primary prostate tissue may suffice to guide treatment selection, even years after tissue collection. Herein, we investigate the ontogeny of BRCAm by comparing CGP of matched primary prostate cancer tissue to CGP of cfDNA. Methods: Eligibility criteria included men diagnosed with metastatic prostate cancer that had matched CGP of both primary prostate cancer tissue and cfDNA. Genomic profiling was performed by CLIA certified laboratories. Only somatic mutations detectable by both platforms were used for concordance analysis. Results: We identified 198 patients that had matched CGP of primary prostate tissue and cfDNA. Thirteen men had a pathogenic BRCAm in at least one test. Of these 13 positive test for BRCAm, 2 were rearrangements, 1 copy number loss, and 5 were germline mutations. Both platforms tend to filter out germline alterations therefore, they were not included in the estimation of concordance. Overall somatic BRCAm concordance between primary prostate tissue and cfDNA was 196/198 (98%). Notably, no new BRCAm were identified in cfDNA with a median difference of 23.62 (0.1 - 232.2) months between prostate cancer tissue and cfDNA collection. Conclusions: There were no BRCAm detected only in cfDNA, suggesting that BRCAm is an early event in the ontogeny of prostate cancer. Based on this, it is unlikely that delaying sequencing would benefit patients with advanced prostate cancer. In the event that tissue is unavailable or inadequate for CGP, profiling of cfDNA is a valuable alternative for detection of BRCAm.