Genomic landscape of advanced prostate cancer patients with BRCA1 versus BRCA2 mutations as detected by comprehensive genomic profiling (CGP) of cell-free DNA (cfDNA)

BRCA1-mutated prostate cancer has been shown to be less responsive to poly (ADP-ribose) polymerase (PARP) inhibitors as compared to BRCA2-mutated prostate cancer. The reason for this differential response is not clear. We hypothesized this differential sensitivity to PARP inhibitors may be explained by distinct genomic landscapes of BRCA1 versus BRCA2 co-segregating genes. Patients with advanced prostate cancer who underwent CGP of cfDNA by a CLIA-certified laboratory (Guardant360 testing) between 11/2016 to 8/2020 were eligible. First available cfDNA CGP results from consecutive patients were evaluated for the presence of BRCA1 and/or BRCA2 mutations. All variants of unknown significance were excluded from the analysis. Differences in the genomic landscape of co-segregating genes was investigated by Fisher’s exact test and probabilistic graphical models (PGMs). In a large dataset of 7,707 men with advanced prostate cancer, 614 men harbored BRCA1 and/or BRCA2 alterations. Results summarized in the table. BRCA1 was significantly associated with 6 other genes, while BRCA2 was not significantly associated with any gene. These findings suggest BRCA2 may be the main driver mutation, while BRCA1 mutations tend to co-segregate with mutations in other molecular pathways contributing to prostate cancer progression.Table: 1383PGeneBRCA1+ p-valueBRCA2+ p-valueERBB20.001NSNOTCH10.002NSARID1A0.008NSAKT10.011NSMTOR0.014NSEGFR0.048NSNS = not significant; Fisher’s exact p-values after Bonferroni correction. Open table in a new tab NS = not significant; Fisher’s exact p-values after Bonferroni correction. These hypothesis generating data may explain the increased sensitivity of PARP inhibitors to BRCA2 mutations due to fewer concurrent resistance pathways and guide towards development of combinatorial drug regimens in those with BRCA1 mutation. The limitations of this study include the lack of clinical annotation such as the disease state and treatment exposure.