Analysis of <i>BRCA1/2</i> pathogenic variants, homologous recombination deficiency, and MYC amplification in the outcomes of advanced ovarian cancer.

e17585 Background: The association between BRCA1/2 pathogenic variants (PVs) and ovarian cancer is well established as these mutations give rise to homologous recombination deficiency (HRD) leading to DNA damage. However, the roles of BRCA1/2 PVs, HRD, and MYC amplifications in survival outcomes of patients with advanced epithelial ovarian carcinoma remain incompletely understood. Methods: Our study examines a large cohort of patients (n = 1060) with advanced epithelial ovarian cancers with genomic profiling performed using next-generation sequencing (StrataNGS). Cox regression modeling was used to examine the association between BRCA1/2 PVs, HRD, and MYC amplifications with overall survival (OS), adjusting for covariates, including age, race/ethnicity, performance status, Charlson Comorbidity Index, and other genomic alterations. Results: Our study cohort consisted of 924 patients with high grade serous ovarian cancer (HGSOC), among which 10.7% had BRCA1 PV and 5.6% had BRCA2 PV. BRCA1 patients had a lower mean age of 56 compared to those with BRCA2 and BRCA1/2 wild type (WT) who had mean ages 64 and 65, respectively (p-value &lt;1e-05). Asian patients compared with White patients had better OS (hazard ratio [HR] = 0.38, [95% confidence interval [CI], 0.17-0.84]). Other racial and ethnic groups did not show significantly different OS compared with White patients. Approximately 87.6% of patients with BRCA1 PV, 76% of patients with BRCA2 PV, and 28.9% of patients with BRCA1/2 WT were exposed to Poly(ADP-ribose) polymerase inhibitor (PARPi). By Kaplan-Meier plots, BRCA1 PV versus WT (42.7 versus 31.6 months, log-rank p = 0.030) and BRCA2 PV versus WT (60.6 versus 31.6 months, log-rank p = 0.019) were associated with superior survival, with HR of 0.63, [95% CI, 0.48-0.83] for combined BRCA1 and BRCA2 PVs. All HRD-positive tumors compared to HRD-negative tumors had superior OS (HR = 0.73, [95% CI, 0.56-0.95]). MYC amplification co-occurred in 12.4% of patients with BRCA1 and 0% of BRCA2 . Within the BRCA1 sub-cohort, MYC amplification was associated with worse OS (HR = 2.80, [95% CI, 1.06-7.38]). Conclusions: Our data confirmed improved OS associated with BRCA1/2 PVs and HRD, likely due to both the biological effect of the genomic alterations and PARPi treatment. Our data suggested that MYC amplification, which only occurred in the BRCA1 sub-cohort, was associated with worse OS. Our findings may aid in prognostic stratification in clinical practice and provide insight for further investigation into the oncogenesis of ovarian carcinoma.