Introduction/Background Pathogenic germline BRCA1/2 alterations (gBRCA) are common in patients with high-grade serous ovarian carcinoma (HGSOC) and are generally associated with better chemotherapy response and longer 5-year-survival. However, fewer gBRCA1-carriers are alive at 10 years compared to non-carriers and gBRCA2-carriers. Clinicopathological and multi-omic features of HGSOC were compared in BRCA1/2-mutated patients with short and long-term survival to identify factors influencing clinical outcomes.

Methodology Whole-genome-sequencing, RNA-sequencing and clinicopathological analysis on primary HGSOC tumors from 35 advanced-stage BRCA1/2-mutant with short survival (≤3-years) was compared with data from 84 patients with >3-year survival (44 BRCA-mutant, 40 BRCA-wildtype), and 35 BRCA-wildtype patients with short survival. We also assessed clinicopathological features and tumor immune markers by multiplexed immunofluorescence in 293 and 146 gBRCA-carriers, respectively.

Results Prognostic features including residual disease, age, grade, FIGO stage, primary site, and BRCA type (BRCA1 vs BRCA2) could not explain short survival in BRCA-mutants relative to those with longer survival. Somatic mutation and neoantigen burden were equivalent between the two survival groups of BRCA-mutants, however the homologous recombination DNA repair deficiency (HRD) score was significantly higher in BRCA-mutants with long survival compared to those with short survival (73.6 vs 65.5, p=0.007). T-cell (PD1+,CD4+) density was associated with good outcomes in BRCA-mutants (p=0.003). Mutational signature clustering identified a group of BRCA-mutants characterised by short survival, low HRD-scores, and DNA copy number signature CN9 which is associated with increased leucocyte fraction and poor disease-specific survival. PIK3CA alterations were enriched in BRCA2-mutants with short survival (5/10, 50%, p=0.061).

Conclusion Survival in BRCA-mutants with HGSOC was associated with distinct mutational signatures, differential immune responses, somatic gene alterations, and differences in the extent of HRD. Integration of multi-omic data with clinical variables can enhance the accuracy of predictive models and inform alternative treatment options in patients predicted to have shorter survival.

Disclosures David D.L. Bowtell reports research support grants from AstraZeneca, Roche-Genentech and BeiGene outside the submitted work; also personal consulting fees from Exo Therapeutics, that are outside the submitted work. Anna DeFazio reports support grants and personal consulting fees from AstraZeneca outside the submitted work. All other authors declare that they have no conflicts of interest.