HRDetect in Ovarian Carcinoma: Stratification and Therapeutic Implications.

In this study, we show that comprehensive DNA profiling using whole genome sequencing (WGS) can offer novel insights into ovarian carcinoma (OC). First, using WGS of 185 OC with HRDetect profiling, a mutational signature-based algorithm for homologous recombination repair deficiency (HRD), we found that patients with HRDetect-high OC had significantly better overall survival, with a median of 6.2 years compared to 4.1 years for those with lower score OC. Second, the rest of the OCs are not simply non-HRD - some carry distinguishing rearrangement signatures that are strongly prognostic. Third, in an independent cohort of 77 patients, we demonstrate predictive value; HRDetect-high patients exhibited better responses to PARP inhibitors (PARPi) (median progression-free survival of 11.1 months versus 7.1 months; overall response rate of 54% versus 22.5%). Critical next steps include fine-tuning therapeutic vulnerabilities associated with the diverse rearrangement signatures, and harnessing the full potential of WGS for OC clinical trial stratification. Statement of SignificanceThis study shows the HRDetect strongly predicts overall survival and PARPi response in ovarian carcinoma. Furthermore, we reveal that non-HRD tumors harbor distinct rearrangement signatures that confer significant prognostic value, underscoring the potential of WGS to refine patient stratification and guide tailored therapeutic strategies in OC.