Benchmarking homologous recombination deficiency algorithms for prediction of clinical outcome in ovarian cancer

Abstract Homologous recombination deficiency (HRD) is a predictive biomarker for response to platinum-based chemotherapy in ovarian cancer. In this retrospective study, we benchmarked three HRD detection algorithms - CHORD, ShallowHRD, and OvaHRDscar - alongside BRCA1/2 mutation status in a cohort of 100 patients with high-grade serous ovarian carcinoma (HGSC). HRD status was derived from whole genome sequencing of tumor/normal samples, and progression-free survival (PFS) was used as the primary endpoint. All three HRD algorithms showed a statistically significant association with improved PFS. In multivariate Cox regression models adjusted for age, FIGO stage, tissue type, and neoadjuvant chemotherapy, HRD-positive status was significant associated with reduced hazard of progression or death: OvaHRDscar (HR = 0.41, 95% CI: 0.25–0.67), ShallowHRD (HR = 0.50, 95% CI: 0.31–0.79), and CHORD (HR = 0.47, 95% CI: 0.24–0.94). In contrast, BRCA1/2 mutation status did not show a significant association (HR = 0.64, 95% CI: 0.35–1.16). These findings support that HRD algorithms may aid in the diagnostic assessment of HRD and support broader genomic profiling to enhance clinical decision-making. Future studies should focus on refining algorithm thresholds and validating these results in larger, multi-center cohorts to facilitate clinical translation. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study received no external funding. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study has been approved by the Danish National Committee on Health Research Ethics (Reference number: 2114546). The project has, according to the General Data Protection Rule (GDPR), been registered at the North Denmark Region's list of projects handling person sensitive data (Reference number: F2022-016). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Statement Data generated during the current study are not publicly available, as they contain information that could compromise the privacy of the research participants. However, they are available from the corresponding author upon reasonable request and following review and approval by the Danish Health Research Ethics Committee.