Deficiency in homologous recombination (HR), a key DNA repair pathway, is a defining characteristic of many tubo-ovarian high-grade serous carcinomas (HGSC) and a major determinant of therapy outcomes. Patients with HR-deficient (HRD) tumors are more sensitive to DNA damaging platinum-based chemotherapy and HR deficiency also confers sensitivity to PARP inhibitors. While PARP inhibitors are highly effective in some patients, they are expensive and not without side effects, thus it is imperative to identify patients most likely to benefit from them. We set out to develop a clinically feasible assay for identifying functionally HRD tumors based on the detection of RAD51, a key HR protein. Our functional HR assay can be performed on FFPE tumor sample sections obtained from both treatment-naive and neoadjuvant chemotherapy treated HGSC patients. We show that the functional HR test predicts key clinical outcomes, including platinum-free survival and overall survival after PARPi treatment. Our results indicate that RAD51-based HRD testing has great potential to predict platinum and PARPi sensitivity in the clinical setting.

The authors have declared no competing interest.

This study was funded by the Sigrid Juselius Foundation, Finnish cancer society, Academy of Finland, AstraZeneca and the European Union Horizon 2020 research and innovation program.

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:

Ethics committee of Varsinais-Suomen Sairaanhoitopiiri (Hospital District of Southwest Finland) gave ethical approval for this work. Ethics committee of Helsingin ja Uudenmaan Sairaanhoitopiiri (Hospital District of Helsinki and Uusimaa) gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors.