Functional homologous recombination assay on FFPE specimens of advanced high-grade serous ovarian cancer predicts clinical outcomes

Deficiency in homologous recombination (HR), a key DNA repair pathway, is a defining characteristic of many high-grade serous ovarian 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-naïve 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.