Quantitative imaging of RAD51 expression as a marker of platinum resistance in Ovarian Cancer

Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A-priori identification of platinum-resistance is therefore crucial to improve on standard first-line carboplatin-paclitaxel treatment. The DNA repair pathway Homologous Recombination (HR) repairs platinum-induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK-compliant study of pre-treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein-expression in-situ. In a discovery cohort (n=284), RAD51-High tumours had shorter progression-free and overall survival compared to RAD51-Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin-monotherapy SCOTROC4 clinical trial cohort (n=264), and was predominantly noted in HR-proficient cancers (Myriad HRDscore<42). Interestingly, overexpression of RAD51 modified expression of immune-regulatory pathways in-vitro, while high-RAD51 tumours showed exclusion of cytotoxic-T-cells in-situ. Our findings highlight RAD51 expression as a determinant of platinum resistance, and suggest possible roles for therapy to overcome immune exclusion in high-RAD51 EOC. The qIHC approach is generalizable to other proteins with a continuum instead of discrete/bimodal expression.