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Quantitative imaging of RAD51 expression as a marker of platinum resistance in ovarian cancer
- Hoppe, Michal M;
- Jaynes, Patrick;
- Wardyn, Joanna D;
- Upadhyayula, Sai Srinivas;
- Tan, Tuan Zea;
- Lie, Stefanus;
- Lim, Diana GZ;
- Pang, Brendan NK;
- Lim, Sherlly;
- Yeong, Joe PS;
- Karnezis, Anthony;
- Chiu, Derek S;
- Leung, Samuel;
- Huntsman, David G;
- Sedukhina, Anna S;
- Sato, Ko;
- Topp, Monique D;
- Scott, Clare L;
- Choi, Hyungwon;
- Patel, Naina R;
- Brown, Robert;
- Kaye, Stan B;
- Pitt, Jason J;
- Tan, David SP;
- Jeyasekharan, Anand D
- et al.
Published Web Location
https://doi.org/10.15252/emmm.202013366Abstract
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 RAD51-High 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 RAD51-High EOC. The qIHC approach is generalizable to other proteins with a continuum instead of discrete/bimodal expression.
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