Data from RAD51 Foci as a Biomarker Predictive of Platinum Chemotherapy Response in Ovarian Cancer

Abstract

<div>AbstractPurpose:<p>To determine the ability of RAD51 foci to predict platinum chemotherapy response in high-grade serous ovarian cancer (HGSOC) patient-derived samples.</p>Experimental Design:<p>RAD51 and γH2AX nuclear foci were evaluated by immunofluorescence in HGSOC patient-derived cell lines (<i>n</i> = 5), organoids (<i>n</i> = 11), and formalin-fixed, paraffin-embedded tumor samples (discovery <i>n</i> = 31, validation <i>n</i> = 148). Samples were defined as RAD51-High if >10% of geminin-positive cells had ≥5 RAD51 foci. Associations between RAD51 scores, platinum chemotherapy response, and survival were evaluated.</p>Results:<p>RAD51 scores correlated with <i>in vitro</i> response to platinum chemotherapy in established and primary ovarian cancer cell lines (Pearson <i>r</i> = 0.96, <i>P</i> = 0.01). Organoids from platinum-nonresponsive tumors had significantly higher RAD51 scores than those from platinum-responsive tumors (<i>P</i> < 0.001). In a discovery cohort, RAD51-Low tumors were more likely to have a pathologic complete response (RR, 5.28; <i>P</i> < 0.001) and to be platinum-sensitive (RR, ∞; <i>P</i> = 0.05). The RAD51 score was predictive of chemotherapy response score [AUC, 0.90; 95% confidence interval (CI), 0.78–1.0; <i>P</i> < 0.001). A novel automatic quantification system accurately reflected the manual assay (92%). In a validation cohort, RAD51-Low tumors were more likely to be platinum-sensitive (RR, ∞; <i>P</i> < 0.001) than RAD51-High tumors. Moreover, RAD51-Low status predicted platinum sensitivity with 100% positive predictive value and was associated with better progression-free (HR, 0.53; 95% CI, 0.33–0.85; <i>P</i> < 0.001) and overall survival (HR, 0.43; 95% CI, 0.25–0.75; <i>P</i> = 0.003) than RAD51-High status.</p>Conclusions:<p>RAD51 foci are a robust marker of platinum chemotherapy response and survival in ovarian cancer. The utility of RAD51 foci as a predictive biomarker for HGSOC should be tested in clinical trials.</p></div>