Predictive Biomarkers and Personalized Medicine Validation of a Radiosensitivity Molecular Signature in Breast Cancer

Purpose: Previously, we developed a radiosensitivity molecular signature [radiosensitivity index (RSI)] that was clinically validated in 3 independent datasets (rectal, esophageal, and head and neck) in 118 patients. Here, we test RSI in radiotherapy (RT)-treated breast cancer patients. Experimental Design: RSI was tested in 2 previously published breast cancer datasets. Patients were treated at the Karolinska University Hospital (n 1⁄4 159) and Erasmus Medical Center (n 1⁄4 344). RSI was applied as previously described. Results: We tested RSI in RT-treated patients (Karolinska). Patients predicted to be radiosensitive (RS) had an improved 5-year relapse-free survival when compared with radioresistant (RR) patients (95% vs. 75%,P1⁄40.0212), but therewas nodifference betweenRS/RRpatients treatedwithout RT (71%vs. 77%,P1⁄4 0.6744), consistent with RSI being RT-specific (interaction term RSI RT, P 1⁄4 0.05). Similarly, in the Erasmus dataset, RT-treated RS patients had an improved 5-year distant metastasis-free survival over RR patients (77% vs. 64%, P 1⁄4 0.0409), but no difference was observed in patients treated without RT (RS vs. RR, 80% vs. 81%, P 1⁄4 0.9425). Multivariable analysis showed RSI is the strongest variable in RT-treated patients (Karolinska, HR 1⁄4 5.53, P 1⁄4 0.0987, Erasmus, HR 1⁄4 1.64, P 1⁄4 0.0758) and in backward selection (removal a of 0.10), RSI was the only variable remaining in the final model. Finally, RSI is an independent predictor of outcome in RT-treated ERþ patients (Erasmus, multivariable analysis, HR1⁄4 2.64, P1⁄4 0.0085). Conclusions: RSI is validated in 2 independent breast cancer datasets totaling 503 patients. Including prior data, RSI is validated in 5 independent cohorts (621 patients) and represents, to our knowledge, the most extensively validated molecular signature in radiation oncology. Clin Cancer Res; 18(18); 5134–43.