Journal
CLINICAL CANCER RESEARCH
Volume 18, Issue 18, Pages 5134-5143Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-12-0891
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Funding
- NIH [R21CA101355/R21CA135620]
- US Army Medical Research and Materiel Command, National Functional Genomics Center [170220051]
- Bankhead-Coley Foundation [09BB-22]
- Merck and Bristol-Myers-Squibb
- Swedish Cancer Society
- Stockholm Cancer Society
- King Gustav V Jubilee Fund
- Swedish Research Council
- Stockholm City Council, Karolinska Institutet and Stockholm County Council Research Strategy Committee
- Swedish Breast Cancer Association (BRO)
- Karolinska Institutet Research Funds
- Marit and Hans Rausing's Initiative against Breast Cancer
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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 = 159) and Erasmus Medical Center (n = 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%, P = 0.0212), but there was no difference between RS/RR patients treated without RT (71% vs. 77%, P 0.6744), consistent with RSI being RT-specific (interaction term RSI x RT, P = 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 = 0.0409), but no difference was observed in patients treated without RT (RS vs. RR, 80% vs. 81%, P = 0.9425). Multivariable analysis showed RSI is the strongest variable in RT-treated patients (Karolinska, HR 5.53, P = 0.0987, Erasmus, HR = 1.64, P = 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 ER+ patients (Erasmus, multivariable analysis, HR = 2.64, P = 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. (c) 2012 AACR.
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