title: Validation of a radiosensitivity molecular signature in breast cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 × 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 α 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.
authors: Department of Bioinformatics, H Lee Moffitt Cancer Center, Tampa, Florida 33612, USA.
authors: Steven A
authors: SA
authors: Eschrich
authors: William J
authors: WJ
authors: Fulp
authors: Yudi
authors: Y
authors: Pawitan
authors: John A
authors: JA
authors: Foekens
authors: Marcel
authors: M
authors: Smid
authors: John W M
authors: JW
authors: Martens
authors: Michelle
authors: M
authors: Echevarria
authors: Vidya
authors: V
authors: Kamath
authors: Ji-Hyun
authors: JH
authors: Lee
authors: Eleanor E
authors: EE
authors: Harris
authors: Jonas
authors: J
authors: Bergh
authors: Javier F
authors: JF
authors: Torres-Roca
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000532:radiotherapy*; D005260:Female; D006801:Humans; D008593:Menopause; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011836:Radiation Tolerance / Q000235:genetics*; D059467:Transcriptome; D016896:Treatment Outcome