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. 2012 Sep 15;18(18):5134-43.
doi: 10.1158/1078-0432.CCR-12-0891. Epub 2012 Jul 25.

Validation of a radiosensitivity molecular signature in breast cancer

Steven A Eschrich  1 , William J Fulp, Yudi Pawitan, John A Foekens, Marcel Smid, John W M Martens, Michelle Echevarria, Vidya Kamath, Ji-Hyun Lee, Eleanor E Harris, Jonas Bergh, Javier F Torres-Roca
Affiliations

Validation of a radiosensitivity molecular signature in breast cancer

Steven A Eschrich et al. Clin Cancer Res. .

Abstract

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 × 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.

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Conflict of interest statement

Conflict of Interest: JTR and SAE are named as inventors in one awarded and two pending patent applications regarding the technology described. Both are c0-founders and officers of Cvergenx, Inc which holds an exclusive license for the commercialization of the technology

Figures

Figure 1
Figure 1. Association of the Radiosensitivity Signature with Clinical Outcome (Karolinksa dataset)
(A) RSI identifies a radiosensitive population (25th percentile) that has an improved 5-yr RFS in patients treated with surgery (lumpectomy/ segmentectomy) and RT. An interaction model between RSI and RT is consistent with RSI being RT-specific (p=0.05). (B) Kaplan-Meier curves of predicted radiosensitive and radioresistant patients treated with mastectomy and no RT. Patients at risk at different time points are indicated
Figure 2
Figure 2. Association of the Radiosensitivity Signature with Distant Metastasis-Free Survival (Erasmus dataset)
A) Kaplan-Meier curves of 282 patients treated with surgery + RT. (B) Kaplan-Meir curves of 62 patients treated with mastectomy alone. Patients at risk at different time points are indicated
Figure 3
Figure 3. Association of the Radiosensitivity Signature with Distant Metastasis-Free Survival in in RT-treated ER+ Subset Patients in the Erasmus dataset
A) Kaplan-Meier curves of 181 RT-treated ER+ patients. B) Kaplan-Meier curves of 101 RT-treated ER− patients. Patients at risk at different time points are indicated
See this image and copyright information in PMC

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