Abstract 678: Validation of a radiosensitivity molecular signature in breast cancer
Authors: Javier F. Torres-Roca, William J. Fulp, Yudi Pawitan, John Foekens, Marcel Smid, Vidya Kamath, Michelle Echevarria, Ji-Hyun Lee, Eleanor E. Harris, Jonas Bergh, Steven Eschrich
Journal: Cancer Research (2012)

Abstract Purpose: In previous studies we developed a radiosensitivity molecular signature that was clinically-validated in three independent datasets (rectal, esophageal and head and neck cancer) in 118 patients. In this study we test whether the radiosensitivity molecular signature predicts for clinical outcome in RT-treated breast cancer patients. Methods: The signature was tested in two previously published clinically-mature breast cancer datasets (n=503). Patients were treated at the Karolinksa University Hospital (n=159) and Erasmus Medical Center (n=344). Treatment and cohort details have been previously published 1, 2. The radiosensitivity signature (RSI) was applied as previously described 3, 4. Results: We examined whether there was any association between radiophenotype (as determined by the radiosensitivity signature) and clinical outcome in patients that underwent primary treatment with surgery and RT in the Karolinska dataset. As hypothesized, RS patients had an improved 5-yr RFS when compared with RR patients (RS vs. RR, 95% vs. 75%, p=0.0212). In contrast, there was no difference in outcome between RS and RR patients that did not receive RT (71% vs. 77%, p=0.6744) suggesting that RSI is RT-specific; i.e. a predictive biomarker. Importantly, the interaction term (RSIxRT) p value was 0.05, consistent with RSI being a predictive biomarker in this cohort. A total of 40 relapse events were observed in the Karolinska cohort (n=159) and 75% of these events were distant relapses. The main impact observed in the RS/RT population when compared with the RR/RT group is a decrease in the development of distant metastasis, consistent with the radiosensitivity signature being predictive of DM risk exclusively in RT-treated patients. To confirm this observation in a second and more clinically homogenous dataset, we tested the radiosensitivity signature (RSI) in the Erasmus dataset. RS patients that received RT had an improved 5-year DMFS when compared with RR patients (77% vs. 64%, p=0.04). In contrast and similar to the Karolinska dataset, the radiosensitivity signature did not identify any differences in patients treated without RT, consistent with RSI being RT-specific (n=62, HR=0.95, p=0.94). A multivariate analysis shows that in both datasets, RSI is the strongest predictive factor in RT treated patients (Karolinska, HR=6.43 p=0.07, Erasmus, HR=1.64, p=0.07). Conclusions: The radiosensitivity molecular signature is validated in five independent datasets in a total of 621 patients. To our knowledge this is the most clinically-validated molecular signature in radiation oncology. 1. Pawitan Y, Bjohle J, Amler L, et al. Breast Cancer Res. 2005;7(6):R953-964. 2. Smid M, Wang Y, Zhang Y, et al. Cancer Res. May 1 2008;68(9):3108-3114. 3. Eschrich S, Zhang H, Zhao H, et al. Int J Radiat Oncol Biol Phys. Oct 1 2009;75(2):497-505. 4. Eschrich SA, Pramana J, Zhang H, et al. Int J Radiat Oncol Biol Phys. Oct 1 2009;75(2):489-496. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 678. doi:1538-7445.AM2012-678