Personalized Medicine and Imaging Development and Validation of a Gene Profile Predicting Benefit of Postmastectomy Radiotherapy in Patients with High-Risk Breast Cancer: A Study of Gene Expression in the DBCG82bc Cohort Trine Tramm 1 , Hayat Mohammed 2 , Simen Myhre 3,4,5 , Marianne Kyndi 1 , Jan Alsner 1 , Anne-Lise Børresen-Dale 3,4 , Therese Sørlie 3,4 , Arnoldo Frigessi 2 , and Jens Overgaard 1 Abstract Purpose: To identify genes predicting benefit of radiotherapy in patients with high-risk breast cancer treated with systemic therapy and randomized to receive or not receive postmastectomy radiotherapy (PMRT). Experimental Design: The study was based on the Danish Breast Cancer Cooperative Group (DBCG82bc) cohort. Gene-expression analysis was performed in a training set of frozen tumor tissue from 191 patients. Genes were identified through the Lasso method with the endpoint being locoregional recurrence (LRR). A weighted gene-expression index (DBCG-RT profile) was calculated and transferred to quantitative real-time PCR (qRT-PCR) in corresponding formalin-fixed, paraffin-embedded (FFPE) sam- ples, before validation in FFPE from 112 additional patients. Results: Seven genes were identified, and the derived DBCG-RT profile divided the 191 patients into "high LRR risk" and "low LRR risk" groups. PMRT significantly reduced risk of LRR in "high LRR risk" patients, whereas "low LRR risk" patients showed no additional reduction in LRR rate. Technical transfer of the DBCG-RT profile to FFPE/qRT-PCR was successful, and the predictive impact was successfully validated in another 112 patients. Conclusions: A DBCG-RT gene profile was identified and validated, identifying patients with very low risk of LRR and no benefit from PMRT. The profile may provide a method to individualize treatment with PMRT. Clin Cancer Res; 20(20); 5272–80. Ó2014 AACR. Introduction Radiotherapy is known to improve locoregional control and disease-free survival (DFS), and shows a long-term improvement in overall survival (OS) in high-risk patients suffering from breast cancer (1). Postmastectomy radio- therapy (PMRT) is currently administered according to clinicopathologic criteria, defining the patient’s a priori risk of subsequent locoregional recurrence (LRR), and not according to individual prediction of the likelihood of benefit from radiotherapy. Results from the randomized trials, Danish Breast Cancer Cooperative Group (DBCG) protocol 82bc and the British Columbia Randomized Radiation trial, showed a substan- tial OS benefit after PMRT even in patients with 1 to 3 positive nodes (2–4), and this has been supported by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) 2014 overview (5) as well. Recommendation for PMRT is especially consolidated in patients estimated to have a high risk of LRR (e.g., involvement of 4 lymph nodes or tumor size > 5 cm; refs. 6, 7). The most recent St. Gallen Consensus (2011; ref. 8) further supports the admin- istration of PMRT to patients <45 years of age with 1 to 3 positive nodes, and to patients of all ages if 1 to 3 positive lymph nodes are accompanied by evidence of lymphovas- cular invasion by histology. The beneficial effect of PMRT is, however, suspected to be more heterogeneous than the conventional clinicopatho- logic parameters are capable of describing. Gene-expression profiles predictive of response to, e.g., docetaxel (9), and 1 Department of Experimental Clinical Oncology, Aarhus University Hospi- tal, Aarhus, Denmark. 2 Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. 3 Department of Genetics, Institute of Cancer Research, Oslo University Hospital, Radium- hospitalet, Norway. 4 K-G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. 5 Atlantis Medical University College, Oslo, Norway. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). T. Tramm and H. Mohammed share first authorship. A. Frigessi and J. Overgaard share last authorship. Corresponding Author: Trine Tramm, Aarhus University Hospital, Nørrebrogade 44, Building 5, 8000 Aarhus C, Denmark. Phone: 004578462602; Fax: 004586197109; E-mail: tramm@oncology.au.dk doi: 10.1158/1078-0432.CCR-14-0458 Ó2014 American Association for Cancer Research. Clinical Cancer Research Clin Cancer Res; 20(20) October 15, 2014 5272 on October 27, 2021. © 2014 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from Published OnlineFirst August 22, 2014; DOI: 10.1158/1078-0432.CCR-14-0458