Type 1 Receptor Tyrosine Kinase Profiles Identify Patients With Enhanced Benefit From Anthracyclines in the BR9601 Adjuvant Breast Cancer Chemotherapy Trial

Purpose Patients with early breast cancer who receive anthracycline-containing chemotherapy experience improved relapse-free (RFS) and overall survival (OS) compared with those who receive non anthracycline-containing chemotherapy. Such benefit, however, may be restricted to women whose tumors have specific molecular characteristics. We tested the hypothesis that HER2, epidermal growth factor receptor (EGFr)/HER1, HER3, Ki67, and topoisomerase II alpha expression are predictive of outcome after anthracycline-based chemotherapy. Methods Tissue microarrays from 322 of 374 women in the BR9601 trial, which compared cyclophosphamide, methotrexate, and fluorouracil (CMF) with epirubicin followed by CMF (epi-CMF), were analyzed for HER1, 2, 3, 4; Ki67; and topoisomerase II alpha protein expression and for HER2/topoisomerase II alpha gene amplification. Their relationships to RFS and OS were investigated, and multiple regression analysis was used to identify interactions. Results A significant interaction was seen between tumors with normal HER1, HER2 fluorescent in situ hybridization (FISH), or HER3 levels and the enhanced benefit from epi-CMF versus CMF for RFS (hazard ratio [HR], 0.36; HR for overexpressed HER1 or HER2 FISH or HER3, 0.92; P = .035) and for OS (HR, 0.30; HR for overexpressed HER1 or HER2 FISH or HER3), 0.98; P = .023). Neither Ki67 nor TII alpha expressions or gene alterations showed clear predictive value for benefit from the addition of the anthracycline. Conclusion Patients with HER2 amplified and those with HER1, HER2 FISH, or HER3-positive tumors did not benefit from the addition of epirubicin to CMF. Conversely, patients with HER2 nonamplified and HER1 through HER3-negative tumors showed significantly increased RFS and OS rates when treated with epi-CMF compared with CMF. J Clin Oncol 26: 5027-5035. (C) 2008 by American Society of Clinical Oncology