Predictive Biomarkers and Personalized Medicine Responsiveness of Intrinsic Subtypes to Adjuvant Anthracycline Substitution in the NCIC.CTG MA.5 Randomized Trial

Purpose: Recent studies suggest that intrinsic breast cancer subtypesmay differ in their responsiveness to specific chemotherapy regimens. We examined this hypothesis on NCIC.CTG MA.5, a clinical trial randomizing premenopausal women with node-positive breast cancer to adjuvant CMF (cyclophosphamide-methotrexate-fluorouracil) versus CEF (cyclophosphamide-epirubicin-fluorouracil) chemotherapy. Experimental Design: Intrinsic subtype was determined for 476 tumors using the quantitative reverse transcriptase PCR PAM50 gene expression test. Luminal A, luminal B, HER2-enriched (HER2-E), and basallike subtypes were correlated with relapse-free survival (RFS) and overall survival (OS), estimated using Kaplan–Meier plots and log-rank testing. Multivariable Cox regression analyses determined significance of interaction between treatment and intrinsic subtypes. Results: Intrinsic subtypes were associated with RFS (P1⁄4 0.0005) andOS (P < 0.0001) on the combined cohort. The HER2-E showed the greatest benefit from CEF versus CMF, with absolute 5-year RFS and OS differences exceeding 20%,whereas therewas a less than2%difference for non–HER2-E tumors (interaction test P 1⁄4 0.03 for RFS and 0.03 for OS). Within clinically defined Her2þ tumors, 79% (72 of 91) were classified as the HER2-E subtype by gene expression and this subset was strongly associated with better response to CEF versus CMF (62% vs. 22%, P 1⁄4 0.0006). There was no significant difference in benefit between CEF and CMF in basal-like tumors [n1⁄4 94; HR, 1.1; 95% confidence interval (CI), 0.6–2.1 for RFS and HR, 1.3; 95% CI, 0.7–2.5 for OS]. Conclusion:HER2-E strongly predicted anthracycline sensitivity. The chemotherapy-sensitive basal-like tumors showed no added benefit for CEF over CMF, suggesting that nonanthracycline regimens may be adequate in this subtype although further investigation is required.Clin Cancer Res; 18(8); 2402–12. 2012