Biomarker Analysis of Neoadjuvant Doxorubicin/Cyclophosphamide Followed by Ixabepilone or Paclitaxel in Early-Stage Breast Cancer

Purpose: Predictive biomarkers offer the potential to improve the benefit: risk ratio of a therapeutic agent. Ixabepilone achieves comparable pathologic complete response (pCR) rates to other active drugs in the neoadjuvant setting. This phase II trial was designed to investigate potential biomarkers that differentiate response to this agent. Experimental Design: Women with untreated, histologically confirmed primary invasive breast adenocarcinoma received neoadjuvant doxorubicin/cyclophosphamide, followed by 1: 1 randomization to ixabepilone (n = 148) or paclitaxel (n 147). Rates of pCR were compared between treatment arms based on predefined biomarker sets: TUBB3, TACC3, and CAPG gene expression, a 20- and 26-gene expression model, MDR1 protein expression, and other potential markers of sensitivity. beta III-tubulin protein expression is reported separately but is referred to here for completeness. All patients underwent a core needle biopsy of the primary cancer for molecular marker analysis before chemotherapy. Gene expression profiling data were used for molecular subtyping. Results: There was no significant difference in the rate of pCR in both treatment arms in beta III-tubulin-positive patients. Higher pCR rates were observed among beta III-tubulin-positive patients than in beta III-tubulin-negative patients. Furthermore, no correlation was evident between TUBB3, TACC3, and CAPG gene expression, MDR1 protein expression, multi-gene expression models, and the efficacy of ixabepilone or paclitaxel, even within the estrogen receptor-negative subset. Conclusion: These results indicate that beta III-tubulin protein and mRNA expression, MDR1 protein expression, TACC3 and CAPG gene expression, and multigene expression models (20- and 26-gene) are not predictive markers for differentiating treatment benefit between ixabepilone and paclitaxel in early-stage breast cancer. Clin Cancer Res; 19(6); 1587-95. (C)2013 AACR.