Predictive biomarker discovery and validation for the targeted chemotherapeutic ixabepilone

作者：H. Lee, L. Xu, Shujian Wu, Bibek Paul, José Baselga, Antonio Llombart‐Cussac, Guenther G. Steger, Susan Galbraith, Edwin Clark · 发表于：Journal of Clinical Oncology · 年份：2006 · DOI：10.1200/jco.2006.24.18_suppl.3011 · 被引用次数：17 · 研究领域：Cancer Treatment and Pharmacology、Breast Cancer Treatment Studies、HER2/EGFR in Cancer Research

3011 Background: Ixabepilone is a microtubule stabilizing agent with significant therapeutic value in breast cancer (BC) patients. To identify predictive biomarkers capable of identifying patients likely to receive optimal benefit from ixabepilone treatment, preclinical and clinical studies were carried out. Several biomarkers discovered using preclinical models were validated in a neoadjuvant BC clinical study ( CA163080 ) and one, estrogen receptor 1 (ER), was shown to double the pathological complete response (pCR) rate in patients treated with ixabepilone. To identify candidate sets of biomarkers that could further increase the pCR rate we have performed post-hoc analyses of the preclinical and clinical data. Methods: Eighteen BC cell lines were classified as sensitive or resistant (S/R) based on the IC50 values for ixabepilone treatment. Gene expression profiling of the BC cell lines was conducted and genes correlated with the S/R classification were identified using a k-Nearest Neighbors algorithm. Patients in clinical study CA163080 underwent a pretreatment core needle biopsy from which RNA was isolated and gene expression profiles generated (data available on 134 patients). Analyses using the preclinical and clinical markers were conducted using various statistical tools. Results: Several markers used in combination with ER were found to be capable of tripling the pCR to ixabepilone in CA163080. In addition to ER other predictive markers were identified that were as p...