The goal of this study was to develop pharmacogenomic predictors in response to standard
chemotherapy drugs in
breast cancer cell lines and test their predictive value in patients who received treatment with the same drugs. Nineteen human
breast cancer cell lines were tested for sensitivity to
paclitaxel (T),
5-fluorouracil (F),
doxorubicin (A) and
cyclophosphamide (C) in vitro. Baseline gene expression data were obtained for each cell line with Affymetrix U133A gene chips, and multigene predictors of sensitivity were derived for each
drug separately. These predictors were applied individually and in combination to human gene expression data generated with the same Affymetrix platform from fine needle aspiration specimens of 133 stage I-III breast
cancers.
Tumor samples were obtained at baseline, and each patient received 6 months of preoperative TFAC
chemotherapy followed by surgery. Cell line-derived prediction results were correlated with the observed pathologic response to
chemotherapy. Statistically robust differentially expressed genes between sensitive and resistant cells could only be found for
paclitaxel. False discovery rates associated with the informative genes were high for all other drugs. For each
drug, the top 100 differentially expressed genes were combined into a
drug-specific response predictor. When these cell line-based predictors were applied to patient data, there was no significant correlation between observed response and predicted response either for individual
drug predictors or combined predictions. Cell line-derived predictors of response to four commonly used
chemotherapy drugs did not predict response accurately in patients.