title: Gene expression profiling of breast tumor cell lines to predict for therapeutic response to microtubule-stabilizing agents.
abstract: Microtubule-targeting agents, including taxanes (Tax) and ixabepilone (Ixa), are important components of modern breast cancer chemotherapy regimens, but no molecular parameter is currently available that can predict for their efficiency. We sought to develop pharmacogenomic predictors of Tax- and Ixa-response from a large panel of human breast tumor cell lines (BTCL), then to evaluate their performance in clinical samples. Thirty-two BTCL, representative of the molecular diversity of breast cancers (BC), were treated in vitro with Tax (paclitaxel (Pac), docetaxel (Doc)), and ixabepilone (Ixa), then classified as drug-sensitive or resistant according to their 50% inhibitory concentrations (IC50s). Baseline gene expression data were obtained using Affymetrix U133 Plus 2.0 human oligonucleotide microarrays. Gene expression set (GES) predictors of response to taxanes were derived, then tested for validation internally and in publicly available gene expression datasets. In vitro IC50s of Pac and Doc were almost identical, whereas some Tax-resistant BTCL retained sensitivity to Ixa. GES predictors for Tax-sensitivity (333 genes) and Ixa-sensitivity (79 genes) were defined. They displayed a limited number of overlapping genes. Both were validated by leave-n-out cross-validation (n = 4; for overall accuracy (OA), P = 0.028 for Tax, and P = 0.0005 for Ixa). The GES predictor of Tax-sensitivity was tested on publicly available external datasets and significantly predicted Pac-sensitivity in 16 BTCL (P = 0.04 for OA), and pathological complete response to Pac-based neoadjuvant chemotherapy in BC patients (P = 0.0045 for OA). Applying Tax and Ixa-GES to a dataset of clinically annotated early BC patients identified subsets of tumors with potentially distinct phenotypes of drug sensitivity: predicted Ixa-sensitive/Tax-resistant BC were significantly (P < 0.05, Fischer's exact test) more frequently ER/PR-positive, Ki67-negative, and luminal subtype than predicted Ixa-resistant/Tax-sensitive BC. Genomic predictors for Tax- and Ixa-sensitivity can be derived from BTCL and may be helpful for better selecting cytotoxic treatment in BC patients.
authors.affiliation: Département de Pharmacologie Moléculaire and U891 INSERM, Centre de Recherche En Cancérologie de Marseille, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Gais
authors.initials: G
authors.lastname: Kadra
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.forename: Yves
authors.initials: Y
authors.lastname: Toiron
authors.forename: Patrice
authors.initials: P
authors.lastname: Viens
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Borg
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.forename: Anthony
authors.initials: A
authors.lastname: Gonçalves
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003198:Computer Simulation; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D034261:Epothilones / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D006801:Humans; D020128:Inhibitory Concentration 50; D008875:Middle Aged; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics; D017239:Paclitaxel / Q000494:pharmacology*; D010641:Phenotype; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000077143:Docetaxel; D034261:Epothilones; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D043823:Taxoids; D050257:Tubulin Modulators; C508053:ERBB2 protein, human; C430592:ixabepilone