Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer

Abstract

Background: Systemic chemotherapy for operable breast cancer substantially decreases the risk of death. Patients often have de novo resistance or incomplete response to docetaxel, one of the most active agents in this disease. We postulated that gene expression profiles of the primary breast cancer can predict the response to docetaxel.

Methods: We took core biopsy samples from primary breast tumours in 24 patients before treatment and then assessed tumour response to neoadjuvant docetaxel (four cycles, 100 mg/m2 daily for 3 weeks) by cDNA analysis of RNA extracted from biopsy samples using HgU95-Av2 GeneChip.

Findings: From the core biopsy samples, we extracted sufficient total RNA (3-6 microg) for cDNA array analysis using HgU95-Av2 GeneChip. Differential patterns of expression of 92 genes correlated with docetaxel response (p=0.001). Sensitive tumours had higher expression of genes involved in cell cycle, cytoskeleton, adhesion, protein transport, protein modification, transcription, and stress or apoptosis; whereas resistant tumours showed increased expression of some transcriptional and signal transduction genes. In leave-one-out cross-validation analysis, ten of 11 sensitive tumours (90% specificity) and 11 of 13 resistant tumours (85% sensitivity) were correctly classified, with an accuracy of 88%. This 92-gene predictor had positive and negative predictive values of 92% and 83%, respectively. Correlation between RNA expression measured by the arrays and semiquantitative RT-PCR was also ascertained, and our results were validated in an independent set of six patients.

Interpretation: If validated, these molecular profiles could allow development of a clinical test for docetaxel sensitivity, thus reducing unnecessary treatment for women with breast cancer.