© 2007 European Society for Medical Oncology
symposium articles |
Markers predicting clinical benefit in breast cancer from microtubule-targeting agents
Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA
* Correspondence to: Dr L. Pusztai, Department of Breast Medical Oncology, Unit 1354, UT MD Anderson Cancer Center, PO Box 30 1439, Houston, TX 77230-1439, USA. Tel: +1-713-792-2817; E-mail: lpusztai{at}mdanderson.org
Taxanes (e.g. paclitaxel, docetaxel) and epothilones (e.g. ixabepilone) are microtubule-targeting agents, which disrupt cellular processes and induce apoptosis. Although their mechanisms of action are similar, clinical data in breast cancer patients support at least partial non-cross resistance between the classes, and even between individual compounds. Several biomarkers might contribute to the identification of patient groups likely to derive benefit from one class of microtubule-targeting agent or even one agent. Overexpression of P-glycoprotein is associated with resistance to taxanes, but not ixabepilone, in vitro; its role in vivo remains unclear. Mutations in β-tubulin linked to resistance to taxanes but not epothilones are observed in vitro; somatic mutations of β-tubulin appear rare clinically. Overexpression of the βIII-tubulin isoform is associated with taxane resistance in cell lines; some clinical studies support a relationship between poor response to taxanes and overexpression of βIII-tubulin. βIII-tubulin overexpression seems not to affect sensitivity to ixabepilone [1]. Estrogen receptor negativity, low expression of microtubule-associated protein tau, and perhaps HER2 amplification may define a subset of patients with higher than average sensitivity to paclitaxel. Large scale pharmacogenomic analysis has identified molecular markers potentially capable of distinguishing patients with differential sensitivity to paclitaxel and ixabepilone. These markers require validation in clinical trials.
Key words: breast cancer, epothilone, ixabepilone, taxane, microtubule-targeting agents, tubulin
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