Markers predicting clinical benefit in breast cancer from microtubule-targeting agents.

Abstract

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 beta-tubulin linked to resistance to taxanes but not epothilones are observed in vitro; somatic mutations of beta-tubulin appear rare clinically. Overexpression of the betaIII-tubulin isoform is associated with taxane resistance in cell lines; some clinical studies support a relationship between poor response to taxanes and overexpression of betaIII-tubulin. BetaIII-tubulin overexpression seems not to affect sensitivity to ixabepilone. 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.