New therapeutic options for chemotherapy-resistant metastatic breast cancer: the epothilones

When taxanes were introduced as anticancer agents some 20 years ago, their broad spectrum of activity was striking and engendered renewed hope for cancer patients. However, they were not without their problems, including a susceptibility to drug resistance caused by the drug efflux pump protein, P-glycoprotein. The epothilones are a new class of chemotherapeutic agents that have a mechanism of action similar enough to the taxanes to retain their broad spectrum of activity, but different enough to escape the multidrug resistance caused by P-glycoprotein. These properties are especially promising for patients with metastatic breast cancer who have run out of therapeutic options as a result of multidrug resistance. Ixabepilone, a semi-synthetic analogue of epothilone B, has recently been granted US FDA approval for the treatment of chemotherapy-resistant advanced breast cancer. Approval was based on results from a phase III study of ixabepilone in combination with capecitabine, as well as phase II studies of ixabepilone monotherapy. Significantly prolonged progression-free survival and increased objective response rates were demonstrated in the phase III study when ixabepilone was administered in combination with capecitabine compared with capecitabine alone. The phase II trials demonstrated robust antitumour activity with single-agent ixabepilone in women with metastatic breast cancer that was resistant to taxanes, anthracyclines and capecitabine. Early data from phase I trials of KOS-1584 and sagopilone are positive and suggest that these drugs may also develop into useful chemotherapeutic agents. Significant, but manageable, toxicities have been observed with the epothilones. In particular, neuropathy has led to the uneven and slower than expected clinical development of ixabepilone as optimal administration regimens were established. Some differences in tolerability profiles exist between the different analogues. Overall, it is expected that the epothilones will play an important role in the treatment of breast cancer and other tumour types.