The search for novel chemotherapeutic agents in the treatment of
breast cancer with lower susceptibility to resistance mechanisms than current agents has led to the discovery of the
epothilones and their analogues.
Epothilones stabilize microtubules in a manner similar to
taxanes but are structurally distinct.
Ixabepilone, an
epothilone B analogue, having demonstrated high antimicrotubule activity in preclinical studies, has shown notable efficacy in phase II trials in patients with early-stage and metastatic
breast cancer. Of particular note, single-agent
ixabepilone is effective in
tumors resistant to
anthracyclines,
taxanes, and
capecitabine, for which there is currently no recommended
therapy. Different mechanisms of action and the non-overlapping toxicities of
ixabepilone with other agents provide the rationale for
ixabepilone in combination as a valid therapeutic approach. Phase II results assessing
ixabepilone in combination with
capecitabine in
anthracycline- and
taxane-pretreated patients are promising. The investigation of
ixabepilone in the neoadjuvant setting has also revealed potential
biomarkers to predict
ixabepilone response.
Ixabepilone has demonstrated activity in patients with
tumors that are
estrogen receptor-,
progesterone receptor-, and HER2-negative. The safety profile throughout the trials has been manageable, with
peripheral neuropathy as one of the more notable adverse events, which has been mostly reversible. A phase III trial comparing
ixabepilone plus
capecitabine versus
capecitabine alone demonstrated significant prolongation of median progression-free survival and reduction in relapse risk. Additionally, other members of the
epothilone family, such as
patupilone,
ZK-EPO, BMS-310705, and
KOS-862, have demonstrated efficacy against
breast cancer in phase I clinical trials. Ongoing phase II/III trials continue to assess
ixabepilone and other members of the
epothilone family in
breast cancer, particularly in combination regimens, as being valid treatment options in multidrug-resistant
breast cancer.