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Breast cancer is the most common female malignancy worldwide, with an annual global incidence of over 1 million and a resulting 450,000 deaths.1 Despite progress in early diagnosis, approximately 10% of breast cancer patients present with metastatic disease.2,3 In addition, around 30% of patients undergoing primary treatment will develop distant metastases.2 Whereas patients whose tumours are hormone-receptorpositive are typically managed with endocrine-based therapies, chemotherapy remains the mainstay of treatment in patients with hormone-negative tumours.
The introduction of new cytotoxic and biological agents in metastatic breast cancer (MBC) has resulted in slightly improved survival. Nevertheless, the prognosis of MBC remains poor, median survival rates from the development of metastases are in the range of two to three years and a cure remains elusive.4 The most frequently used agents in MBC are anthracyclines and taxanes, which in multidrug schedules produce response rates in the range of 50–70%.5 However, median time to diseaseprogression following chemotherapy for MBC is only six to 10 months as a proportion of patients are primarily resistant to anthracyclines and taxanes, and of those who initially respond the majority will subsequently develop resistance. Additionally, an increasing proportion of early breast cancer patients are given anthracyclines and taxanes as part of their adjuvant treatment, and the number of MBC patients who develop resistance to these agents may further increase. Hence, there is a need for new effective agents at the time a relapse occurs.
This article reviews current knowledge on epothilones, a new class of cytotoxic agents that have recently shown activity in MBC that is resistant to multiple prior therapies.
Mechanisms of Resistance to Anthracyclines and Taxanes in Breast Cancer
Resistance to chemotherapy manifests as tumour insensitivity to initial treatment (known as intrinsic or primary resistance) or occurs after an initial response to therapy (acquired resistance). Acquired resistancemay develop during chemotherapy due to the emergence of a subpopulation of intrinsically resistant cells. The main cellular mechanisms involved in the development of tumour resistance to treatment include alterations in drug efflux, microtubule alterations, inadequate induction of apoptotic signalling and altered drug metabolism. Of these, the most recognised are alterations of drug efflux mechanisms involving members of the adenosine–triphosphate (ATP)-binding cassette (ABC) membrane transporter family, particularly P-glycoprotein (P-gp) encoded by the MDR1 gene, multidrug-resistant protein 1 (MRP1) and breast cancer-resistance protein (BRCP) encoded by the MXR gene.6,7