Resistance to cancer chemotherapy is a common phenomenon especially in metastatic breast cancer (MBC), a setting in which patients typically have had exposure to multiple lines of prior therapy. The subsequent development of drug resistance can result in rapid disease progression during or shortly after completion of treatment. Moreover, cross-class multidrug resistance limits patient treatment choices, particularly in a setting where treatments options are few. One attempt to minimize the impact of drug resistance has been the concurrent use of two or more chemotherapy agents with unrelated mechanisms of action and differing modes of drug resistance, with the intent of blocking the development of multiple intracellular escape pathways essential for tumor survival. Within the past decade, an array of mechanistically diverse agents has augmented the list of combination regimens that may be both synergistic and efficacious in pretreated MBC. The aim of this paper is to review mechanisms of resistance to common chemotherapy agents and to consider current combination treatment options for heavily pretreated and/or drug-resistant patients with MBC. 1. Introduction Metastatic breast cancer (MBC) is a heterogeneous disease and among the leading causes of cancer mortality, accounting for more than 400,000 deaths annually worldwide [1]. The aim of this article is to review mechanisms of drug resistance to common chemotherapy agents and current combination treatment options for heavily pretreated, drug-resistant, or refractory patients with MBC. 1.1. Prognostic and Predictive Value of Breast Cancer Subtypes Patients with MBC have a poor prognosis, and optimal therapeutic regimens are yet to be established. However, in recent years, the introduction of new chemotherapeutic regimens has led to modest improvements in survival [2]. Current treatment algorithms take into account the tumor expression of human epidermal growth factor receptor 2 (HER2) and/or hormone cell surface receptors. Expression of these receptors as well as unique gene expression patterns, identified through genomic profiling studies, can be used to further categorize breast cancer into at least five common subtypes: luminal-like subtypes A and B (expression of hormone receptors and luminal cytokeratins 8 and 18), basal-like (expression of cytokeratins 5 and 17 and typically no expression of hormone or HER2 receptors), HER2-positive or -enriched (mostly, but not all, HER2 amplified), and normal-like [3–5]. The patterns of gene expression are hoped to one day carve out individual treatment choices.
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