The first ADC targeting the HER2 receptor is T-DM1 (ado-trastuzumab emtansine T-MCC-DM1 Kadcyla®), which is a conjugate of trastuzumab and a cytotoxic moiety (DM1, derivative of maytansine). The components of an effective ADC typically consist of: (i) a humanized or human monoclonal antibody that selectively and specifically delivers a cytotoxic agent to cancer cells by evoking receptor-mediated endocytosis (ii) a cytotoxic agent that will kill the cell and (iii) a linker that binds the cytotoxic agent to the antibody. The delivery is followed by internalization of the ADC and release of free, highly active cytotoxic agents within cancer cells, leading eventually to cell death. Īntibody-drug conjugates (ADCs) are a means to deliver cytotoxic drugs specifically to cancer cells. T-DM1 is an excellent example of a principle suggested already in the 1970s to use antibodies as carriers of drugs to highly specific targets. In this review we discuss the mechanisms of action of trastuzumab emtansine (T-DM1), a novel agent that has challenged in efficacy and safety all existing systemic therapies for HER2-positive MBC, and the resistance mechanisms to it. ĭespite these new therapeutic options, HER2-positive MBC still remains an incurable disease. Recently, pertuzumab, a recombinant humanized monoclonal antibody that binds to subdomain II of the extracellular portion of HER2 and inhibits receptor dimerization, was found to be more effective in combination with trastuzumab and docetaxel compared with placebo, trastuzumab and docetaxel as first-line treatment of HER2-positive MBC. As to trastuzumab, resistance to lapatinib develops frequently among patients who initially respond. Lapatinib, an orally administered small molecule inhibitor of the HER1 and HER2 tyrosine kinases, was found to be superior in combination with capecitabine compared with capecitabine alone in the treatment of metastatic breast cancer (MBC) that had progressed after trastuzumab-based therapy. Several other HER2-targeted agents have been evaluated in clinical trials since the introduction of trastuzumab in 1998. However, resistance to trastuzumab eventually emerges in the great majority of patients treated. Trastuzumab showed substantial anti-tumor efficacy in both preclinical and clinical trials, and introduction of trastuzumab for the treatment of HER2-positive breast cancer can be considered a milestone in medical oncology. In the past, patients with HER2-positive breast cancer generally had unfavorable outcome, but this changed radically after discovery of trastuzumab, a recombinant humanized monoclonal antibody that binds to the extracellular subdomain IV of HER2. Overexpression and amplification of human epidermal growth factor receptor-2 (HER2, ErbB2) is present in 15 to 20% of primary human breast cancers. In this review we discuss the mechanism of action of T-DM1 and the key clinical results obtained with it, the combinations of T-DM1 with other cytotoxic agents and anti-HER drugs, and the potential resistance mechanisms and the strategies to overcome resistance to T-DM1. The effect of T-DM1 may also be compromised by multidrug resistance proteins that pump DM1 out of cancer cells. The cytotoxic effect of T-DM1 may be impaired by inefficient internalization or enhanced recycling of the HER2-T-DM1 complex in cancer cells, or impaired lysosomal degradation of trastuzumab or intracellular trafficking of HER2. The mechanisms of resistance are incompletely understood, but mechanisms limiting the binding of trastuzumab to cancer cells may be involved. Primary resistance of HER2-positive metastatic breast cancer to T-DM1 appears to be relatively infrequent, but most patients treated with T-DM1 develop acquired drug resistance. The cytotoxic effect of T-DM1 likely varies depending on the intracellular concentration of DM1 accumulated in cancer cells, high intracellular levels resulting in rapid apoptosis, somewhat lower levels in impaired cellular trafficking and mitotic catastrophe, while the lowest levels lead to poor response to T-DM1. It has several mechanisms of action consisting of the anti-tumor effects of trastuzumab and those of DM1, a cytotoxic anti-microtubule agent released within the target cells upon degradation of the human epidermal growth factor receptor-2 (HER2)-T-DM1 complex in lysosomes. T-DM1 is currently being evaluated as adjuvant treatment for early breast cancer. Efficacy has now been demonstrated in randomized trials as first line, second line, and later than the second line treatment of advanced breast cancer. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that is effective and generally well tolerated when administered as a single agent to treat advanced breast cancer.
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