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. Efficacy has now been demonstrated in randomized trials as first line, second line, and later than the second line treatment of advanced
breast cancer. T-DM1 is currently being evaluated as adjuvant treatment for early
breast cancer. 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 thetarget cells upon degradation of the human
epidermal growth factor receptor-2 (HER2)-T-DM1 complex in lysosomes. 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. 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 mechanisms of resistance are incompletely understood, but mechanisms limiting the binding of
trastuzumab to
cancer cells may be involved. 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 effect ofT-DM1 may also be compromised by
multidrug resistance proteins that pump DM1 out of
cancer cells. In this review we discuss the mechanism of action of T-DM1 and the key clinical results obtained with it, the combinations ofT-DM1 with other
cytotoxic agents and anti-HER drugs, and the potential resistance mechanisms and the strategies to overcome resistance to T-DM1.