ERBB2 and breast carcinoma: Although treatment with T-DM1 significantly improves outcomes in HER2-positive breast cancer, a substantial fraction of patients are refractory to T-DM1 and, as with all drugs currently indicated for metastatic breast cancer, acquired resistance to T-DM1 almost always presents in initial responders.2,3 To address this problem of resistance, considerable effort has been undertaken to investigate the complex mechanisms of action of T-DM1 and to understand how evasion of these mechanisms can lead to treatment failure.