BACKGROUND: There has been substantial interest in HER2 intratumoral 
heterogeneity as an explanation for the development of resistance to anti-HER2 
therapies in breast cancer, particularly to trastuzumab emtansine (T-DM1).
METHODS: Through a literature-based approach, we discuss mechanisms of 
resistance to HER2-targeting antibody-drug conjugates (ADCs) in breast cancer.
RESULTS: We describe results from clinical studies reporting the effect of 
anti-HER2 strategies particularly ADCs and their mechanistic effect. We review 
biological findings underlying HER2 heterogeneity and its implication in the 
development of novel anti-HER2 drugs including new ADCs in clinical development 
like trastuzumab deruxtecan (DS-8201).
CONCLUSIONS: We suggest potential mechanisms to optimize these compounds and 
their future clinical implementation.