Session: S77-Emerging Paradigm of ErbB Family Function
Room 304 (Moscone Center)
Approximately 25% of human breast cancers overexpress the HER2 (ErbB2) proto-oncogene, which confers a more virulent cancer behavior and poor patient outcome. Three FDA-approved therapies targeting HER2, the monoclonal antibodies trastuzumab and pertuzumab and the tyrosine kinase inhibitor lapatinib, are active against this type of breast cancer. However, a significant fraction of patients with HER2+ breast cancer treated with these agents eventually relapse or develop progressive disease. This suggests that tumors acquire or possess intrinsic mechanisms of resistance that allow escape from HER2 inhibition. This presentation will focus on mechanisms of intrinsic and/or acquired resistance to HER2-targeted therapies that have been identified in preclinical and clinical studies. These mechanisms involve alterations to HER2 itself, coexpression or acquisition of bypass signaling through other receptor or intracellular signaling pathways, defects in mechanisms of cell cycle regulation or apoptosis, and host factors that may modulate drug response. Emerging clinical evidence already suggests that combinations of therapies targeting HER2 as well as these resistance pathways will be effective in overcoming or preventing resistance.