Trastuzumab has been clearly demonstrated to improve overall survival for both
early and metastatic HER2 positive breast cancer. However, despite the improved clinical
outcomes seen with the addition of HER2 targeted therapy to conventional cytotoxic agents,
the response rates remain between 30-55% and the majority of patients with advanced
breast cancer experience disease progression within 1 year. In this review article, we provide
a summary of the key mechanisms of resistance to trastuzumab, including the truncated
form of HER2 (p95HER2), compensatory up-regulation of receptor cross-talk, genetic mutations and aberrancies
in molecular pathways that allow tumor cells to evade cell cycle regulations. In recent years, treatment
options for patients with trastuzumab-resistant disease have been developed and approved, including lapatinib
and T-DM1. Ongoing research is evaluating multiple other therapeutic regimens that include novel HER2-
targeting agents for the treatment of resistant disease. We will review these newer therapies as well as the scientific
rationale behind treatment regimens that have been studied in patients with trastuzumab-resistant
HER2 positive breast cancer.
Keywords: Breast cancer, HER2, lapatinib, neratinib, metastatic, T-DM1, trastuzumab resistance.
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