Targeting the human epidermal growth factor receptor 2 pathway in breast cancer.

The discovery of amplification of human epidermal growth factor receptor 2 (HER2), a member of the epidermal growth factor receptor family, was an important milestone in our understanding of the biology of breast cancers. This heralded the discovery of trastuzumab, a humanized monoclonal antibody targeting HER2. Trastuzumab is the foundation of treatment of HER2-positive breast cancers, demonstrating dramatic responses in patients with metastatic disease. Unfortunately, most tumors will inevitably develop resistance to trastuzumab, necessitating the need for alternate HER2-directed therapeutic approaches. Recent advances in our understanding of the interaction between HER2 and other members of the epidermal growth factor receptor family have led to identification of newer agents, resulting in the expansion of the clinical armamentarium of available agents for the treatment of HER2-positive tumors. In this article, we review the molecular biology of the ERbb receptor family, the use of HER2-targeted agents in early and advanced breast cancer, and the next-generation anti-HER2 agents that are currently in clinical evaluation.