Trastuzumab: mechanisms of resistance and therapeutic opportunities.

Many breast cancer patients with HER2 overexpression do not respond to initial therapy with trastuzumab (Herceptin), and the vast majority of those who initially respond to the agent develop resistance to treatment within 1 year. This review will discuss several molecular mechanisms that can lead to the development of trastuzumab resistance, including loss of PTEN, activation of alternative pathways, receptor-antibody interaction block, and circulating HER2 extracellular domain, as well as the possibility of exploring these aberrations as therapeutic targets that could help avoid or overcome resistance to trastuzumab.