The selective activity and demonstrated safety of targeted therapies has generated new hope for improving the treatment of patients with cancer. In some cases, the administration of these emerging agents, either biologic or pharmacologic, has increased patient survival and minimized damage to normal, uninvolved tissues.[1,2] The activity of targeted therapies and, ultimately, the strategies for using them are directly related to the underlying biology of the disease. Effective agents disrupt or abolish signal transduction through the pathways that are critical to the proliferation and survival of cancer cells. The molecular target is of vast importance, and it is likewise essential to anticipate and to eliminate the alternative pathways that may be used to escape control. The ability to restrict tumor growth requires, at least in theory, the uninterrupted targeting of selected signal transduction pathways while eliminating the possibility for tumor escape through secondary mechanisms. The epidermal growth factor receptors, and HER2 in particular, are becoming important therapeutic options for the treatment of breast cancer. Several characteristics of HER2-overexpressing tumors make HER2 signaling an attractive target for intervention: HER2 overexpression is correlated with disease prognosis, HER2 overexpression occurs more often in tumor cells than in normal human tissues, and HER2 overexpression occurs both in the primary tumor site and in distant metastases. Consequently, several anti-HER2 agents, including monoclonal antibodies and protein tyrosine kinase inhibitors, have been developed to interfere with the growth and differentiation of HER2-overexpressing breast tumors. The accompanying article reviews the molecular mechanisms behind the oncogenicity of HER2 and the molecular targets for these therapies. In addition, we also address several unresolved clinical questions, the answers to which will help optimize the treatment of patients with HER2- overexpressing tumors:
- How should anti-HER2 therapy be used in the adjuvant setting?
- Should anti-HER2 therapy be continued after disease progression?
- Should anti-HER2 therapy be incorporated into sequential treatment through multiple lines of chemotherapy?