The selective activity and demonstratedsafety of targetedtherapies has generated newhope for improving the treatment ofpatients with cancer.
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:
In the absence of clinical trial data, we propose that anti-HER2 agents- used alone and in combination with other therapies-should be chosen by assessing the molecular and clinical characteristics of the tumor. We provide rational choices for combining anti-HER2 agents in both the presence and the absence of tumor resistance, based on the molecular mechanisms for escaping HER2 suppression. The integration and success of anti- HER2 therapies in metastatic breast cancer requires, however, that they be evaluated in clinical trials. Clinical trials will help identify not only optimal combination therapy regimens, but also the patient populations that are most sensitive to these combinations. Thus, to improve clinical outcomes, these unanswered questions should be the focus of ongoing clinical trials in patients with HER2- overexpressing breast cancer.
The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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