The development of
human epidermal growth factor receptor 2 (HER2)-targeting agents for the treatment of HER2-amplified
breast cancer has dramatically improved outcomes for patients with this disease. The value of HER2 as a therapeutic target encompasses 2 entirely different mechanistic dimensions. The first approach exploits the fact that HER2 is clearly a disease-driving oncogene to deliver HER2
kinase inhibitors, apparently a highly rational approach to the treatment of HER2-amplified
cancers. However, the functionally relevant HER2-HER3 complex has proven much more difficult to inhibit than had been anticipated, and because of its modest efficacy, the HER2 inhibitor
lapatinib is currently used predominantly in combinations and in very advanced stages of disease. The second approach exploits the massive cell surface expression of HER2 and delivers of a variety of cytotoxic or immunologic effectors with great selectivity to these
cancer cells. This approach has proven transformative, with 3 such drugs introduced into practice to date. The HER2-specific antibody
trastuzumab, in combination with
chemotherapy, has shown substantial effect in the management of HER2-amplifed
breast cancer at all stages of disease and lines of
therapy-and the addition of the second HER2 antibody
pertuzumab substantially increases the magnitude of this effect in all of the contexts tested thus far. While the immunologic effectors stimulated by these naked HER2
antibodies provide only modest activity as monotherapy, the toxin-carrying antibody
trastuzumab-emtansine provides substantial single-agent activity and is being developed for both early- and late-stage disease. The diverse mechanistic landscape afforded by the target HER2 has proven to be fertile ground for
drug development, but it has also created complexity and misconception in understanding these agents' modes of action, undermining the development of clinically useful predictive
biomarkers. This accounts for the failure of signaling-based
biomarkers to predict clinical
trastuzumab resistance and shifted the focus to markers of immunologic activity with greater success. The evolving world of HER2 targeting is reviewed herein.