The Evolving Landscape of HER2 Targeting in Breast Cancer.

Abstract

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.