Targeting the function of the HER2 oncogene in human cancer therapeutics

Abstract

The year 2007 marks exactly two decades since human epidermal growth factor receptor-2 (HER2) was functionally implicated in the pathogenesis of human breast cancer (Slamon et al., 1987). This finding established the HER2 oncogene hypothesis for the development of some human cancers. An abundance of experimental evidence compiled over the past two decades now solidly supports the HER2 oncogene hypothesis. A direct consequence of this hypothesis was the promise that inhibitors of oncogenic HER2 would be highly effective treatments for HER2-driven cancers. This treatment hypothesis has led to the development and widespread use of anti-HER2 antibodies (trastuzumab) in clinical management resulting in significantly improved clinical antitumor efficacies that have transformed the clinical practice of oncology. In the shadows of this irrefutable clinical success, scientific studies have not yet been able to mechanistically validate that trastuzumab inhibits oncogenic HER2 function and it remains possible that the current clinical advances are a consequence of the oncogene hypothesis, but not a translation of it. These looming scientific uncertainties suggest that the full promise of the treatment hypothesis may not yet have been realized. The coming decade will see a second generation of HER2-targeting agents brought into clinical testing and a renewed attempt to treat HER2-driven cancers through the inactivation of HER2. Here, I review the development of treatments that target HER2 in the context of the HER2 oncogene hypothesis, and where we stand with regards to the clinical translation of the HER2 oncogene hypothesis.

Figure 1

Outcome results with a median follow-up time of 2.0 years in 3351 patients with early stage breast cancer treated with chemotherapy and randomized to the addition of trastuzumab or control. Panel A shows the proportion of patients in each arm that remain cancer-free at the indicated years of follow-up. Many more patients from the trastuzumab-treated arm (solid line) are cancer-free compared with the control arm (broken line). Panel B shows the proportion of patients in each arm that are alive at the indicated years. More patients from the trastuzumab-treated arm are alive compared with the control arm. The effect of trastuzumab on disease-free and overall survival is highly statistically significant. (Romond et al. 2005) Copyright 2005 Massachusetts Medical Society, All rights reserved.