Combined anti-EGF receptor and anti-HER2 receptor therapy in breast cancer: A promising strategy ready for clinical testing

Abstract

In summary, the findings of Normanno et al. provide a strong rationale for studying the combination of ZD1839 and trastuzumab in the clinic, and clinical trials are already ongoing in patients with advanced breast cancer. As with trastuzumab, several issues will only be addressed in carefully planned and executed clinical trials. In addition to choosing clinically meaningful endpoints to assess efficacy and to monitor safety, the most burning question would appear to be how to select the patients that may benefit from the combined therapy? Ideally, the levels of EGF receptor and HER2 receptor expression would have to be prospectively and analyzed in order to be able to establish correlations between receptor expression profiles and benefit from therapy. Furthermore, taking into consideration the richly interactive network of downstream signaling triggered by these two receptors, a major effort will have to be directed at identifying additional molecular markers that are predictive of a response to the combination. Other important questions that will need addressing will be the optimal dosages of each of these compounds when given in combination and whether this combination will be active in other tumor types in addition to breast cancer. While we eagerly await the results of these clinical trials, it would seem logical to continue to explore in pre-clinical models the antitumor activity of combination therapy with targeted agents against growth factor receptor and downstream signaling molecules.