Resistance to trastuzumab: a necessary evil or a temporary challenge?

The aim of this review article is to examine the potential mechanisms of resistance to trastuzumab. In the clinical setting, when trastuzumab is given as a single agent for first-line treatment of HER2-overexpressing metastatic breast cancer, it is associated with a 40% objective response rate. In the remaining cases, no tumor regression is observed, although HER2 protein is overexpressed and/or the corresponding gene is amplified. Hence, some other factors besides HER2 must play a role in determining the level of sensitivity to trastuzumab. The identification of the potential mechanisms of resistance to trastuzumab can be very helpful for the development of new compounds, which might overcome that resistance and/or have additive/synergistic antitumor effect when given in association with trastuzumab. Moreover, thorough understanding of the HER2 pathway is essential to the identification of new predictive markers of response to trastuzumab that will help to better define the patients who are most likely to benefit from this drug.