Toxicology of Trastuzumab: An Insight into Mechanisms of Cardiotoxicity

Trastuzumab is a humanized monoclonal antibody that is approved for the treatment of breast and gastric malignancies. Although it has shown promise as a biotherapeutic, its cardiotoxicity remains a major concern. Genotoxic anticancer anthracyclines such as doxorubicin and epirubicin are also known for their cardiotoxic effects. However, trastuzumab and anthracyclines are suggested to mediate cardiotoxicity via different pathways. The available lines of evidence suggest that trastuzumab can exacerbate the cardiotoxic effects of anthracyclines and thus, prior exposure to anthracyclines is regarded as one of the risk factors for trastuzumab-induced cardiotoxcity. Although it is generally believed that the trastuzumab-induced cardiotoxic effects are reversible, various preclinical studies have revealed its apoptotic effects on cardiomyocytes. Thus, the issue of the reversibility of its cardiotoxic effects remains to be fully resolved. This article discusses various mechanisms that have been proposed for the cardiotoxic effects of trastuzumab and the potential risk factors that can lead to cardiotoxicity. The recently approved anti-HER2 monoclonal antibodies including pertuzumab and ado-trastuzumab (T-DM1) are also discussed.