The Pharmaceutical Journal
Vol 268 No 7196 p597-604
4 May 2002

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Molecular evidence discovered for trastuzumab's cardiotoxicity

Research published in Nature Medicine this week reveals direct molecular evidence that trastuzumab (Herceptin) causes cardiomyopathy (2002;8:459).

Trastuzumab is used to treat metastatic breast cancer in patients whose tumours overexpress the human epidermal growth factor receptor 2 (HER2). It is associated with cardiotoxicity in patients previously or concurrently treated with anthracyclines and carries the warning that cardiac function should be monitored if anthracyclines need to be used.

Dr Steven Crone, Salk Institute, La Jolla, California, and colleagues created mice whose hearts lacked the gene for HER2. Although the animals appeared normal, their hearts were dilated and functioned poorly. The researchers found that cardiomyocytes isolated from these mice were more sensitive to doxorubicin cardiotoxicity than those isolated from control mice. "The essential role of HER2 in cardiomyocytes for the prevention of cardiomyopathy suggests that trastuzumab-related cardiac dysfunction is not immune-mediated or secondary to effects of trastuzumab outside the heart.

"Future experiments aimed at elucidating the molecular basis for this interaction may prove invaluable for preventing cardiomyopathy in patients receiving trastuzumab and anthracyclines," the researchers say.

Furthermore, HER2 agonists could be used to prevent trastuzumab-related cardiac dysfunction, as well as other forms of heart failure.