Cardiac toxicity of trastuzumab (Herceptin): implications for the design of adjuvant trials.

Trastuzumab (Herceptin; Genentech, South San Francisco, CA) is a humanized version of the murine monoclonal antibody 4D5 that was recently approved for the treatment of advanced breast cancer that overexpresses the HER2/neu oncogene. Cardiac toxicity was an unexpected side effect of trastuzumab treatment in the pivotal trials that led to its approval. The incidence of cardiac dysfunction was highly dependent on prior or concurrent doxorubicin exposure. For patients with minimal prior anthracycline exposure, the risk of cardiac dysfunction was 1%. For patients with more extensive prior doxorubicin exposure, the risk of cardiac dysfunction was 7% for trastuzumab monotherapy and 12% for trastuzumab plus paclitaxel (Taxol; Bristol-Myers Squibb Oncology, Princeton, NJ). For patients treated with trastuzumab concurrently with doxorubicin, the risk of cardiac dysfunction was 29%. The etiology of trastuzumab-associated cardiac dysfunction is unknown, although its dependence on concurrent or prior doxorubicin exposure suggests a common pathophysiologic basis with anthracycline-induced myocardial injury. A number of trials are in progress to evaluate the efficacy and safety of trastuzumab in patients with early stage disease and that will investigate novel strategies to circumvent this serious toxicity.