The potential for
cardiac toxicity in association with targeted biologic agents was first observed with
trastuzumab, a
monoclonal antibody that targets the ErbB2/HER2 receptor. In the pivotal trial of
trastuzumab in ErbB2-positive metastatic
cancer, an increased incidence of serious
cardiac events was observed, particularly when
trastuzumab was administered in combination with
anthracyclines. The ErbB2 receptor is expressed on cardiomyocytes, in addition to
tumor tissue, where it exerts a protective effect on cardiac function; thus, interference with ErbB2-signaling may block this protective effect. However, in contrast to
anthracycline-induced
cardiac toxicity,
trastuzumab-related cardiac dysfunction does not appear to increase with cumulative dose or to be associated with ultrastructural changes in the myocardium and is generally reversible. When used in adjuvant regimens for the treatment of ErbB2-positive early-stage
breast cancer,
trastuzumab has been shown to significantly improve disease-free and overall survival. The incidence of class III/IV
congestive heart failure (CHF) ranged from 0.4%-3.8% in the major adjuvant
trastuzumab trials. More recently, small-molecule
tyrosine kinase inhibitors such as
lapatinib have been investigated for the treatment of ErbB2-positive metastatic
breast cancer. In a comprehensive analysis of cardiac safety data from all
lapatinib trials completed to date, which included 3558 healthy volunteers and patients with a variety of solid
cancers on 43 trials, the overall incidence of left ventricular ejection fraction declines was 1.6%, with 0.2% of patients experiencing symptomatic CHF. Risk factors that might predict for cardiac dysfunction with ErbB2-targeted
therapy are actively under investigation and will aid in the identification of at-risk populations and in the development of strategies for risk minimization in the future. It is important to note that, while careful cardiac monitoring is required for all patients receiving ErbB2-targeted
therapy in any disease setting, the overall impact of these agents on the outcomes of patients with ErbB2-positive
breast cancer has been dramatic and positive.