Importance of the field: Trastuzumab has become a mainstay in the treatment of women with human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer in the metastatic and adjuvant settings. Although trastuzumab is generally well tolerated, cardiac toxicity has emerged as a rare but potentially serious complication that limits its use in some patients. It is critically important to understand the nature of this cardiac risk when counseling patients, especially as new anti-HER2 agents are developed and tested in combination with trastuzumab. Areas covered in this review: This review describes the incidence, risk factors and natural history of trastuzumab-associated cardiac toxicity reported in updated efficacy and cardiac safety analyses of metastatic and adjuvant trastuzumab clinical trials. Mechanisms of trastuzumab-associated cardiotoxicity are proposed and compared to what is known about anthracycline-induced cardiotoxicity. The existing cardiac safety data for lapatinib and other newer HER2-targeted therapies are also discussed, both as single agents and in combination with trastuzumab. What the reader will gain: The reader will gain a comprehensive understanding of the existing cardiac safety data for trastuzumab including the notable differences in trial design and study populations between each of the major adjuvant trials. Readers will become familiar with the risk factors associated with trastuzumab-induced cardiotoxicity as well as with the natural history of its course. Take home message: The majority of trastuzumab-related cardiac events observed have been asymptomatic declines in left ventricular ejection fraction. The incidence of severe congestive heart failure and cardiac death observed in the large adjuvant trastuzumab trials ranges from 0.6 to 4%. Both symptomatic and asymptomatic events are largely reversible and manageable; however, little is known about the significance of asymptomatic left ventricular ejection fraction decline and longer cardiac follow-up is needed. Close cardiac monitoring must be performed for all patients receiving anti-HER2 agents currently in the clinic or in development.
