Cancer Therapy–Induced Cardiac Toxicity in Early Breast Cancer
Authors: Michel G. Khouri, Pamela S. Douglas, John R. Mackey, Miguel Martin, Jessica M. Scott, Marielle Scherrer-Crosbie, Lee W. Jones
Journal: Circulation (2012)

landscape of early breast cancer has changed dramat- ically with significant advancements in early screening and diagnosis and curative-intent therapies.Indeed, breast cancer-specific survival has improved by 20% during the past 30 years, and 5-year survival is now 98% for early-stage disease. 1 As a consequence, the risk and nature of adjuvant therapy-induced immediate and late-occurring cardiovascular injury have similarly evolved.In women with early breast cancer, particularly those Ͼ65 years of age, cardiovascular disease (CVD) is now the predominant cause of mortality as indicated by Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data. 2 Additionally, these women are also at increased risk of CVD compared with age-matched women without a history of breast cancer. 3ignificant cardiac safety concerns about anticancer therapy were first described by Von Hoff and colleagues, 4 identifying dose-dependent and progressive left ventricular (LV) dysfunction manifesting as symptomatic heart failure in patients receiving anthracyclines.From this work and others, 5,6 anthracycline-induced cardiac toxicity 7,8 is now a well-recognized adverse side effect.More recently, randomized trials have demonstrated that human epidermal growth factor receptor 2 (HER2)-directed monoclonal antibodies (ie, trastuzumab) and newer multitargeted small-molecule inhibitors interfere with molecular pathways crucial to normal cardiac homeostasis, 9 resulting in relatively high incidences of subclinical and overt cardiac toxicity. 10Although cardiac toxicity with newer therapies has demonstrated reversibility, 11 recovery of LV function after treatment cessation is uncertain at this time. 12Thus, to identify those individuals at high risk of cardiac toxicity, baseline measurement of LV ejection fraction (LVEF) is recommended by the American College of Cardiology (ACC) and American Heart Association (AHA) as standard of care for all breast cancer patients being considered for potentially cardiac-toxic treatment regimens. 13,14In addition, measurement of LVEF is Food and Drug Administration (FDA) mandated in all registrational breast cancer adjuvant trials involving an anthracycline-or a trastuzumab-containing regimen.Finally, use of endocrine therapy (eg, tamoxifen and aromatase inhibitors) in women with hormone receptor-positive breast cancer may also increase the risk of cardiovascular complications. 15espite the rapidly changing landscape of breast cancer management and the resultant changes in cardiovascular safety, several critical issues in the emerging field of "cardiooncology" remain unresolved.To ensure that this field keeps pace, a full understanding of the incidence, magnitude, and consequences of cardiovascular side effects of adjuvant therapy is an essential first step in optimizing early breast cancer management.Against this background, the purpose of this article is to comprehensively review several pivotal unaddressed issues concerning the definition, incidence, detection, and clinical importance of cardiac toxicity in early breast cancer.The evidence supporting the efficacy of preventive and treatment strategies is also discussed.In this article, we use the term cardiac toxicity to refer to myocardial injury related to anticancer pharmacological therapies.The principal manifestations of myocardial injury, LV dysfunction and heart failure, are the primary focus of our review.Additional cardiovascular toxicities associated with anticancer therapies, including sequelae of vascular injury (ie, myocardial ischemia/infarction and stroke), are also considered in discussions of CVD events.Finally, the range of potential cardiovascular effects of currently approved adjuvant breast cancer systemic therapies is summarized and highlighted by class of agent in Table 1. Definition and Clinical ImportanceSeveral oncology and cardiology organizations provide definitions for cardiac toxicity that encompass overt clinical events and subclinical injury (Table 2), although there is no universally accepted definition or clinical cut points.In registrational oncology trials, the most widely adopted criteria for adjudicating cardiovascular events is the Common Terminology Criteria for Adverse Events, developed by the National Cancer Institute. 17,18The Common Terminology