Abstract
Treatment with trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of Human Epidermal Growth Factor Receptor 2 (HER2), very successfully improves outcomes for women with HER2-positive breast cancer. However, trastuzumab treatment was recently linked to potentially irreversible serious cardiotoxicity, the mechanisms of which are largely elusive. This study reports that trastuzumab significantly alters the expression of myocardial genes essential for DNA repair, cardiac and mitochondrial functions, which is associated with impaired left ventricular performance in mice coupled with significant ultrastructural alterations in cardiomyocytes revealed by electron microscopy. Furthermore, trastuzumab treatment also promotes oxidative stress and apoptosis in myocardium of mice, and elevates serum levels of cardiac troponin-I (cTnI) and cardiac myosin light chain-1 (cMLC1). The elevated serum levels of cMLC1 in mice treated with trastuzumab highlights the potential that cMLC1 could be a useful biomarker for trastuzumab-induced cardiotoxicity.
Highlights
Treatment with trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of Human Epidermal Growth Factor Receptor 2 (HER2), significantly improves outcomes for women with HER2-positive breast cancer [1,2,3,4]
At 1.5 fold change cutoff and an unadjusted P < 0.05, we found that 243 transcripts had a significantly different expression pattern in the trastuzumab-treated animal as compared to vehicle-treated animals
In this study we provide evidence that trastuzumab treatment decreases the expression of myocardial genes that play a critical role in cardiac and mitochondrial functions, adaptation to stress, and DNA repair, which is associated with decline in left ventricular function and the thinning of the left ventricular posterior wall (LVPW) in mice, coupled with significant ultrastructural alterations in cardiomyocytes
Summary
A humanized monoclonal antibody directed against the extracellular domain of Human Epidermal Growth Factor Receptor 2 (HER2), significantly improves outcomes for women with HER2-positive breast cancer [1,2,3,4]. Trastuzumab is clinically efficacious either as a single agent or in combination with standard chemotherapy regimens such as anthracyclines [1]. Both anthracyclines and trastuzumab are associated with considerable cardiotoxicity [5,6,7]. Trastuzumab-induced cardiotoxicity initially was thought to be reversible upon stopping treatment, and was considered not to be associated with ultrastructural changes [9,10]. Trastuzumab-induced cardiotoxicity manifests clinically as a decrease in left ventricular ejection fraction (LVEF) and heart failure [2,3,4,11], and was reported to occur in up to 7% of patients when trastuzumab is used as a single agent. When combined with an anthracycline, cardiotoxicity is notably increased and has been reported to occur in up to 27% of patients [6]
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