Trastuzumab and cardiac dysfunction: update on preclinical studies

https://doi.org/10.1053/j.seminoncol.2003.08.007Get rights and content

Abstract

Trastuzumab, a humanized, recombinant antibody directed against HER2, can significantly improve survival in women with HER2-positive metastatic breast cancer. Treatment with trastuzumab has been associated with cardiac toxicity, most commonly manifested as asymptomatic decreases in left ventricular ejection fraction on multiple gated acquisition scans. These asymptomatic decreases appear to be reversible, and their clinical significance is not well understood. Fortunately, studies are beginning to show that the majority of women with decreases in left ventricular ejection fraction never develop clinical evidence of cardiac dysfunction. Although cardiotoxicity has been difficult to study, in part because of the small number of actual clinical events, preliminary evidence appears to indicate that the mechanism of trastuzumab-related cardiotoxicity is different than that induced by anthracyclines. The development of animal models may yield further understanding of the mechanism(s) of trastuzumab-associated cardiac dysfunction, and may provide a focus for clinical trials of treatment or prevention. Current investigations with rodent and primate models of cardiac dysfunction are briefly discussed in this article.

Section snippets

Preclinical studies

General preclinical toxicology studies of trastuzumab included acute (single) and multiple-dose studies of up to 6 months’ duration using weekly intravenous administration in mice and monkeys (data on file, Genentech, Inc, South San Francisco, CA, 2002). Standard toxicologic parameters were evaluated, including clinical and anatomic pathology endpoints, as well as the assessment of production of antibodies to trastuzumab. No significant toxicities were discovered in any of these studies, and

Clinical studies

Studying trastuzumab-associated cardiotoxicity has proven to be a difficult undertaking. First, clinical cardiac events are rare, making prospective studies in this group difficult, except in very large trials. Second, and more importantly, there is currently no good historical control group against which to compare the incidence and nature of trastuzumab-related cardiac dysfunction. The overall incidence of cardiac dysfunction in women with breast cancer has not been carefully characterized.

Animal models of trastuzumab-associated cardiac dysfunction

The development of animal models may yield an understanding of the mechanism(s) of cardiac dysfunction, thus providing a focus for clinical trials of treatment or prevention. Such information may prove useful as trastuzumab moves into the adjuvant setting, where there is a much lower tolerance for any level of cardiotoxicity.

The critical role of HER2 in rodent cardiac myocyte development has been shown in several studies using gene deletion models. Restoration of HER2 to the heart only of

Summary

Trastuzumab offers a survival advantage when used in combination with chemotherapy and remains a component of standard care for women with metastatic HER2-positive breast cancer.3 The occurrence of clinical cardiac dysfunction is an infrequent but potentially serious toxicity of trastuzumab therapy. Fortunately, early data suggest that the majority of cardiac events are asymptomatic decreases in LVEF, the clinical significance of which have not been clearly established. Studying these changes

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1

Drs Klein and Dybdal are employees of Genentech, Inc.

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