Trastuzumab and cardiac dysfunction: update on preclinical studies
1Genentech, Inc, South San Francisco, CA 99048, USA.
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.
Insights
Trastuzumab improves survival for HER2-positive metastatic breast cancer but can cause cardiac toxicity. Many patients experience reversible ejection fraction decreases without clinical heart dysfunction, suggesting a distinct mechanism from anthracyclines.
Area of Science:
- Oncology
- Cardiology
- Pharmacology
Background:
- Trastuzumab is a HER2-targeted therapy improving survival in HER2-positive metastatic breast cancer.
- Cardiac toxicity, often asymptomatic decreases in left ventricular ejection fraction, is an identified side effect.
- The clinical significance and reversibility of trastuzumab-induced cardiac dysfunction require further investigation.
Purpose of the Study:
- To review the cardiac toxicity associated with Trastuzumab treatment.
- To explore the potential mechanisms of Trastuzumab-related cardiotoxicity.
- To discuss the utility of animal models in studying and potentially preventing this cardiac dysfunction.
Main Methods:
- Review of clinical data and case studies on Trastuzumab-associated cardiac events.
- Comparison of Trastuzumab cardiotoxicity mechanisms with other chemotherapy agents like anthracyclines.
- Discussion of ongoing research utilizing rodent and primate models to understand cardiac dysfunction.
Main Results:
- Trastuzumab significantly improves survival in HER2-positive metastatic breast cancer.
- Asymptomatic decreases in left ventricular ejection fraction are common but often reversible.
- The majority of patients with ejection fraction changes do not develop clinical cardiac dysfunction.
- Preliminary evidence suggests Trastuzumab cardiotoxicity mechanism differs from anthracyclines.
Conclusions:
- While Trastuzumab offers survival benefits, its cardiac toxicity necessitates careful monitoring.
- The reversible nature and low rate of clinical manifestation of ejection fraction changes suggest a manageable risk profile.
- Further research, particularly using animal models, is crucial for elucidating mechanisms and developing preventative strategies for Trastuzumab-associated cardiotoxicity.
