Abstract 253: The Tyrosine Kinase ErbB2 Inhibitor Lapatinib and the Anti-ErbB2 Antibody Trastuzumab Depress Cardiac Function Without Inducing Left Ventricular Dilation in Mice
Background: ErbB2, tyrosine kinase receptor of the EGFR family, overexpressed in about 25% of breast cancers, modulates development and function in the myocardium. Lapatinib (LAP) is a small molecule that inhibits ErbB2-tyrosine kinase domain. The few existing trials report it to be associated with a low risk of LV dysfunction (2%), while the prototypical antibody Trastuzumab (TRAS) increases the frequency of asymptomatic ejection fraction decrease by 3-18%, and the risk of heart failure by 2-4%. Here, we characterize our LAP murine cardiotoxicity model in vivo by echocardiography, comparing it to TRAS and doxorubicin (DOX) cardiotoxicities.
Methods: LV end-diastolic and end-systolic diameters (LVEDD and LVESD) were assessed. LV function was measured with fractional shortening (FS) by M-mode echo, and with radial myocardial strain (%) with speckle tracking (ST) in sedated C57BL6 mice (2-4 mo. old) at day 0, and after 2 and 7 days of daily administration of LAP (100mg/kg/day orally), and in control mice. For comparison we used our well-established models with TRAS (2.25 mg/kg/day, ip), and DOX (2.17 mg/kg/day ip) as positive control.
Results: FS was already reduced with DOX at 2 days: 52±.2%, p<.001 vs 60±.4% (sham), while LAP and TRAS decreased FS only at 7 days (56±2 and 49±1.5%, respectively, both p<.05 vs 60±.5% for sham). Interestingly, FS reduction with LAP was milder than with TRAS (p=.01). At 7 days, both LAP and TRAS only increased LVESD: 1.23±.07 and 1.49±.07mm, respectively, both p<.05 vs 1.1±.03mm (sham). On the other hand, at 7 days DOX induced LV dilation, with significant enlargement of both LVESD (1.55±.08mm) and LVEDD (3.04±.06mm; sham=2.81±.03mm), both p<.005. Importantly, from a diagnostic point of view, myocardial strain was reduced early at 2 days with LAP and TRAS, predicting cardiotoxicity: 34±7% for LAP, 44±7% for TRAS, both p<.05 vs sham (66±.6%).
Conclusions: Differently from DOX, ErbB2 inhibition in mice does not produce LV dilation, but only decreases LV function. In particular, specifically targeting ErbB2-tyrosine kinase domain with LAP confers less cardiotoxicity than TRAS. Myocardial strain identifies LV systolic dysfunction earlier than conventional echo and can be a useful tool to predict ErbB2 inhibitors cardiotoxicity.
- © 2012 by American Heart Association, Inc.