Analysis of HER2 and HER4 in Human Myocardium to Clarify the Cardiotoxicity of Trastuzumab (Herceptin™)

Fuchs, Ilka; Landt, Solveig; Bueler, Helmut; Kuehl, Uwe; Coupland, Sarah E.; Kleine-Tebbe, A.; Lichtenegger, W.; Schäller, G.

doi:10.1023/b:brea.0000003916.39959.73

Cited by 35 publications

(18 citation statements)

References 19 publications

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“…24 Thus it is possible that trastuzumab has a direct cardiotoxic effect that is mediated by the cardiac HER2 receptor. In fact, Fuchs et al 26 theorized that trastuzumab-associated cardiotoxicity is a consequence of interaction with myocardial cells that pathologically overexpress HER2. However, analysis of HER2 status in heart biopsy tissue from patients with decreased left ventricular function but without previous exposure to trastuzumab did not reveal overexpression or gene amplification.…”

Section: Pathogenesismentioning

confidence: 99%

Trastuzumab‐associated cardiotoxicity

Keefe

2002

Cancer

318

184

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Section: Pathogenesismentioning

confidence: 99%

Trastuzumab‐associated cardiotoxicity

Keefe

2002

Cancer

318

184

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“…It appears unlikely that trastuzumab-associated heart damage occurs directly as a result of HER-2 expression on heart muscle. In 60 patients with evidence of cardiac dysfunction, including 25 patients with previous anthracycline exposure, Fuchs and colleagues found only faint membrane staining in less than 10% of cardiac biopsies and no evidence of gene amplification by FISH (Fuchs et al 2001). It also seems unlikely that trastuzumab alters the pharmacokinetic properties of anthracyclines and one study has failed to demonstrate any difference in the pharmacokinetics of doxorubicin when it was administered before or after trastuzumab (Gianni et al 2001).…”

Section: Clinical Safety Of Trastuzumabmentioning

confidence: 99%

The development and clinical use of trastuzumab (Herceptin).

Harries¹,

Smith²

2002

Endocrine-Related Cancer

171

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HER-2 is a member of the c-erbB family of receptor tyrosine kinases and is overexpressed by 20-30% of human breast cancers. HER-2 overexpression is an independent adverse prognostic factor and may also predict for response to both chemotherapy and endocrine agents. Trastuzumab is a humanised monoclonal antibody that binds with high affinity to the extracellular domain of HER-2. In HER-2-overexpressing preclinical models trastuzumab has been shown to have a marked antiproliferative effect and demonstrates synergy with a number of cytotoxic drugs. Several phase II and phase III clinical trials have now been performed in patients with advanced breast cancer that overexpress HER-2. Trastuzumab was initially shown to be active and well tolerated as a single agent in heavily pretreated women. Subsequently, studies of first-line treatment for metastatic breast cancer have demonstrated an improvement in survival for trastuzumab when used in combination with either paclitaxel or an anthracycline-cyclophosphamide regimen compared with chemotherapy alone. Unexpectedly, the combination of trastuzumab and the anthracycline-containing regimen was associated with a significant incidence of cardiac dysfunction. The benefit of trastuzumab is generally confined to patients whose tumours have gene amplification as detected by fluorescence in situ hybridisation (FISH) and this is tightly associated with immunohistochemical (IHC) staining at the highest (3 + ) level. A small number of patients have IHC 2 + tumours together with FISH evidence of gene amplification and may also derive benefit from treatment. Trastuzumab has also been shown to be effective when used as first-line monotherapy for advanced breast cancer. Trials to date have employed trastuzumab in a weekly schedule, but there is emerging evidence that a three-weekly regimen may be as effective. Trastuzumab has shown encouraging activity when used with other agents including docetaxel and vinorelbine. The combination of trastuzumab, docetaxel, and platinum salts also appears to be very active. The role of trastuzumab as adjuvant therapy for early breast cancer is being tested in a number of large randomised trials.

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“…A role for ERBB signaling in adult cardiac homeostasis is also emerging. Three of the four receptors, EGFR, ERBB2, and ERBB4, are detected in the adult human and mouse heart; among these ERBB4 appears to be the most abundant (Srinivasan et al, 1998;Zhao et al, 1998;Zhao et al, 1999;Fuchs et al, 2003). The expression and activity of ERBB2 and ERBB4 receptors are depressed in clinical and experimentally-induced heart failure (Rohrbach et al, 1999;Uray et al, 2002;Rohrbach et al, 2005) and signaling via NRG1 to ERBB2/ ERBB4 heterodimers is critical for adult cardiomyocyte survival (Zhao et al, 1998;Schneider et al, 2001;Fukazawa et al, 2003;Liu et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Chronic pharmacologic inhibition of EGFR leads to cardiac dysfunction in C57BL/6J mice

Barrick

Chao

et al. 2008

Toxicology and Applied Pharmacology

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Molecule-targeted therapies like those against the epidermal growth factor receptor (EGFR) are becoming widely used in the oncology clinic. With improvements in treatment efficacy, many cancers are being treated as chronic diseases, with patients having prolonged exposure to several therapies that were previously only given acutely. The consequence of chronic suppression of EGFR activity may lead to unexpected toxicities like altered cardiac physiology, a common organ site for adverse drug effects. To explore this possibility, we treated C57BL/6J (B6) mice with two EGFR small molecule tyrosine kinase inhibitors (TKIs), irreversible EKB-569 and reversible AG-1478, orally for three months. In B6 female mice, chronic exposure to both TKIs depressed body weight gain and caused significant changes in left ventricular (LV) wall thickness and cardiac function. No significant differences were observed in heart weight or cardiomyocyte size but histological analysis revealed an increase in fibrosis and in the numbers of TUNEL-positive cells in the hearts from treated female mice. Consistent with histological results, LV apoptotic gene expression was altered, with significant downregulation of the anti-apoptotic gene Bcl2l1. Although there were no significant differences in any of these endpoints in treated male mice, suggesting sex may influence susceptibility to TKI mediated toxicity, the LVs of treated male mice had significant upregulation of Egf, Erbb2 and Nppb over controls. Taken together, these data suggest that chronic dietary exposure to TKIs may result in pathological and physiological changes in the heart.

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Analysis of HER2 and HER4 in Human Myocardium to Clarify the Cardiotoxicity of Trastuzumab (Herceptin™)

Cited by 35 publications

References 19 publications

Trastuzumab‐associated cardiotoxicity

Trastuzumab‐associated cardiotoxicity

The development and clinical use of trastuzumab (Herceptin).

Chronic pharmacologic inhibition of EGFR leads to cardiac dysfunction in C57BL/6J mice

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