Radiation- and anthracycline-induced cardiac toxicity and the influence of ErbB2 blocking agents

• Published in: Breast cancer research and treatment Vol. 141; no. 3; pp. 385 - 395
• Main Authors: Seemann, Ingar, te Poele, Johannes A. M., Song, Ji-Ying, Hoving, Saske, Russell, Nicola S., Stewart, Fiona A.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.10.2013; Springer; Springer Nature B.V
• Subjects: Animals; Anthracyclines; Antibiotics, Antineoplastic - toxicity; Antibodies, Monoclonal, Humanized - pharmacology; Biological and medical sciences; Breast cancer; Cancer; Cancer research; Cancer therapies; Cardiovascular system; Cell Survival - drug effects; Cell Survival - radiation effects; Cells, Cultured; Chemotherapy; Coronary Vessels - pathology; Coronary Vessels - radiation effects; Doxorubicin - toxicity; Epidermal growth factor; Fibrosis; Gynecology. Andrology. Obstetrics; Heart Diseases - chemically induced; Heart Diseases - pathology; Heart Diseases - prevention & control; Humans; Inhibitor drugs; Male; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Microvessels - pathology; Microvessels - radiation effects; Mitochondria, Heart - drug effects; Mitochondria, Heart - pathology; Myocardium - pathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - physiology; Myocytes, Cardiac - radiation effects; Nuclear radiation; Oncology; Pericardium - radiation effects; Preclinical Study; Quinazolines - pharmacology; Radiation Injuries, Experimental - pathology; Radiation Injuries, Experimental - prevention & control; Radiation therapy; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - metabolism; Rodents; Toxicity; Trastuzumab; Tumors; Ventricular Function, Left - drug effects; Von Willebrand factor; Irradiation; Anthracyclines; Cardiac microvasculature; ErbB2; Heart; Toxicity; C-Onc gene; erbB2 Gene; Anthracyclins; Circulatory system; Protooncogene; Human Epidermal growth factor Receptor 2
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-013-2707-7

In Her2-positive breast cancer patients, inhibition of epidermal growth factor receptor 2 (ErbB2)-signaling is often combined with chemotherapy and radiotherapy. The risk of cardiac toxicity after anthracyclines and radiotherapy is recognized, but little is known about increased risk when these treatments are combined with ErbB2 inhibition. This study investigated whether ErbB2 inhibition increased radiation or anthracycline-induced toxicity. In an in vitro study, human cardiomyocytes were treated with irradiation or doxorubicin, alone or in combination with trastuzumab, and evaluated for cell survival and growth. Groups of mice received 0 or 14 Gy to the heart, alone or in combination with lapatinib, or 3 × 4 mg/kg doxorubicin alone or in combination with lapatinib. Mice were evaluated 40 weeks after treatment for cardiac damage. Changes in cardiac function ( 99m Tc-Myoview gated SPECT) were related to histomorphology and microvascular damage. Radiation or doxorubicin-induced cardiomyocyte toxicity (in vitro) were not exacerbated by trastuzumab. Cardiac irradiation of mice decreased microvascular density (MVD) and increased endothelial damage in surviving capillaries (decrease alkaline phosphatase expression and increased von Willebrand factor), but these changes were not exacerbated by lapatinib. Inflammatory responses in the irradiated epicardium (CD45+ and F4/80+ cells) were significantly reduced in combination with lapatinib. Irradiation, doxorubicin, and lapatinib each induced cardiac fibrosis but this was not further enhanced when treatments were combined. At the ultra-structural level, both lapatinib and doxorubicin induced mitochondrial damage, which was enhanced in combined treatments. Lapatinib alone also induced mild changes in cardiac function but this was not enhanced in the combined treatments. Trastuzumab did not enhance direct radiation or anthracycline toxicity of cardiomyocytes in vitro. Lapatinib did not enhance the risk of radiation or anthracycline-induced cardiac toxicity in mice up to 40 weeks after treatment, but mitochondrial damage was more severe after doxorubicin combined with lapatinib.