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Cancer Control Section Heading Section sub Target therapies-induced Cardiotoxicity Ludovico Lazzari, Marcella De Paolis, Daniella Bovelli and Enrico Boschetti Division of Cardiology, Santa Maria University Hospital, University Hospital of Terni, University of Perugia, Italy Abstract Target therapies have become an important component of the treatment of many cancers, with significant evidence of a gain in survival in their use, but at the same time, with increasing concern about their ability to cause a wide spectrum of secondary cardiovascular adverse events (left ventricular dysfunction, heart failure, hypertension, ischaemic heart disease, QT prolongation, sudden cardiac death), partly because of an increased use of combination therapies and a growing population with cardiovascular risk factors. The following article summarises the recent data in the literature on the epidemiology and pathophysiology of cardiotoxicity induced by different target drugs, as well as strategies for patient management before, during and after antineoplastic treatment, early diagnosis of cardiovascular adverse events, with particular attention on the role of echocardiography. The delicate balance between effective cancer therapy and the risk of secondary cardiovascular disease that could affect the gain of survival, requires a profound collaboration between oncologists and cardiologists, with the aim of creating a personalised therapy for the patient and their illness. Keywords Target therapies, trastuzumab, heart failure, QT prolongation, hypertension, myocardial ischaemia Disclosure: The authors have no conflicts of interest to declare. Received: 6 February 2013 Accepted: 16 April 2013 Citation: European Oncology & Haematology, 2013;9(1):56–60 Correspondence: Ludovico Lazzari, Research Fellow, University Hospital of Terni, University of Perugia, Perugia, Italy. E: ludovicolazzari@alice.it Antineoplastic therapy is frequently complicated by the development of cardiotoxicity, either as the direct effects of chemotherapy on the heart, such as left ventricular dysfunction (LVD), heart failure (HF) or ischaemia, or as indirect effects due to haemodynamic changes, thrombotic events or hypertension. 1 Simultaneously, with the improvement in the management of cancer patients and prolonged survival, cardiotoxicity has become increasingly important, as the adverse effects on the heart may create new challenges in the long-term management of the patients, reducing the effectiveness of treatment and survival, due to the appearance of comorbidities. Chemotherapy-Related Left Ventricular Dysfunction and Heart Failure Over the last 20 years, considerable progress has been made in the management of cancer due to the introduction of targeted molecular therapies. 2 However, even these new target drugs have been shown to have a cardiotoxic potential, especially when used as combination therapies, by inhibition of transduction pathways in normal or non-cancerous cells. 3 Monoclonal Antibodies Trastuzumab is a humanised monoclonal antibody against the human epidermal growth factor receptor (HER2), a tyrosine kinase receptor overexpressed at the time of diagnosis in 15 % of breast cancer (BC) and up to 20–30 % of metastatic BC, 4 which is associated with more aggressive disease, poor response to therapy and survival. Trastuzumab is used to treat BC cells that overexpress HER2, increasing the overall survival, but at the same time, the risk of cardiotoxicity. 5,6 A 2001 pivotal study reported a gain of survival of 4.8 months when trastuzumab is administered with anthracycline; however, 27  % of patients who received the combination therapy developed signs of HF (16 % were in New York Heart Association 56 [NYHA] class III–IV). 4 Pooled data on the use of trastuzumab have reported an incidence of LVD of 3–7  % (trastuzumab alone), up to 27  % when administered with anthracyclines; 5,7 while adjuvant trastuzumab after anthracyclines and paclitaxel is associated with an incidence of 4–18.6 % for LVD and 1.6–3.3  % for HF. 6,8,9 Analysis of more than 45,000 cases of early-stage BC treated in woman >65 years old has shown that patients who received both trastuzumab and anthracycline had an absolute 23.8 % higher rate, and those treated with anthracycline chemotherapy alone has an absolute 2.1 % higher rate of HF or cardiomyopathy (CM) events over 3 years compared with patients who received no adjuvant chemotherapy or trastuzumab. 10 Use of trastuzumab was associated with an absolute 14 % higher adjusted incidence rate for HF or CM over 3 years. 10 Furthermore, among BC survivors >65 years old, 29.2  % were observed to have pre- existing cardiovascular diseases (CVDs) or diabetes at the time of diagnosis. 11 The risk factors described for the development of trastuzumab-induced cardiotoxicity include age >50 years, borderline left ventricular ejection fraction (LVEF) before treatment, history of CVD, cardiovascular risk factors (CVRFs) such as diabetes, dislipidaemia or elevated body mass index (>30), prior treatment with anthracyclines 12–14 and, possibly, genetic background and immune status. 15 There are some differences between anthracycline and trastuzumab cardiotoxicity: the first is irreversible, dose-related and associated with ultrastructural changes at the endomyocardial biopsy, while the second is reversible, responsive to medical therapy and does not appear to be dose related. 16,17 What are the causes of trastuzumab’s cardiotoxicity, especially in co- administration with anthracyclines? HER2 plays an important role in © Touch ME d ica l ME d ia 2013