Adjuvant breast cancer treatments cardiotoxicity and modern methods of detection and prevention of cardiac complications.

Introduction

Epidemiology breast cancer

The most common cancer diagnosis in women is breast cancer, which affects about 2.0 million women worldwide every year between 45 and 69 years of age, and about half a million die because of it. 1 The most important factors increasing the risk of breast cancer include alcohol abuse, smoking (especially before the age of 44 years), genetic factors, a family history of cancer, high socioeconomic status, the use of hormone replacement therapy in postmenopausal women and also contraceptives, a history of benign breast lesions, more advanced age (over 50 years), and reproductive factors. Genetic factors particularly include gene mutations affecting BRCA1 (breast cancer susceptibility gene 1; breast cancer 1, early onset located on a long arm of chromosome 17) and BRCA2 (breast cancer susceptibility gene 2; breast cancer 2, early onset located on a long arm of chromosome 13). Reproductive factors embrace early puberty, late menopause, and late age of the first full‐term pregnancy. 1 , 2 Owing to the introduction of population screening tests in 1986 in the UK and in the USA as well as in 2003 in the European Union member countries, the detection of breast cancer at an early stage of the disease development has increased. The related mortality has decreased. Currently, mammography is a screening test recommended by European and American Cancer Societies; in Europe, mammography is intended for women aged 50–69 years to be performed every 2 years. 1 , 2 , 3 , 4

Search strategy

We searched the electronic database PUBMED (2000 to 2020). Additionally, abstracts from national and international cardiovascular meetings, summaries of product characteristics, and selected monographs were searched. When necessary, the relevant authors were contacted to obtain further data. The main data search terms were breast cancer, adjuvant therapy, radiotherapy, toxicity of oncological treatment, diagnosis and cardiotoxicity, biomarker(s), marker(s), microRNA, anthracycline transporter proteins, and diagnosis and heart failure.

Pathomechanism and clinical symptoms of cardiovascular damage in patients undergoing chemotherapy and radiotherapy for breast cancer

The improvement in the effectiveness of oncological treatments and the prolongation patients' life expectancy are in some patients associated with the occurrence of organ complications as side effects of this treatment. The most common complications involve the dysfunction of the cardiovascular system manifested by damage of cardiomyocytes. Such damage can lead to asymptomatic left ventricular dysfunction or even overt heart failure, abnormal valve function, cardiac arrhythmias and conduction disorders, myocarditis, pericarditis, as well as endothelial damage and premature development of atherosclerosis and thromboembolic complications. 5 , 6 , 7 , 8 , 9

Myocardial damage after the use of cardiotoxic drugs in women (chemotherapy‐related cardiac dysfunction; CTRCD) is defined as a decrease in left ventricular ejection fraction (LVEF) of >10 percentage points, to a value <53%. 10 , 11 Among oncological drugs with proven cardiotoxic effects, there are cytostatic agents (anthracycline antibiotics, 5‐fluorouracil, and cyclophosphamide), molecularly targeted drugs (trastuzumab and pertuzumab), taxanes, and radiotherapy. 5 , 6 , 8 , 9

Anthracyclines

Anthracyclines are antibiotics produced by Streptomyces peucetius var . caesius , which are commonly used in the treatment of breast cancer. 12 , 13 Their cardiotoxic effects are related to several mechanisms like DNA structure damage, lipid peroxidation, and changes in the structure of cell membranes 12 , 13 as well as in the activation of p53 (tumour‐suppressor protein), mitochondrial dysfunction, the generation of free oxygen radicals, and, in consequence, the death of myocardial cells. 14 , 15 , 16

Another important mechanism for the cardiotoxicity of anthracycline drugs is associated with excessive accumulation of iron ions in cardiomyocytes and the production of free radicals. 17 , 18

Apoptosis is another mechanisms of myocardial cell damage. Anthracyclines inhibit the phosphatidylinositol 3‐kinase (PI3K/Akt) pathway, 19 , 20 , 21 , 22 altering cell susceptibility to anthracycline‐induced apoptosis ( Figure 1 ). 19 , 20 , 21 , 22

Regardless of the mechanism, the action of anthracyclines finally causes the damage to genetic material and blocks cell proliferation, which consequently leads to the death of both cancer and myocardial cells. 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22

Anthracycline‐induced cardiotoxicity can be divided into acute, early‐onset chronic progressive cardiotoxicity, and late‐onset chronic progressive cardiotoxicity. 23 , 24 , 25 , 26 Acute toxicity is quite rare (<1%), and it does not depend on the dose. It occurs during the infusion of cytostatics or up to 2 weeks after its completion. The most common clinical image of acute anthracycline‐induced cardiotoxicity are the supraventricular arrhythmias, symptoms suggestive of myocarditis and pericarditis, left ventricular systolic dysfunction, and changes in the electrocardiogram (non‐specific ST‐T segment changes and QTc interval prolongation). The acute cardiotoxicity is usually reversible, but if it is accompanied by an increase in cardiac biochemical markers, it can lead to progressive heart failure. 23 , 24 , 25 Early‐onset chronic progressive cardiotoxicity occurs in 1.6–2.1% of patients, and it often develops asymptomatically within the first 12 months after the completion of treatment. Late‐onset chronic progressive cardiotoxicity occurs in 1.5–5% of patients after 1 year from the initial exposure and even after 10–20 years after the completion of anthracyclines treatment. 23 , 24 , 25 , 26 The anthracycline cardiotoxicity depends on a total cumulative dose. Currently, the maximum doxorubicin dose is 450–550 mg/m 2 . The dose of 450 mg/m 2 is used in case of patients with concomitant risk factors for cardiomyopathy, while the dose of 550 mg/m 2 can be used in those without additional risk factors. 27 The use of doxorubicin at a dose exceeding the maximum dose significantly increases the risk of myocardial damage and left ventricular dysfunction. 27 , 28 This risk is around 5% for the 400 mg/m 2 dose, 26% for the 550 mg/m 2 dose, and over 48% for the total dose of 700 mg/m 2 . 28 Anthracycline‐induced cardiotoxicity is manifested by progressive and mostly irreversible impairment of diastolic function, followed by left ventricular systolic dysfunction, accompanied by cardiac arrhythmias, low electrocardiographic QRS voltage and an increase in cardiac troponin levels. 23 , 24 , 25 , 26 However, there is increasing evidence of myocardial recovery after anthracycline‐induced damage. Cardinale et al ., in the study of 201 patients with myocardial injury after anthracycline treatment (LVEF < 45%), observed normalization of the LVEF in 64% of the patients that treatment with enalapril and carvedilol within 2 months after the completion of chemotherapy. 29

Targeted therapy for breast cancer

Recently, oncological treatment of breast cancer has been supplemented with targeted therapy involving drugs directed at specific molecular targets, such as membrane receptor kinases. The membrane receptor kinases are engaged in signalling pathways that are essential for the development of cancer. They include substances that act extracellularly (monoclonal antibodies) or intracellularly (tyrosine kinase inhibitors). 5 , 8 , 27 Monoclonal antibodies bind to specific receptors on cell surface, thus inhibiting signalling pathways regulated by these receptors. Antibodies and small molecule inhibitors of specific HER2 receptor kinases are main compounds used in targeted therapy of breast cancer. 5 , 8 , 27 , 28

Monoclonal antibodies

Trastuzumab—human epidermal growth factor receptor type 2 (HER2) antagonist

Trastuzumab is the representative of the first group of drugs used in the therapy of breast cancer overexpressing HER2 receptors. 5 , 8 , 30 It is a humanized monoclonal antibody targeting the human epidermal growth factor HER2 receptor. 6 , 30 , 31 , 32 , 33 Trastuzumab‐related myocardial dysfunction, especially in combination with anthracyclines, is a significant limitation of oncological therapy. HER2 receptor is expressed by myocardial cells. As a result of trastuzumab activity, oxidative stress increases the concentration of angiotensin II in cardiomyocytes, which blocks the binding of neuregulin 1 to HER receptors, inhibiting anti‐apoptotic cell pathways. Blocking HER2‐activated cell pathways impairs growth and repair mechanisms in cardiomyocytes, which results in myocardial dysfunction. 34 , 35 Myocardial damage is in most cases reversible. However, the evidence from retrospective studies indicates that the cardiotoxic side effects of trastuzumab may persist many years after the completion of the therapy; consequently, they are not always reversible as it was initially suggested. 34 , 36 , 37 Cardiotoxicity involves structural and functional changes in contractile proteins and mitochondria and rarely leads to cell death. Moreover, it does not depend on the drug dose. It develops during treatment or in a short period after the completion of chemotherapy. The most common clinical image of anti‐HER2‐related cardiotoxicity is left ventricular systolic dysfunction, without any associated changes in electrocardiographic records, with rarely co‐existing severe symptoms of heart failure. 36 , 37

Therapies based on the combined administration of anthracyclines and trastuzumab improve treatment results by over 50% and increase the survival rate of patients with HER2 positive breast cancer by 35%. 38 , 39 , 40 , 41 The effectiveness of the combined use of these drugs is unfortunately limited by an increased risk (5–10%) of myocardial dysfunction and severe heart failure. 39 Cardiomyocyte damage related to anthracycline activity increases HER2 expression, which activates intracellular repair processes. 39 , 40 , 41 Inhibition of HER2 activity by trastuzumab increases myocardial cell susceptibility to anthracycline toxicity. 39 , 40 , 41 Myocardial injury following the combination therapy of anthracyclines and trastuzumab is usually irreversible. 41

Bevacizumab—VEGF endothelial growth factor antagonist

Despite the breast cancer indication for bevacizumab had been withdrawn by FDA after concluding that the drug has not been shown to be safe and effective for the treatment of breast cancer, 42 , 43 some experts consider it an option for extensive cutaneous inflammatory disease due to its potential antiangiogenic effect. 43

Tyrosine kinase inhibitors

Lapatinib is an oral, reversible inhibitor of EGFR and HER2 tyrosine kinases approved for the treatment of patients with HER2‐positive metastatic breast cancer who fail to respond to anthracyclines, taxanes, and trastuzumab therapy. 5 , 7 , 44 , 45 Cardiotoxicity induced by tyrosine kinase inhibitors develops when the target of an inhibitor is a kinase whose function is important for the proper functioning of the cardiovascular system. 28

Lapatinib treatment is associated with a lower risk of cardiovascular adverse reactions than trastuzumab. 46 , 47 Lapatinib‐related cardiotoxicity in the form of reversible left ventricular systolic dysfunction develops in approximately 1.5% of patients. However, it is not a reason for a permanent discontinuation of oncological treatment. 48

Alkylating agents—cyclophosphamide

Apart from anthracycline drugs, in a conventional chemotherapy for breast cancer, alkylating agents such as cyclophosphamide are also used. 5 , 8 , 49 The pathogenesis of cyclophosphamide‐related cardiotoxicity is associated with toxic effects of its active metabolites on cardiomyocytes and endothelial cells, through the production of free oxygen radicals and lipid peroxidation. 50 In consequence, this leads to vascular endothelial damage, exudate, haemorrhage, and interstitial oedema, which clinically manifest as haemorrhagic myocarditis, myocarditis, and pericarditis with accompanying pericardial fluid and asymptomatic left ventricular dysfunction or symptomatic heart failure that is usually reversible. 51 , 52 , 53 Moreover, changes in electrocardiographic record, including supraventricular and ventricular tachyarrhythmias, atrioventricular conduction blocks, low amplitude of QRS complexes, and changes in the ST‐T segment are observed. 20 , 54 Symptoms of myocardial damage occur up to 10 days after drug administration, and usually, they disappear after few days. One of the most important risk factor for cyclophosphamide‐induced cardiotoxicity is the use of high drug doses (Santos et al . more than 270 mg/kg over 1–4 days and Goldberg et al . doses equal or greater than 1.55 g/m 2 ). 55 , 56 However, acute toxicity has been reported even after total doses of 100 mg/kg. 53 Furthermore, it seems that cyclophosphamide cardiotoxicity manifests more often in lymphoma patients than breast cancer patients (Brockstein et al .). 57 The advanced age, pre‐existing heart disease, concomitant or previous use of cardiotoxic drugs, and the history of local radiation of the heart region are also associated with cyclophosphamide‐related cardiotoxicity. 55 , 56 , 57

Antimetabolites

Antimetabolites, fluoro‐derivatives of pyrimidine, such as 5‐fluorouracil (5‐FU) and its oral prodrug, capecitabine, are compounds that cytostatic activity is related to the inhibition of the production of nucleic acid precursors necessary for DNA replication. 58 , 59 , 60 , 61 The pathomechanism of fluoropyrimidine‐related cardiotoxicity is associated with the toxic effects of their metabolites, that is, fluoroacetate and fluoro‐β‐alanine, on coronary artery myocytes and direct damage to cardiomyocytes. 62 , 63 Resting and exercise angina as well as myocardial infarction resulting from coronary vasospasm and reduced myocardial perfusion are the most common clinical images of fluoropyrimidine‐related cardiotoxicity. 64 , 65 , 66 , 67 , 68 Moreover, supraventricular 69 and ventricular tachyarrhythmias, 70 bradycardia, 71 myocarditis and pericarditis, 72 , 73 heart failure, 74 and even deaths. 75 , 76 , 77

Microtubule inhibitors

Substances belonging to microtubule inhibitors used in oncological therapy of breast cancer include taxanes: paclitaxel, isolated from short‐leaf yew ( Taxusbrevifolia ) and docetaxel, isolated from English yew ( Taxusbaccata ). 5 , 8 , 78 Taxanes in combination with anthracyclines exert the strongest toxic effect on the heart muscle. 79 , 80 , 81 , 82 Taxanes stimulate the transformation of an anthracycline molecule into its alcohol derivative in a NADPH reductase‐dependent manner, thus resulting in the formation of doxorubicinol and epirubicinol, which impair iron and calcium homeostasis and increase the production of oxygen free radicals more intensively than doxorubicin and epirubicin. 83 Symptoms of taxane‐induced cardiotoxicity include left ventricular dysfunction, asymptomatic bradycardia, arrhythmias, and conduction disorders. 84 , 85

Ionizing radiation

Apart from systemic treatment, radiation therapy plays a very important role in adjuvant therapy for breast cancer. 5 , 8 , 86 Due to the widespread use of this method of treatment, adverse effects of radiation therapy on the cardiovascular system are more often observed, even many years after irradiation. 87 , 88 , 89 , 90

The pathomechanism of the damaging effect of radiation therapy on cardiovascular system structures involves direct ionization and damage of cell components by radiation and by water radiolysis products. 91 The coronary and microcirculation damage is one of radiotherapy complication. It can lead to faster development of coronary heart disease, complicated by atherosclerotic plaque rupture, thrombosis, and frequently asymptomatic myocardial infarction as a result of radiation‐related nerve ending damage. 87 In case of radiation due to left breast cancer, the left anterior descending artery of the left coronary artery is most often affected, and stenoses are usually located in the ostial part of the vessel. 92 Significant lesions in coronary vessels occur 10–15 years after radiotherapy. 93

Valve defects are another significant complication after ionizing radiation treatment for breast cancer, which occurs in about 10% of patients. 90 This defect mainly affects the valves of the left part of the heart, and pathological changes include fibrosis and calcification of the aortic bulb, aortic valve leaflets, mitral ring, and a basal and a central part of the mitral valve leaflets. 94 , 95 , 96 This most often leads to mitral and aortic valve regurgitation and also to aortic stenosis. 94 , 95 , 96 Mean time to onset of clinical symptoms of radiation‐induced valve injury is approximately 98 months. 94

Heart failure is a complication, which is also observed after the use of ionizing radiation. 90 Radiation induces the formation of interstitial fibrosis loci with varying diameters in the myocardium. These loci are frequently located on the anterior wall of the heart, and they rarely cover the entire muscle. 90 , 97 It can also cause microcirculation damage by creating inflammatory infiltrates within small‐sized and medium‐sized arteries, fibrosis, and endothelial cell damage. 88 , 90 HFrEF is more frequently observed in patients who received both anthracycline and radiation therapy. 90

Currently, the incidence of this complication is decreasing due to the introduction of modern radiotherapy techniques based on a computerized treatment planning system (TPS). 98 , 99 Acute radiation‐induced pericarditis occurs after 2 to 145 months (mean 58 months) after radiotherapy in 2–5% of patients. 100 , 101 Late radiation‐induced pericardial disease develops between 6 months to 15 years after radiation therapy, on average, after 12 months. 92 , 102 , 103 It can occur in the form of acute late pericarditis or the presence of chronic fluid in the pericardial sac, which is often asymptomatic. 23 In most of cases, it resolves spontaneously; however, in up to 20% of patients, especially those who received high doses of radiation, the development of chronic and/or constrictive pericarditis has been reported. 23 , 102 The damage to the cardiac conduction system and heart autonomic system is a very rare but equally important complication of radiation therapy. It occurs especially after the administration of high doses of radiation, including high fractional doses. 23 , 103 The clinical picture involves mainly sinus bradycardia, conduction blocks at all levels of the conduction system, and sick sinus syndrome. 23 , 90 Also, QTc prolongation has been observed in patients receiving combination therapy with anthracyclines. Autonomic system damage is manifested by inadequate sinus tachycardia and a lack of heart rate variability. 23 , 91 , 103

Toxic effects of radiation therapy on the heart muscle are mainly determined by the dose, the location of the tumour, and the volume of the heart exposed to radiation (the risk increases significantly when the volume of the heart irradiated exceeds 50%). 90

The summary of cardiotoxic symptoms related to adjuvant breast cancer treatment as well as prevention methods is presented in Table 1 . 8 , 11 , 23 , 24 , 25 , 26 , 36 , 39 , 40 , 41 , 46 , 48 , 51 , 56 , 57 , 60 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 82 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132

Predictors of myocardial damage after chemotherapy and radiation therapy for breast cancer

Adjuvant therapy for breast cancer (both systemic and radiation therapy) is necessary to reduce morbidity and mortality. 5 , 8 The cardiotoxicity of this therapy can lead to the development of heart failure and may negatively affect quality of life and prognosis. 11 , 23 , 24 The high cardiotoxicity‐related morbidity and mortality rates associated with antineoplastic therapy for breast cancer could be reduced with the early use of cardioprotective drugs. 23 , 24 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131

Therefore, it is important to assess the cardiovascular system in each patient before starting oncological therapy and to closely monitor heart muscle during and after treatment. 23 , 24 , 132 , 133 The choice of myocardial function assessment method and the time at which it should be performed in patients with planned adjuvant treatment of breast cancer are precisely specified in the recommendations of American (ASCO, ASE, the American Society of Echocardiography) and European (ESMO, European Society for Medical Oncology; ESC, European Society of Cardiology; EACVI, the European Association of Cardiovascular Imaging) experts in oncology and cardiology. 11 , 23 , 24 , 133 Echocardiography is the first‐line diagnostic tool for the assessment of the cardiovascular system in patients undergoing therapy for breast cancer, which is recommended by the aforementioned experts. 11 , 23 , 24 , 133 The ESC, ESMO, and ASE/ECACVI guidelines also recommend the measurement of cardiac biomarkers together with echocardiography after each chemotherapy cycle (ESC;ESMO) 23 , 24 or during follow‐up echocardiography (ASE/ECACVI). 11

The most important current recommendations are summarized in Table 2 . 11 , 23 , 24 , 133 , 134 , 135

The detection of myocardial damage at the subclinical stage enables early initiation of cardioprotective therapy and prevents the development of irreversible heart failure. 23 , 24 , 133 Diagnostic methods, both imaging and biochemical, which are recommended and currently used in the monitoring of patients with breast cancer who receive potentially cardiotoxic chemotherapy, are an important tool in the prevention of heart failure. 11 , 23 , 24 , 133 , 134 , 135 However, the low sensitivity of left ventricular ejection fraction assessment limits its use in preventive strategy. 136 , 137 New parameters, such as biomarkers and new imaging parameters, might be used in the early detection of myocardial dysfunction.

Imaging tests

Echocardiography

Besides electrocardiography (including measurement of heartrate QTc), also echocardiography is the primary diagnostic test for chemotherapy‐related myocardial damage (CTRCD). 11 , 23 , 24 , 133 , 134 , 135 It is the most commonly used tool for the assessment of cardiac function before the qualification for chemotherapy, as well as during treatment, due to its widespread availability, low cost, and safety. 11 , 23 , 24 , 133 , 134 , 135

Left ventricular ejection fraction (LVEF), estimated using the 2D biplane Simpson's method or more precisely, with the use of three‐dimensional (3D) technique, is the basic parameter assessed during this examination. 11 , 23 , 136 , 137 According to the ASE/EACVI consensus, the decrease of LVEF by 10% to a value below 53% is considered as the evidence of an existing CTRCD. 11

The decrease in left ventricular ejection fraction is a late, often irreversible sign of toxic damage to myocardium. 132 The assessment of global longitudinal strain (GLS) is a sensitive echocardiographic method for the detection of early myocardial damage. 138 , 139 , 140 , 141 , 142 Myocardial deformation is measured using tissue Doppler mode or the speckle tracking echocardiography (STE). They evaluate both segmental and generalized disorders of systolic and diastolic functions of both ventricles. 138 , 139 , 140 , 141 , 142 The measurement of myocardial deformation, especially with the use of STE method, is characterized by high repeatability of measurements and precedes the decrease in left ventricular ejection fraction during oncological treatment. 138 , 139 , 140 , 141 , 142 The ASE/EACVI consensus defines that a relative percentage decrease of GLS by >15% from baseline is a clinically relevant evidence of subclinical left ventricular dysfunction. 11 The disadvantage of this method involves the variability of results depending on the device, software, or patient's age and sex. 11 Therefore, it is recommended to evaluate GLS, preferably on the same device, by the same examiner, before the initiation of treatment, during and after the completion of treatment; subsequent measurements should be compared with baseline measurements. 11 , 23

Echocardiography can also be used to assess other parameters of myocardial function, which have not been included in current recommendations and which may be important in predicting the subclinical cardiotoxicity of radiotherapy and chemotherapy. 143 , 144 , 145 , 146 , 147 , 148

Changes in left ventricular diastolic function parameters, including mitral inflow wave velocity, E/A ratio, pulmonary vein flow, isovolumetric diastolic time, or tissue Doppler velocity, can be observed in patients undergoing oncological treatment a few hours after chemotherapy. 143

A significant decrease in right ventricular systolic and diastolic function and changes in the volume and function of the left atrium in treated oncological patients are also considered as an early marker of CTRCD. 143 , 145 , 146 , 148

Studies and results presenting promising parameters of significant importance in the assessment of oncological treatment related complications are summarized in Table 3 . 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148

Other imaging techniques

Radioisotope ventriculography (MUGA, multiple gate acquisition scan) eliminates inter‐observer variation in LVEF assessment. However, it exposes patients to radiation and provides limited information on cardiac structure and diastolic function. In turn, magnetic resonance imaging of the heart allow to thoroughly estimate myocardial structures and function, which are difficult to evaluate by echocardiography, particularly in case of unsatisfactory quality of echocardiographic imaging. 11 , 149 Moreover, it is the non‐invasive tool for assessment and monitoring of cardiotoxicity, including cardiac tissue characterization, perfusion, and features, which may assist the differential diagnosis (ischaemic and non‐ischaemic) and management of myocardial injury in cancer survivors. 149 However, due to the high cost and limited availability, this imaging method is not the first‐line examination used in routine monitoring of patients undergoing cardiotoxic therapy. 23

Biomarkers

The monitoring of myocardial function with the use of repeated echocardiographic examinations in order to detect toxic effects of adjuvant breast cancer therapy on myocardium is still a suboptimal approach. 11 The determination of cardiomyocyte‐specific plasma biomarkers has proved to be a promising complement to routine echocardiography. 150 Plasma biomarkers, cardiac troponins and natriuretic peptides, have been evaluated in many studies for their usefulness for early detection of myocardial damage in patients without clinical symptoms. 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 Troponin concentration shows high specificity and sensitivity for myocardial damage detection. Its measurement is minimally invasive, cheaper than imaging tests, standardized (there is no variability between observers), and shows high negative predictive value, and the result is independent of the mechanism of cardiotoxicity. 24 , 160 , 161 Cardinale et al . proved the superior diagnostic value of cardiac troponins in patients receiving high‐dose (>240 mg/m 2 ) anthracycline chemotherapy than low‐dose anthracycline therapy. 162 The troponin levels closely correlate with the subsequent reduction of LVEF 161 ; therefore, it allows identification of patients who will require further cardiovascular monitoring or cardioprotective therapy. 24 , 152 , 153 , 154

In turn, the study of Rüger et al . revealed that N‐terminal‐pro‐brain natriuretic peptide (NT‐proBNP) and haemoglobin but not cardiac troponin T are strongly associated with cardiotoxic reactions. In this study, electrocardiogram, echocardiographic, and haemodynamic parameters as well as NT‐proBNP and cardiac troponin T were assessed in 853 early‐stage breast cancer women to establish predictors of cardiotoxic reactions while undergoing chemotherapy. 163 Natriuretic peptides, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and their N‐terminal fragments (NT‐proANP, N‐terminal‐pro‐atrial natriuretic peptide; NT‐proBNP) are released by cardiomyocytes in response to volume or pressure overload and wall stretching. It results in increased glomerular filtration and the excretion of water and sodium, as well as the inhibition the activity of renin‐angiotensin‐aldosterone (RAA) system. Moreover, they inhibit the sympathetic nervous system and directly dilate blood vessels. 159 Therefore, they are involved in the maintenance of homeostasis related to blood pressure and circulating blood volume. Plasma level of natriuretic peptide is an important prognostic indicator of 30 day mortality in patients with decompensated heart failure related to ischaemic and non‐ischaemic causes. 164 , 165 Moreover, in combination with cardiac troponins, they are also biomarkers of chronic and functional heart damage. 166 , 167 Therefore, their measurement is recommended and commonly used in the diagnosis and monitoring of heart failure treatment (mainly BNP and NT‐proBNP due to their longest half‐life). 168 In the largest study on the role of BNP in the detection of early cardiotoxicity, Skovgaard et al . 156 demonstrated that in a group of 333 patients with different types of cancers, undergoing potentially cardiotoxic treatment, BNP level >100 pg/mL was a marker of early heart failure (HR: 5.5; 95% CI: 1.8 to 17.2, P = 0.003). The usefulness of BNP measurement in predicting early cardiotoxicity has also been demonstrated in meta‐analysis of eight cohort studies performed by Ya‐di Wang et al . 153 The study on the role of NT‐proBNP as an early marker of cardiac dysfunction after the use of high doses of chemotherapy in patients with aggressive tumours revealed that persistent elevation of plasma NT‐proBNP levels was associated with the deterioration of diastolic and systolic parameters of LV function as IRT (90 ms vs. 141 ms; P < 0.0001), DecT (162 vs. 224 ms; P = 0.0004), and LVEF (62.8% vs, 45.6%, P < 0.0001). 158 However, the interpretation of cardiac troponin and natriuretic peptide levels with reference to oncological therapy‐induced cardiotoxicity has some limitations. The significant limitations of those methods are the lack of final agreement regarding the cut‐off values for these parameters and their levels variability depending on the presence of concomitant diseases. Moreover, increased levels of cardiac biomarkers confirm pre‐existing damage to the heart muscle cell. 159 Currently, ESC 23 and ASE/EACVI 11 experts recommend the determination of cardiac troponin as a supplement to the LVEF assessment during routine monitoring of patients undergoing cardiotoxic therapy. 11 , 23

New plasma biomarkers

Many studies evaluated the clinical utility of new plasma biomarkers, such as C‐reactive protein (CRP), 160 , 161 , 169 , 170 myeloperoxidase (MPO), 160 , 161 , 171 galectin 3 (gal‐3) (fibrosis marker), 160 , 161 , 172 BB glycogen phosphorylase (GPBB), 173 , 174 placental growth factor (PIGF), 160 , 161 , 171 growth differentiation factor (GDF‐15), 151 , 160 endothelin‐1, 175 as well as circulating microRNAs 176 , 177 in the monitoring of myocardial toxicity of adjuvant breast cancer therapy.

Putt et al . 161 assessed the role of selected‐biomarkers [hs‐cTnI, NT‐proBNP, hsCRP, GDF‐15, MPO, PIGF, soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and gal‐3] in the prediction of early cardiotoxicity in 78 patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab, and they found a significant correlation between the analysed markers (except for NT‐proBNP and gal‐3) and the development of cardiotoxicity in the 3rd month of therapy. After 15 months of follow‐up, elevated levels hsTnI and, to a lesser extent, GDF‐15 and PIGF were observed. Finally, the authors concluded that the analysis of three of the aforementioned biomarkers (MPO, PIGF, and GDF‐15) could improve the identification of patients who are at risk of cardiotoxicity. However, in this study, no such relationship was found for troponin I, NT‐proBNP, or hsCRP. 161 Ky et al . 160 have demonstrated that MPO could be used in combination with TnI to identify patients who had a significantly higher risk of cardiotoxicity as a result of combination anthracycline therapy. Patients with MPO levels in the 90th percentile had a predicted cardiotoxicity rate of 36.1% after 15 months. 160

A pilot study performed by Gullo et al . 171 assessed the role of selected biomarkers (VEGF, endothelial growth factor; PIGF, placental growth factor; MPO, myelopreoxidase, cTnI, troponin I) in the detection of early cardiotoxicity in patients with early stage of HER‐2 negative breast cancer treated with bevacizumab in combination with docetaxel and cyclophosphamide as an adjunctive therapy. In their study, only elevated PIGF level at baseline correlated with a subsequent significant decrease in LVEF (especially in the third cycle of chemotherapy). The decrease in VEGF concentration after 6 months correlated with higher LVEF assessed at the same time in comparison with LVEF assessed at the beginning of the study. In turn, Onitilo et al . 172 showed that regular monitoring of hs‐CRP could be beneficial for the identification of women with early stage of breast cancer and a low risk of asymptomatic trastuzumab‐induced cardiotoxicity. However, this study failed to reveal such relationship for troponin I and BNP. 171

Recently, more and more studies have been devoted to the assessment of microRNAs as markers of early cardiotoxicity. 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 Small non‐coding single‐stranded RNAs—microRNAs (miRs)—regulate gene expression at the post‐transcriptional level under both physiological and pathophysiological conditions. Therefore, they play an important role in the regeneration of various tissues and organs, including myocardium. 182 , 183 , 184 The repair of myocardial cells involves the regulation of apoptosis, proliferation, metabolism, angiogenesis, and aging by miRs. 189 MiR‐590 promotes cardiac regeneration by activating cardiomyocyte proliferation, 176 a set of specific miRs (miR‐1, miR‐133, miR‐208, and miR‐499) is efficient at converting cardiac fibroblasts into cardiomyocytes, 183 while miR‐34a inhibits heart regeneration via the induction of apoptosis. 176 The change in plasma level of circulating miR, including miR‐1, miR‐34a, and miR‐150 after the exposure to anthracyclines, occurs before myocardial cell damage. 176 , 184 , 185 Therefore, circulating miRs may pose early markers of myocardial damage, for example, after chemotherapy or ischaemia, the detection of which is possible even before the increase in other biomarkers, such as cardiac troponins or natriuretic peptides. 177 , 184 , 185

New plasma biomarkers can pose a promising tool for detecting early cardiotoxicity and for the identification of patients who require increased cardiovascular monitoring or cardioprotective therapy.

Studies and results presenting new biomarkers with potential significance in the detection of early cardiotoxicity are summarized in Table 4 . 160 , 161 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177

Genetic polymorphisms predictors of cardiotoxicity

The aforementioned new echocardiographic parameters and plasma biomarkers are considered as useful in the detection of early cardiotoxicity. They allow the identification of patients with pre‐existing myocardial damage before a decrease in LVEF or the appearance of heart failure symptoms. However, this myocardial damage has irreversibly activated compensatory mechanisms and reserves in the heart muscle, which can only be slowed down by cardioprotective therapy.

Therefore, the search for a genetic predisposition to the toxic effects of chemotherapy or resistance to the adjuvant treatment of breast cancer seems to be an important direction of current clinical research. It could help to design more individualized treatment regimens with a minimal risk of cardiotoxicity for the patient. Anthracyclines, due to their high anti‐cancer efficacy, are still the basis of breast cancer treatment. 5 , 8 , 133 The limitation of their use is associated with the dose‐dependent cardiotoxicity, which may occur even without exceeding the total dose, but also at lower doses (150 mg/m 2 ) that are considered as safe. 186 This suggests the existence of inter‐individual differences in the pharmacogenetics of anthracycline metabolism, which may have a significant impact on the anti‐tumour efficacy and toxicity of these chemotherapeutics. 187

Genes encoding proteins, which play an important role in anthracycline metabolic pathway, include, but are not limited to, genes encoding drug metabolizing enzymes and proteins involved in drug transport. 188 Two types of anthracycline, efflux transporter proteins (ABC, ATP‐binding cassette family) and influx transporters (SLC, solute carrier family transporter), have been identified. 188 Transporters belonging to the ABC family 189 are transmembrane ATP‐dependent pumps present, among others, in the liver, kidneys, intestines, as well as in the heart, lungs, and reproductive organs. They regulate the distribution of endogenous metabolites and xenobiotics, including chemotherapeutics and also participate in their excretion from the body. In the heart, they participate in the protection of this organ against toxic compounds and drug‐induced oxidative stress. 189 Moreover, proteins belonging to the ABC family are associated with cancer cell resistance to chemotherapy (MRP1, multidrug resistance‐associated protein 1). 190

Influx transporters (SLC, solute carrier family transporter) are involved in the transport of substances and xenobiotics to the cell. 188 Furthermore, SLC is involved in anthracycline uptake by cancer cells and other tissues, including cardiomyocytes. 188 The role of polymorphisms within genes encoding transporter proteins (ABC and SLC) in anthracycline‐induced cardiotoxicity or cancer cell resistance to cancer treatment is currently the subject of numerous studies since such polymorphisms may affect the efficacy and safety of chemotherapy. 191 , 192 , 193 , 194 , 195

The correlation between SLC28A3 rs7853758 and rs885004 polymorphisms and anthracycline toxicity has been demonstrated in two cohort studies involving paediatric anthracycline‐treated patients. 191 , 192 However, a study of adult patients with breast cancer failed to show such relationship in case of SLC28A3 rs7853758 polymorphism. 193 In turn, in a study of patients with breast cancer, 194 the presence of SLC22A16 polymorphisms was associated with lower (rs714368, rs6907567, and rs723685) or greater (rs12210538) anthracycline toxicity. In a study of adult patients treated with anthracyclines for acute myeloid leukaemia, the presence of ABCG2 rs2231142 polymorphism was associated with a higher risk of cardiotoxicity. 195

The aforementioned studies suggest that genotyping combined with clinical image analysis can help to identify patients predisposed to oncological treatment‐induced cardiotoxicity. This method also enables the individualization of both the treatment plan and cardiovascular monitoring.

Clinical relevance and novelty aspects in cardiotoxicity of adjuvant breast cancer treatment breast cancer cardiotoxicity

Adjuvant therapy for breast cancer (both systemic and radiation therapy) is necessary to reduce morbidity and mortality. Unfortunately, its cardiotoxicity is a limitation of this therapy. The main reason is that its use can lead to the development of heart failure and may negatively affect quality of life and prognosis. Therefore, the knowledge of the mechanisms of toxic effects of modern oncological treatment methods and the optimization of cardiovascular risk factors is of high importance. The American (ASCO and ASE) and European (ESMO, ESC, and EACVI) experts in oncology and cardiology offer general guidelines for monitoring high risk patients for cardiotoxicity. A number of risk factors are common to both breast cancer and cardiovascular disease (CVD). The cardiac risk factors and pre‐existing CVD can have also an influence on cancer treatment methods. 196 During breast cancer treatment, surveillance, prevention, and secondary management of cardiotoxicity are crucial. Thereafter, long‐term post‐treatment monitoring for late cardiotoxicity and even non‐treatment‐related development of CVD is essential. Modifications of risk factors owing to blood pressure control, diabetes mellitus management, a proper lipid profile as well as a promoting a healthy diet, a healthy weight, physical activity and abstinence from tobacco, can prevent about 80% CVD. 197 Risk factors for breast cancer have only been discussed more recently, but there is growing awareness that through risk factor modification, some cases of breast cancer might be prevented. 198 The time when best start cardioprotection is still not clearly specified. Moreover, the use of cardiovascular drugs such as beta‐blockers, angiotensin‐converting‐enzyme inhibitors (ACEIs), and angiotensin receptor blockers, statins, or aerobic exercise to prevent cardiotoxicity is controversial and based on a limited number of clinical trials.

In meta‐analysis included randomized clinical trials of adult patients that underwent chemotherapy and neurohormonal therapies (beta‐blockers, ACEIs, angiotensin receptor blockers, and mineralocorticoid receptor antagonists) observed association between treatment with cardiovascular drug and higher LVEF in follow‐up among cancer patients receiving chemotherapy. 199 In turn, the CECCY (Carvedilol Effect in Preventing Chemotherapy Induced Cardiotoxicity) trial tested the use of beta‐blocker (carvedilol) versus placebo in 200 patients with breast cancer and normal LVEF receiving anthracycline 240 mg/m 2 . Carvedilol had no impact on the incidence of early onset of LVEF reduction. 200 Statins are another class of drugs that have been evaluated for their cardioprotective role in cancer patients exposed to cardiotoxic agents. In retrospective study of Seicean et al ., women receiving uninterrupted statin therapy throughout the approximately 3 year follow‐up period demonstrated significantly lower hazard ratios (HR: 0.3; 95% CI: 0.1–0.9; P = 0.03) for development of heart failure as compared with the control groups. More studies regarding the use of statins are emerging in the field of cardio‐oncology. 201

In prospective analysis of 2973 non‐metastatic breast cancer women (8.6 year median follow‐up), routine exercise of ≥9 MET‐hour/week was associated with a reduction in CV events (new diagnosis of coronary artery disease, valve abnormality, arrhythmia, stroke, or CVD death). 202 Furthermore, there are data suggesting those who start physical activity after a diagnosis of breast cancer have a lower risk of death in general. 203 The American Heart Association (AHA) recommend physical activity as an individualized cardiac rehabilitation intervention for those most at risk of developing cardiotoxicity 204 and the European Society for Medical Oncology (ESMO) to recommend exercise for all cancer survivors. 24 However, further large‐scale studies are needed to determine specific exercise recommendations based on population and risk stratification.

Echocardiography, electrocardiography as well as with the analysis of the concentration of cardio‐specific serum biomarkers (such troponin T and NT‐proBNP) are the first‐line diagnostic tool for the assessment of the cardiovascular system in such patients. Elevated troponin levels predict LV dysfunction in patients receiving cancer therapy. Assessment of troponin levels may be a screening test to identify patients who require referral to cardio‐oncology units and benefit from preventive strategies. 205

The low sensitivity of left ventricular ejection fraction assessment limits its use in preventive strategy. New imaging parameter, such as GLS, is more useful echocardiographic method for the detection of early myocardial damage. Moreover, the assessment of other parameters of myocardial function, which have not been included in current recommendations such right ventricular function, changes in left ventricular diastolic function or changes in the volume and function of the left atrium may be important in predicting the subclinical cardiotoxicity of radiotherapy and chemotherapy.

The search for and the analysis of new cardio‐specific biomarkers in serum, such as C‐reactive protein (CRP), myeloperoxidase (MPO), BB glycogen phosphorylase (GPBB), placental growth factor (PIGF), as well as circulating microRNAs in the monitoring of myocardial toxicity of adjuvant breast cancer therapy, can pose a promising tool for detecting early cardiotoxicity and for the identification of patients who require increased cardiovascular monitoring or cardioprotective therapy. Moreover, a genetic predisposition to the toxic effects of chemotherapy or resistance to the adjuvant treatment of breast cancer seems to be an important direction of current clinical research. The genes encoding proteins, which play an important role in anthracycline metabolic pathway, in particular presented by us genes encoding proteins involved in drug transport, suggest that genotyping combined with clinical condition and imaging biomarkers may become a useful method for identifying patients at risk of developing cardiotoxicity. It could help to design more individualized treatment regimens with a minimal risk of cardiotoxicity for the patient.

Conflict of interest

The authors declare no conflict of interest.

Funding

The project is financed by Polish Mother’s Memorial Hospital Research Institute and the Polish National Agency for Academic Exchange.

Bikiewicz, A. , Banach, M. , von Haehling, S. , Maciejewski, M. , and Bielecka‐Dabrowa, A. (2021) Adjuvant breast cancer treatments cardiotoxicity and modern methods of detection and prevention of cardiac complications. ESC Heart Failure, 8: 2397–2418. 10.1002/ehf2.13365.

References

1. Bray F, Ferlay J, Soerjomataram I, Siegel R, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68: 394–424.

2. Momenimovahed Z, Salehiniya H. Epidemiological characteristics of and risk factors for breast cancer in the world. Breast Cancer (Dove Med Press) 2019; 11: 151–164.

3. Smith RA, Andrews KS, Brooks D, Fedewa SA, Manassaram‐Baptiste D, Saslow D, Wender RC. Cancer screening in the United States, 2019: a review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin 2019; 69: 184–210.

4. Schünemann HJ, Lerda D, Quinn C, Follmann M, Alonso‐Coello P, Rossi PG, Lebeau A, Nyström L, Broeders M, Ioannidou‐Mouzaka L, Duffy SW, Borisch B, Fitzpatrick P, Hofvind S, Castells X, Giordano L, Canelo‐Aybar C, Warman S, Mansel R, Sardanelli F, Parmelli E, Gräwingholt A, Saz‐Parkinson Z. European Commission Initiative on Breast Cancer (ECIBC) Contributor Group. Breast cancer screening and diagnosis: a synopsis of the European breast guidelines. Ann Intern Med 2020; 172: 46–56.

5. Burstein HJ, Curigliano G, Loibl S, Dubsky P, Gnant M, Poortmans P, Colleoni M, Denkert C, Piccart‐Gebhart M, Regan M, Senn HJ, Winer EP, Thurlimann B. Estimating the benefits of therapy for early‐stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer. Ann Oncol 2019; 30: 1541–1557.

6. Hoon Tan P, Ellis I, Allison K, Brogi E, Fox SB, Lakhani S, Lazar AJ, Morris EA, Sahin A, Salgado R, Sapino A, Sasano H, Schnitt S, Sotiriou C, van Diest P, White VA, Lokuhetty D, Cree IA. WHO Classification of Tumours Editorial Board. The 2019 WHO classification of tumours of the breast. Histopathology 2020; 77: 181–185.

7. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lønning PE, Børresen‐Dale AL, Brown PO, Botstein D. Molecular portraits of human breast tumours. Nature 2000; 406: 747–752.

8. Gradishar WJ, Anderson BO, Balassanian R, Blair SL, Burstein HJ, Cyr A, Elias AD, Farrar WB, Forero A, Giordano SH, Goetz MP, Goldstein LJ, Isakoff SJ, Lyons J, Marcom PK, Mayer IA, McCormick B, Moran MS, O'Regan RM, Patel SA, Pierce LJ, Reed EC, Salerno KE, Schwartzberg LS, Sitapati A, Smith KL, Smith ML, Soliman H, Somlo G, Telli M, Ward JH, Shead DA, Kumar R. NCCN guidelines insights: breast cancer, version 1.2017. J Natl Compr Canc Netw 2017; 15: 433–451.

9. Herrmann J, Lerman A, Sandhu NP, Villarraga HR, Mulvagh SL, Kohli M. Evaluation and management of patients with heart disease and cancer: cardio‐oncology. Mayo Clin Proc 2014; 89: 1287–1306.

10. Ewer MS, Lippman SM. Type II chemotherapy‐related cardiac dysfunction: time to recognize a new entity. J Clin Oncol 2005; 23: 2900–2902.

11. Plana JC, Galderisi M, Barac A, Ewer MS, Ky B, Scherrer‐Crosbie M, Ganame J, Sebag IA, Agler DA, Badano LP, Banchs J, Cardinale D, Carver J, Cerqueira M, DeCara JM, Edvardsen T, Flamm SD, Force T, Griffin BP, Jerusalem G, Liu JE, Magalhães A, Marwick T, Sanchez LY, Sicari R, Villarraga HR, Lancellotti P. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2014; 15: 1063–1093.

12. Zhang S, Liu X, Bawa‐Khalfe T, Lu LS, Lyu YL, Liu LF, Yeh ETH. Identification of the molecular basis of doxorubicin‐induced cardiotoxicity. Nat Med 2012; 18: 1639–1642.

13. Blum RH, Carter SK. Adriamycin. A new anticancer drug with significant clinical activity. Ann Intern Med 1974; 80: 249–259.

14. Tewey KM, Rowe TC, Yang L, Halligan BD, Liu LF. Adriamycin‐induced DNA damage mediated by mammalian DNA topoisomerase II. Science 1984; 226: 466–468.

15. Cuomo A, Rodolico A, Galdieri A, Russo M, Campi G, Franco R, Bruno D, Aran L, Carannante A, Attanasio U, Tocchetti C, Varricchi G, Mercurio V. Heart failure and cancer: mechanisms of old and new cardiotoxic drugs in cancer patients. Card Fail Rev 2019; 5: 112–118.

16. Moazeni S. Anthracycline induced cardiotoxicity: biomarkers and “Omics” technology in the era of patient specific care. Clin Transl Med 2017; 6: 17.

17. Canzoneri JC, Oyelere AK. Interaction of anthracyclines with iron responsive element mRNAs. Nucleic Acids Res 2008; 36: 6825–6834.

18. Nebigil CG, Désaubry L. Updates in anthracycline‐mediated cardiotoxicity. Front Pharmacol 2018; 9: 1262.

19. Damilano F, Franco I, Perrino C, Schaefer K, Azzolino O, Carnevale D, Cifelli G, Carullo P, Ragona R, Ghigo A, Perino A, Lembo G, Hirsch E. Distinct effects of leukocyte and cardiac phosphoinositide 3‐kinase γ activity in pressure overload‐induced cardiac failure. Circulation 2011; 123: 391–399.

20. Patrucco E, Notte A, Barberis L, Selvetella G, Maffei A, Brancaccio M, Marengo S, Russo G, Azzolino O, Rybalkin SD, Silengo L, Altruda F, Wetzker R, Wymann MP, Lembo G, Hirsch E. PI3Kγ modulates the cardiac response to chronic pressure overload by distinct kinase‐dependent and ‐independent effects. Cell 2004; 118: 375–387.

21. Matsui T, Tao J, del Monte F, Lee KH, Li L, Picard M, Force TL, Franke TF, Hajjar RJ, Rosenzweig A. Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation 2001; 104: 330–335.

22. Fukazawa R, Miller TA, Kuramochi Y, Frantz S, Kim YD, Marchionni MA, Kelly RA, Sawyer DB. Neuregulin‐1 protects ventricular myocytes from anthracycline‐induced apoptosis via erbB4‐dependent activation of PI3‐kinase/Akt. J Mol Cell Cardiol 2003; 35: 1473–1479.

23. Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano R, Galderisi M, Habib G, Lenihan DJ, Lip GYH, Lyon AR, Lopez Fernandez T, Mohty D, Piepoli MF, Tamargo J, Torbicki A, Suter TM. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines The: Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016; 37: 2768–2801.

24. Curigliano G, Lenihan D, Fradley M, Ganatra S, Barac A, Blaes A, Herrmann J, Porter C, Lyon AR, Lancellotti P, Patel A, DeCara J, Mitchell J, Harrison E, Moslehi J, Witteles R, Calabro MG, Orecchia R, de Azambuja E, Zamorano JL, Krone R, Lakobishvili Z, Carver J, Armenian S, Ky B, Cardinale D, Cipolla CM, Dent S, Jordan K. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol 2020; 31: 171–190.

25. Monsuez JJ, Charniot JC, Vignat N, Artigou JY. Cardiac side‐effects of cancer chemotherapy. Int J Cardiol 2010; 144: 3–15.

26. Mehta LS, Watson KE, Barac A, Beckie TM, Bittner V, Cruz‐Flores S, Dent S, Kondapalli L, Ky B, Okwuosa T, Piña IL, Volgman AS. American Heart Association Cardiovascular Disease in Women and Special Populations Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; and Council on Quality of Care and Outcomes Research. Cardiovascular Disease and Breast Cancer: Where These Entities Intersect: A Scientific Statement From the American Heart Association. Circulation 2018; 137: e30–e66.

27. Blume‐Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001; 411: 355–365.

28. Hartmann JT, Haap M, Kopp HG, Lipp HP. Tyrosine kinase inhibitors ‐ a review on pharmacology, metabolism and side effects. Curr Drug Metab 2009; 10: 470–481.

29. Cardinale D, Colombo A, Lamantia G, Colombo N, Civelli M, De Giacomi G, Rubino M, Veglia F, Fiorentini C, Cipolla CM. Anthracycline‐induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol 2010; 55: 213–220.

30. Howe LR, Brown PH. Targeting the HER/EGFR/ErbB family to prevent breast cancer. Cancer Prev Res 2011; 4: 1149–1157.

31. Yarden Y. The EGFR family and its ligands in human cancer. Eur J Cancer 2001; 37: 3–8.

32. Moasser MM. The oncogene HER2; its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 2007; 26: 6469–6487.

33. Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER‐2 receptor and breast cancer: ten years of targeted anti‐HER‐2 therapy and personalized medicine. Oncologist 2009; 14: 320–368.

34. Odiete O, Hill MF, Sawyer DB. Neuregulin in cardiovascular development and disease. Circulation Research 2012; 111(10): 1376–1385.

35. Hudis CA. Trastuzumab—mechanism of action and use in clinical practice. N Engl J Med 2007; 357: 39–51.

36. Ewer SM, Ewer MS. Cardiotoxicity profile of trastuzumab. Drug Saf 2008; 31: 459–467.

37. Ewer MS, Vooletich MT, Durand J‐B, Woods ML, Davis JR, Valero V, Lenihan DJ. Reversibility of trastuzumab‐related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol 2005; 23: 7820–7826.

38. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah‐Fisch I, Lindsay MA, Riva A, Crown J. Adjuvant trastuzumab in HER2‐positive breast cancer. N Engl J Med 2011; 365: 1273–1283.

39. Perez EA, Suman VJ, Davidson NE, Sledge GW, Kaufman PA, Hudis CA, Martino S, Gralow JR, Dakhil SR, Ingle JN, Winer EP, Gelmon KA, Gersh BJ, Jaffe AS, Rodeheffer RJ. Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol 2008; 26: 1231–1238.

40. Costa RB, Kurra G, Greenberg L, Geyer CE. Efficacy and cardiac safety of adjuvant trastuzumab‐based chemotherapy regimens for HER2‐positive early breast cancer. Ann Oncol 2010; 21: 2153–2160.

41. Bowles EJ, Wellman R, Feigelson HS, Onitilo AA, Freedman AN, Delate T, Allen LA, Nekhlyudov L, Goddard KAB, Davis RL, Habel LA, Yood MU, Mccarty C, Magid DJ, Wagner EH. Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst 2012; 104: 1293–1305.

42. Food and Drug Association (FDA) . Commissioner announces Avastin decision—drug not shown to be safe and effective in breast cancer patients. 2011. http://www.fda.gov/downloads/News‐Events/Newsroom/UCM280546.pdf Accessed November 18, 2011.

43. Cardoso F, Paluch‐Shimon S, Senkus E, Curigliano G, Aapro MS, Andre F, Barrios CH, Bergh J, Bhattacharyya GS, Biganzoli L, Boyle F, Cardoso MJ, Carey LA, Cortes J, El Saghir NS, Elzayat M, Eniu A, Fallowfield L, Frnacis PA, Gelmon K, Gligorov J, Haidinger R, Harbeck N, Hu X, Kaufamn B, Kaur R, Kiely BE, Kim SB, Lin NU, Mertz SA, Neciosup S, Offersen BV, Ohno S, Pagani O, Prat A, Penault‐Llorca F, Rugo HS, Sledge GW, Thomssen C, Vorobiof DA, Wiseman T, Xu B, Norton L, Costa A, Winer EP. ESO‐ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 5). Ann Oncol 2020; 31: 1623–1649.

44. Riemsma R, Forbes CA, Amonkar MM, Lykopoulos K, Diaz JR, Kleijnen J, Rea DW. Systematic review of lapatinib in combination with letrozole compared with other first‐line treatments for hormone receptor positive (HR+) and HER2+ advanced or metastatic breast cancer (MBC). Curr Med Res Opin 2012; 28: 1263–1279.

45. Tevaarwerk AJ, Kolesar JM. Lapatinib: a small‐molecule inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor‐2 tyrosine kinases used in the treatment of breast cancer. Clin Ther 2009; 31: 2332–2348.

46. Choi HD, Chang MJ. Cardiac toxicities of lapatinib in patients with breast cancer and other HER2‐positive cancers: a meta‐analysis. Breast Cancer Res Treat 2017; 166: 927–936.

47. Spector NL, Xia W, Burris H 3rd, Hurwitz H, Dees EC, Dowlati A, O'Neil B, Overmoyer B, Marcom PK, Blackwell KL, Smith DA, Koch KM, Stead A, Mangum S, Ellis MJ, Liu L, Man AK, Bremer TM, Harris J, Bacus S. Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies. J Clin Oncol 2005; 23: 2502–2512.

48. Perez EA, Koehler M, Byrne J, Preston AJ, Rappold E, Ewer MS. Cardiac safety of lapatinib: pooled analysis of 3689 patients enrolled in clinical trials. Mayo Clin Proc 2008; 83: 679–686.

49. Fu D, Calvo JA, Samson LD. Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat Rev Cancer 2012; 12: 104–120.

50. Iqubal A, Iqubal MK, Sharma S, Ansari MA, Najmi AK, Ali SM, Ali J, Haque SE. Molecular mechanism involved in cyclophosphamide‐induced cardiotoxicity: Old drug with a new vision. Life Sci 2019; 218: 112–131.

51. Appelbaum FR, Strauchen JA, Graw RG, Savage DD, Kent KM, Ferrans VJ, Herzig GP. Acute lethal carditis caused by high‐dose combination chemotherapy. A unique clinical and pathological entity. Lancet 1976; 1: 58–32.

52. Katayama M, Imai Y, Hashimoto H, Kurata M, Nagai K, Tamita K, Morioka S, Furukawa Y. Fulminant fatal cardiotoxicity following cyclophosphamide therapy. J Cardiol 2009; 54: 330–334.

53. Kamezaki K, Fukuda T, Makino S, Harada M. Cyclophosphamide‐induced cardiomyopathy in a patient with seminoma and a history of mediastinal irradiation. Intern Med 2005; 44: 120–123.

54. Nakamae H, Tsumura K, Hino M, Hayashi T, Tatsumi N. QT dispersion as a predictor of acute heart failure after high‐dose cyclophosphamide. Lancet 2000; 355: 805–806.

55. Santos GW, Sensenbrenner LL, Burke PJ, Colvin M, Owens AH Jr, Bias WB, Slavin RE. Marrow transplanation in man following cyclophosphamide. Transplant Proc 1971; 3: 400–404.

56. Goldberg MA, Antin JH, Guinan EC, Rappeport JM. Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor. Blood 1986; 68: 1114–1118.

57. Brockstein BE, Smiley C, Al‐Sadir J, Williams SF. Cardiac and pulmonary toxicity in patients undergoing high‐dose chemo‐therapy for lymphoma and breast cancer: prognostic factors. Bone Marrow Transplant 2000; 25: 885–894.

58. Santi DV, McHenry CS, Sommer H. Mechanism of interaction of thymidylate synthetase with 5‐fluorodeoxyuridylate. Biochemistry 1974; 13: 471–481.

59. Sommer H, Santi DV. Purification and amino acid analysis of an active site peptide from thymidylate synthetase containing covalently bound 5‐fluoro‐2′‐deoxyuridylate and methylenetetrahydrofolate. Biochem Biophys Res Commun 1974; 57: 689–695.

60. Johnston PG, Kaye S. Capecitabine: a novel agent for the treatment of solid tumors. Anticancer Drugs 2001; 12: 639–646.

61. Malet‐Martino M, Jolimaitre P, Martino R. The prodrugs of 5‐fluorouracil. Curr Med Chem Anticancer Agents 2002; 2: 267–310.

62. Polk A, Vistisen K, Vaage‐Nilsen M, Nielsen DL. A systematic review of the pathophysiology of 5‐fluorouracil‐induced cardiotoxicity. BMC Pharmacol Toxicol 2014; 4: 47.

63. Layoun ME, Wickramasinghe CD, Peralta MV, Yang EH. Fluoropyrimidine‐Induced Cardiotoxicity: Manifestations, Mechanisms, and Management. Curr Oncol Rep 2016; 18: 6.

64. Jensen SA, Sorensen JB. 5‐fluorouracil‐based therapy induces endovascular injury having potential significance to development of clinically overt cardiotoxicity. Cancer Chemother Pharmacol 2012; 69: 57–64.

65. Ozturk MA, Ozveren O, Cinar V, Erdik B, Oyan B. Takotsubo syndrome: an underdiagnosed complication of 5‐fluorouracil mimicking acute myocardial infarction. Blood Coagul Fibrinolysis 2013; 24: 90–94.

66. Joy G, Eissa H, Karoudi AR, White SK. Fluorouracil‐induced Takotsubo cardiomyopathy causing cardiogenic shock: a case report of clinical and acute cardiac magnetic resonance imaging features. Eur Heart J Case Rep 2019; 3: 1–6.

67. Chong JH, Ghosh AK. Coronary artery vasospasm induced by 5‐fluorouracil: proposed mechanisms, existing management options and future directions. Interv Cardiol 2019; 14: 89–94.

68. Tsiamis E, Synetos A, Stefanadis C. Capecitabine may induce coronary artery vasospasm. Hellenic J Cardiol 2012; 53: 320–323.

69. Moriyama S, Yokoyama T, Irie K, Ito M, Tsuchihashi K, Fukata M, Kusaba H, Maruyama T, Akashi K. Atrial fibrillation observed in a patient with esophageal cancer treated with fluorouracil. J Cases 2019; 20: 183–186.

70. Hayasaka K, Takigawa M, Takahashi A, Kuwahara T, Okubo K, Tanaka Y, Misawa T, Mizusawa M, Yamakami Y, Kojima K, Sagawa Y, Hishikari K, Yamao K, Nakashima E, Nakajima J, Kimura S, Takagi K, Hikita H, Isobe M. A case of ventricular fibrillation as a consequence of capecitabine‐induced secondary QT prolongation: A case report. J Cardiol Cases 2017; 16: 26–29.

71. Talapatra K, Rajesh I, Rajesh B, Selvamani B, Subhashini J. Transient asymptomatic bradycardia in patients on infusional 5‐fluorouracil. J Cancer Res Ther 2007; 3: 169–171.

72. Calik AN, Celiker E, Velibey Y, Cagdas M, Guzelburc O. Initial dose effect of 5‐fluorouracil: rapidly improving severe, acute toxic myopericarditis. Am J Emerg Med 2012; 30: 257–253.

73. Killu A, Madhavan M, Prasad K, Prasad A. 5‐fluorouracil induced pericarditis. BMJ Case Rep 2011; 15: bcr0220113883.

74. Iskandar ZM, Quasem W, El‐Omar M. 5‐Fluorouracil cardiotoxicity: reversible left ventricular systolic dysfunction with early detection. BMJ Case Rep 2015; 2015: bcr2015209347.

75. Tsalic M, Bar‐Sela G, Beny A, Visel B, Haim N. Severe toxicity related to the 5‐fluorouracil/leucovorin combination (the Mayo Clinic regimen): a prospective study in colorectal cancer patients. Am J Clin Oncol 2003; 26: 103–106.

76. Tsavaris N, Kosmas C, Vadiaka M, Efremidis M, Zinelis A, Beldecos D, Sakelariou D, Koufos C, Stamatelos G. Cardiotoxicity following different doses and schedules of 5‐fluorouracil administration for malignancy—a survey of 427 patients. Med Sci Monit 2002; 8: I51–I57.

77. Labianca R, Beretta G, Clerici M, Fraschini P, Luporini G. Cardiac toxicity of 5‐fluorouracil: a study on 1083 patients. Tumori 1982; 68: 505–510.

78. O'Leary J, Volm M, Wasserheit C, Muggia F. Taxanes in adjuvant and neoadjuvant therapies for breast cancer. Oncology (Williston Park) 1998; 12: 23–27.

79. Ojima I, Lichtenthal B, Lee S, Wang C, Wang X. Taxane anticancer agents: a patent perspective. Expert Opin Ther Pat 2016; 26: 1–20.

80. Jordan MA, Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer 2004; 4: 253–265.

81. Thomas S, Quinn BA, Das SK, Dash R, Emdad L, Dasgupta S, Wang X‐Y, Dent P, Reed JC, Pellecchia M, Sarkar D, Fisher PB. Targeting the Bcl‐2 family for cancer therapy. Expert Opin Ther Targets 2013; 17: 61–75.

82. Perotti A, Cresta S, Grasselli G, Capri G, Minotti G, Gianni L. Cardiotoxic effects of anthracycline‐taxane combinations. Expert Opin Drug Saf 2003; 2: 59–71.

83. Salvatorelli E, Menna P, Cascegna S, Liberi G, Calafiore AM, Gianni L, Minotti G. Paclitaxel and docetaxel stimulation of doxo‐rubicinol formation in the human heart: implications for cardio‐toxicity of doxorubicin‐taxane chemotherapies. J Pharmacol Exp Ther 2006; 318: 424–433.

84. Rowinsky EK, Eisenhauer EA, Chaudhry V, Arbuck SG, Donehower RC. Clinical toxicities encountered with paclitaxel (Taxol). Semin Oncol 1993; 20: 1–15.

85. Gianni L, Salvatorelli E, Minotti G. Anthracycline cardiotoxicity in breast cancer patients: synergism with trastuzumab and taxanes. Cardiovasc Toxicol 2007; 7: 67–71.

86. Wöckel A, Wolters R, Wiegel T, Novopashenny I, Janni W, Kreienberg R, Wischnewsky M, Schwentner L. BRENDA study group. The impact of adjuvant radiotherapy on the survival of primary breast cancer patients: a retrospective multicenter cohort study of 8935 subjects. Ann Oncol 2014; 25: 628–632.

87. Jaworski C, Mariani JA, Wheeler G, Kaye DM. Cardiac complications of thoracic irradiation. J Am Coll Cardiol 2013; 61: 2319–2328.

88. Darby SC, McGale P, Taylor CW, Peto R. Long‐term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol 2005; 6: 557–565.

89. Taylor CW, Nisbet A, McGale P, Darby SC. Cardiac exposures in breast cancer radiotherapy: 1950s‐1990s. Int J Radiat Oncol Biol Phys 2007; 69: 1484–1495.

90. Aleman BMP, Moser EC, Nuver J, Suter TM, Maraldo MV, Specht L, Vrieling C, Darby SC. Cardiovascular disease after cancer therapy. EJC Suppl 2014; 12: 18–28.

91. Holley AK, Miao L, St. Clair DK, St. Clair WH. Redox‐modulated phenomena and radiation therapy: the central role of superoxide dismutases. Antioxid Redox Signal 2014; 20: 1567–1589.

92. Sato K, Mizuno Y, Fuchikami H, Kato M, Shimo T, Kubota J, Takeda N, Inoue Y, Seto H, Okawa T. Comparison of radiation dose to the left anterior descending artery by whole and partial breast irradiation in breast cancer patients. J Contemp Brachytherapy 2015; 7: 23–28.

93. Demirci S, Nam J, Hubbs JL, Nguyen T, Marks LB. Radiation‐induced cardiac toxicity after therapy for breast cancer: interaction between treatment era and follow‐up duration. Int J Radiat Oncol Biol Phys 2009; 73: 980–987.

94. Gujral DM, Lloyd G, Bhattacharyya S. Radiation‐induced valvular heart disease. Heart 2016; 102: 269–276.

95. Brand MD, Abadi CA, Aurigemma GP, Dauerman HL, Meyer TE. Radiation‐associated valvular heart disease in Hodgkin's disease is associated with characteristic thickening and fibrosis of the aortic‐mitral curtain. J Heart Valve Dis 2001; 10: 681–685.

96. Bijl JM, Roos MM, van Leeuwen‐Segarceanu EM, Vos JM, Bos WW, Biesma DH, Post MC. Assessment of valvular disorders in survivors of Hodgkin's lymphoma treated by mediastinal radiotherapy ± chemotherapy. Am J Cardiol 2016; 117: 691–696.

97. Liu LK, Ouyang W, Zhao X, Su SF, Yang Y, Ding WJ, Luo DX, He ZX, Lu B. Pathogenesis and prevention of radiation‐induced myocardial fibrosis. Asian Pac J Cancer Prev 2017; 18: 583–587.

98. Gagliardi G, Constine LS, Moiseenko V, Correa C, Pierce LJ, Allen AM, Marks LB. Radiation dose‐volume effects in the heart. Int J Radiat Oncol Biol Phys 2010; 76: S77–S85.

99. Garibaldi C, Jereczek‐Fossa BA, Marvaso G, Dicuonzo S, Rojas DP, Cattani F, Starzyńska A, Ciardo D, Surgo A, Leonardi MC, Ricotti R. Recent advances in radiation oncology. Ecance Mmed Sci 2017; 11: 785.

100. Tapio S. Pathology and biology of radiation‐induced cardiac disease. J Radiat Res 2016; 57: 439–448.

101. Veinot JP, Edwards WD. Pathology of radiation‐induced heart disease: a surgical and autopsy study of 27 cases. Hum Pathol 1996; 27: 766–773.

102. Takata N, Kataoka M, Hamamoto Y, Tsuruoka S, Kanzaki H, Uwatsu K, Nagasaki K, Mochizuki T. Risk factors for pericardial effusion after chemoradiotherapy for thoracic esophageal cancer—comparison of four‐field technique and traditional two opposed fields technique. J Radiat Res 2018; 59: 291–297.

103. Adams MJ, Lipsitz SR, Colan SD, Tarbell NJ, Treves ST, Diller L, Greenbaum N, Mauch P, Lipshultz SE. Cardiovascular status in long‐term survivors of Hodgkin's disease treated with chest radiotherapy. J Clin Oncol 2004; 22: 3139–3148.

104. Gaya AM, Ashford RF. Cardiac complications of radiation therapy. Clin Oncol 2005; 17: 153–159.

105. Coccaro M, Gallucci G. Late cardiac effects of adjuvant radiotherapy and chemotherapy in early breast cancer. J Clin Oncol 2008; 26: 3288.

106. Hancock SL, Donaldson SS, Hoppe RT. Cardiac disease following treatment of Hodgkin's disease in children and adolescents. J Clin Oncol 1993; 11: 1208–1215.

107. Eldabaje R, Le DL, Huang W, Yang LX. Radiation‐associated cardiac injury. Anticancer Res 2015; 35: 2487–2492.

108. Carver JR, Szalda D, Ky B. Asymptomatic cardiac toxicity in long‐term cancer survivors: defining the population and recommendations for surveillance. Semin Oncol 2013; 40: 229–238.

109. Barry E, Alvarez JA, Scully RE, Miller TL, Lipshultz SE. Anthracycline‐induced cardiotoxicity: course, pathophysiology, prevention and management. Expert Opin Pharmacother 2007; 8: 1039–1058.

110. Smith LA, Cornelius VR, Plummer CJ, Levitt G, Verrill M, Canney P, Jones A. Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta‐analysis of randomised controlled trials. BMC Cancer 2010; 10: 337.

111. Jay SM, Murthy AC, Hawkins JF, Wortzel JR, Steinhauser ML, Alvarez LM, Gannon J, Macrae CA, Griffith LG, Lee RT. An engineered bivalent neuregulin protects against doxorubicin‐induced cardiotoxicity with reduced proneoplastic potential. Circulation 2013; 128: 152–161.

112. Lipshultz SE, Miller TL, Lipsitz SR, Neuberg DS, Dahlberg SE, Colan SD, Silverman LB, Henkel JM, Franco VI, Cushman LL, Asselin BL, Clavell LA, Athale U, Michon B, Laverdière C, Schorin MA, Larsen E, Usmani N, Sallan SE. Dana‐Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium. Continuous versus bolus infusion of doxorubicin in children with all: long‐term cardiac outcomes. Pediatrics 2012; 130: 1003–1011.

113. van Dalen EC, Michiels EMC, Caron HN, Kremer LCM. Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Database Syst Rev 2010; 3: Cd005006.

114. Scott JM, Khakoo A, Mackey JR, Haykowsky MJ, Douglas PS, Jones LW. Modulation of anthracycline‐induced cardiotoxicity by aerobic exercise in breast cancer: current evidence and underlying mechanisms. Circulation 2011; 124: 642–650.

115. Chicco AJ, Hydock DS, Schneider CM, Hayward R. Low‐intensity exercise training during doxorubicin treatment protects against cardiotoxicity. J Appl Physiol 2006; 100: 519–527.

116. Hornsby WE, Douglas PS, West MJ, Kenjale AA, Lane AR, Schwitzer ER, Ray KA, Herndon JE, Coan A, Gutierrez A, Hornsby KP, Hamilton E, Wilke LG, Kimmick GG, Peppercorn JM, Jones LW. Safety and efficacy of aerobic training in operable breast cancer patients receiving neoadjuvant chemotherapy: a phase II randomized trial. Acta Oncol 2014; 53: 65–74.

117. Haykowsky MJ, Mackey JR, Thompson RB, Jones LW, Paterson DI. Adjuvant trastuzumab induces ventricular remodeling despite aerobic exercise training. Clin Cancer Res 2009; 15: 4963–4967.

118. van Dalen EC, Caron HN, Dickinson HO, Kremer LC. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev 2011; 6: Cd003917.

119. Vejpongsa P, Yeh ET. Topoisomerase 2β: a promising molecular target for primary prevention of anthracycline‐induced cardiotoxicity. Clin Pharmacol Ther 2014; 95: 45–52.

120. Lyu YL, Kerrigan JE, Lin CP, Azarova AM, Tsai YC, Ban Y, Liu LF. Topoisomerase IIbeta mediated DNA double‐strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res 2007; 67: 8839–8846.

121. Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N, Civelli M, Martinelli G, Veglia F, Fiorentini C, Cipolla CM. Prevention of high‐dose chemotherapy‐induced cardiotoxicity in high‐risk patients by angiotensin‐converting enzyme inhibition. Circulation 2006; 114: 2474–2481.

122. Nakamae H, Tsumura K, Terada Y, Nakane T, Nakamae M, Ohta K, Yamane T, Hino M. Notable effects of angiotensin II receptor blocker, valsartan, on acute cardiotoxic changes after standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone. Cancer 2005; 104: 2492–2498.

123. Cadeddu C, Piras A, Mantovani G, Deidda M, Dessì M, Madeddu C, Massa E, Mercuro G. Protective effects of the angiotensin II receptor blocker telmisartan on epirubicin‐induced inflammation, oxidative stress, and early ventricular impairment. Am Heart J 2010; 160: 487.e1–487.e7.

124. Dessì M, Piras A, Madeddu C, Cadeddu C, Deidda M, Massa E, Antoni G, Mantovani G, Mercuro G. Long‐term protective effects of the angiotensin receptor blocker telmisartan on epirubicin‐induced inflammation, oxidative stress and myocardial dysfunction. Exp Ther Med 2011; 2: 1003–1009.

125. Bosch X, Rovira M, Sitges M, Domènech A, Ortiz‐Pérez JT, de Caralt TM, Morales‐Ruiz M, Perea RJ, Monzó M, Esteve J. Enalapril and carvedilol for preventing chemotherapy‐induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies). J Am Coll Cardiol 2013; 61: 2355–2362.

126. Kaya MG, Ozkan M, Gunebakmaz O, Akkaya H, Kaya EG, Akpek M, Kalay N, Dikilitas M, Yarlioglues M, Karaca H, Berk V, Ardic I, Ergin A, Lam YY. Protective effects of nebivolol against anthracycline‐induced cardiomyopathy: a randomized control study. Int J Cardiol 2013; 167: 2306–2310.

127. Liu L, Liu ZZ, Liu YY, Zheng ZD, Liang XF, Han YL, Xie XD. Preventive effect of low‐dose carvedilol combined with candesartan on the cardiotoxicity of anthracycline drugs in the adjuvant chemotherapy of breast cancer. Zhonghua Zhong Liu Za Zhi 2013; 35: 936–940.

128. Akpek M, Ozdogru I, Sahin O, Inanc M, Dogan A, Yazici C, Berk V, Karaca H, Kalay N, Oguzhan A, Ergin A. Protective effects of spironolactone against anthracycline‐induced cardiomyopathy. Eur J Heart Fail 2015; 17: 81–89.

129. Acar Z, Kale A, Turgut M, Demircan S, Durna K, Demir S, Meriç M, Ağaç MT. Efficiency of atorvastatin in the protection of anthracycline‐induced cardiomyopathy. J Am Coll Cardiol 2011; 58: 988–989.

130. Seicean S, Seicean A, Alan N, Plana JC, Budd GT, Marwick TH. Cardioprotective effect of β‐adrenoceptor blockade in patients with breast cancer undergoing chemotherapy: follow‐up study of heart failure. Circ Heart Fail 2013; 6: 420–426.

131. Kalam K, Marwick TH. Role of cardioprotective therapy for prevention of cardiotoxicity with chemotherapy: a systematic review and meta‐analysis. Eur J Cancer 2013; 49: 2900–2909.

132. Thakur A, Witteles RM. Cancer therapy‐induced left ventricular dysfunction: interventions and prognosis. J Card Fail 2014; 20: 155–158.

133. Armenian SA, Lacchetti C, Barac A, Carver J, Constine LS, Denduluri N, Dent S, Douglas PS, Durand JB, Ewer M, Fabian C, Hudson M, Jessup M, Jones LW, Ky B, Mayer EL, Moslehi J, Oeffinger K, Ray K, Ruddy K, Lenihan D. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J ClinOncol 2017; 35: 893–911.

134. Food and Drug Administration (FDA) . Adriamycin (DOXOrubicinHCl) for Injection. 2012. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/062921s022lbl.pdf Accessed November 15, 2017.

135. Food and Drug Administration (FDA) HERCEPTIN (trastuzumab). 2010. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/103792s5250lbl.pdf (15 November 2017).

136. Thavendiranathan P, Grant AD, Negishi T, Plana JC, Popović ZB, Marwick TH. Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: application to patients undergoing cancer chemotherapy. J Am Coll Cardiol 2013; 61: 77–84.

137. Walker J, Bhullar N, Fallah‐Rad N, Lytwyn M, Golian M, Fang T, Summers AR, Singal PK, Barac I, Kirkpatrick ID, Jassal DS. Role of three‐dimensional echocardiography in breast cancer: comparison with two‐dimensional echocardiography, multiple‐gated acquisition scans, and cardiac magnetic resonance imaging. J Clin Oncol 2010; 8: 3429–3436.

138. Lo Q, Hee L, Batumalai V, Allman C, MacDonald P, Lonergan D, Delaney GP, Thomas L. Strain imaging detects dose‐dependent segmental cardiac dysfunction in the acute phase after breast irradiation. Int J Radiat Oncol Biol Phys 2017; 99: 182–190.

139. Luo R, Cui H, Huang D, Li G. Early assessment of the left ventricular function by epirubicin‐induced cardiotoxicity in postoperative breast cancer patients. Echocardiography 2017; 34: 1601–1609.

140. Wang W, Kang Y, Shu XH, Shen XD, He B. Early detection of the cardiotoxicity induced by chemotherapy drug through two‐dimensional speckle tracking echocardiography combined with high‐sensitive cardiac troponin T. ZhonghuaZhong Liu ZaZhi 2017; 39: 835–840.

141. Laufer‐Perl M, Derakhshesh M, Milwidsky A, Mor L, Ravid D, Amrami N, Sherez J, Keren G, Topilsky Y, Arbel Y. Usefulness of global longitudinal strain for early identification of subclinical left ventricular dysfunction in patients with active cancer. Am J Cardiol 2018; 122: 1784–1789.

142. ArciniegasCalle MC, Sandhu NP, Xia H, Cha SS, Pellikka PA, Ye Z, Herrmann J, Villarraga HR. Two‐dimensional speckle tracking echocardiography predicts early subclinical cardiotoxicity associated with anthracycline‐trastuzumab chemotherapy in patients with breast cancer. BMC Cancer 2018; 18: 1037.

143. Yaylali YT, Saricopur A, Yurtdas M, Senol H, Gokoz‐Dogu G. Atrial function in patients with breast cancer after treatment with anthracyclines. Arq Bras Cardiol 2016; 107: 411–419.

144. Barros MVL, Macedo AVS, Sarvari SI, Faleiros MH, Felipe PT, Silva JLP, Edvardsen T. Left ventricular regional wall motion abnormality is a strong predictor of cardiotoxicity in breast cancer patients undergoing chemotherapy. Arq Bras Cardiol 2019; 112: 50–56.

145. Abdar Esfahani M, Mokarian F, Karimipanah M. Alterations in the echocardiographic variables of the right ventricle in asymptomatic patients with breast cancer during anthracycline chemotherapy. Postgrad Med J 2017; 93: 271–274.

146. Wang Y, Zhang P, Liu K, Zhang J, Ma X, Li L, Li M, Liu J. Evaluation of changes in right ventricular myocardial mechanical properties in breast cancer patients receiving pirarubicin using three‐dimensional speckle tracking imaging. Nan Fang Yi Ke Da XueXueBao 2018; 38: 1032–1038.

147. Choe JC, Choi JH, Choi JH, Ahn J, Park JS, Lee HW, Oh JH, Lee HC, Cha KS, Hong TJ. Prolonged electromechanical delay as an early predictor of trastuzumab‐induced cardiotoxicity in patients undergoing treatment for breast cancer. ClinCardiol 2018; 41: 1308–1314.

148. Bergamini C, Dolci G, Rossi A, Torelli F, Ghiselli L, Trevisani L, Vinco G, Truong S, La Russa F, Golia G, Molino A, Benfari G, Ribichini FL. Left atrial volume in patients with HER2‐positive breast cancer: one step further to predict trastuzumab‐related cardiotoxicity. Clin Cardiol 2018; 41: 349–353.

149. Karamitsos TD, Arvanitaki A, Karvounis H, Neubauer S, Ferreira VM. Myocardial tissue characterization and fibrosis by imaging. JACC Cardiovasc Imaging 2020; 13: 1221–1234.

150. van Boxtel W, Bulten BF, Mavinkurve‐Groothuis AMC, Bellersen L, Mandigers CMPW, Joosten LAB, Kapusta L, de Geus‐Oei LF, van Laarhoven HWM. New biomarkers for early detection of cardiotoxicity after treatment with docetaxel, doxorubicin and cyclophosphamide. Biomarkers 2015; 2: 143–148.

151. Cardinale D, Salvatici M, Sandri MT. Role of biomarkers in cardio‐oncology. ClinChem Lab Med 2011; 49: 1937–1948.

152. Christenson ES, James T, Agrawal V, Park BH. Use of biomarkers for the assessment of chemotherapy‐induced cardiac toxicity. Clin Biochem 2015; 48: 223–235.

153. Cardinale D, Sandri MT, Martinoni A, Tricca A, Civelli M, Lamantia G, Cinieri S, Martinelli G, Cipolla CM, Fiorentini C. Left ventricular dysfunction predicted by early troponin I release after high dose chemotherapy. J Am Coll Cardiol 2000; 36: 517–522.

154. Novo G, Cadeddu C, Sucato V, Pagliaro P, Romano S, Tocchetti CG, Zito C, Longobardo L, Nodari S, Penco M. Role of biomarkers in monitoring antiblastic cardiotoxicity. Special issue on cardiotoxicity from antiblastic drugs and cardioprotection. J Cardiovasc Med 2016; 17: 27–34.

155. Auner HW, Tinchon C, Linkesch W, Tiran A, Quehenberger F, Link H, Sill H. Prolonged monitoring of troponin T for the detection of anthracycline cardiotoxicity in adults with hematological malignancies. Ann Hematol 2003; 82: 218–222.

156. Skovgaard D, Hasbak P, Kjaer A. BNP predicts chemotherapy‐related cardiotoxicity and death: comparison with gated equilibrium radionuclide ventriculography. PLoS One 2014; 9: e96736.

157. Wang Y, Chen S, Ren L. Serum B‐type natriuretic peptide levels as a marker for anthracycline‐induced cardiotoxicity. Oncol Lett 2016; 11: 3483–3492.

158. Stein BC, Levin RI. Natriuretic peptides: Physiology, therapeutic potential, and risk stratification in ischemic heart disease. Am Heart J 1998; 135: 914–923.

159. Sandri MT, Salvatici M, Cardinale D, Zorzino L, Passerini R, Lentati P, Leon M, Civelli M, Martinelli G, Cipolla CM. N‐terminal pro‐B‐type natriuretic peptide after high‐dose chemotherapy: a marker predictive of cardiac dysfunction? Clin Chem 2005; 51: 1405–1410.

160. Ky B, Putt M, Sawaya H, French B, Januzzi JL Jr, Sebag IA, Plana JC, Cohen V, Banchs J, Carver JR, Wiegers SE, Martin RP, Picard MH, Garszten RE, Halpern EF, Passeri J, Kuter I, Scherrer‐Crosbie M. Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab. J Am Coll Cardiol 2014; 63: 809–816.

161. Putt M, Hahn VS, Januzzi JL, Sawaya H, Sebag IA, Plana JC, Picard MH, Carver JR, Halpern EF, Kuter I, Passeri J, Cohen V, Banchs J, Martin RP, Gerszten RE, Scherrer‐Crosbie M, Ky B. Longitudinal changes in multiple biomarkers are associated with cardiotoxicity in breast cancer patients treated with doxorubicin, taxanes, and trastuzumab. Clin Chem 2015; 61: 1164–1172.

162. Cardinale D, Sandri MT, Colombo A, Colombo N, Boeri M, Lamantia G, Civelli M, Peccatori F, Martinelli G, Fiorentini C, Cipolla CM. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high‐dose chemotherapy. Circulation 2004; 109: 2749–2754.

163. Rüger AM, Schneeweiss A, Seiler S, Tesch H, van Mackelenbergh M, Marmé F, Lübbe K, Sinn B, Karn T, Stickeler E, Müller V, Schem C, Denkert C, Fasching PA, Nekljudova V, Garfias‐Macedo T, Hasenfuß G, Haverkamp W, Loibl S, von Haehling S. Cardiotoxicity and cardiovascular biomarkers in patients with breast cancer: data from the GeparOcto‐GBG 84 trial. J Am Heart Assoc 2020; 9: e018143.

164. Luers C, Sutcliffe A, Binder L, Irle S, Pieske B. NT‐proANP and NT‐proBNP as prognostic markers in patients with acute decompensated heart failure of different etiologies. Clin Biochem 2013; 46: 1013–1019.

165. Scrutinio D, Ammirati E, Guida P, Passantino A, Raimondo R, Guida V, Braga S, Pedretti RF, Lagioia R, Frigerio M, Catanzaro R, Oliva F. Clinical utility of N‐terminal pro‐B‐type natriuretic peptide for risk stratification of patients with acute decompensated heart failure. Derivation and validation of the ADHF/NT‐proBNP risk score. Int J Cardiol 2013; 168: 2120–2126.

166. Walker DB. Serum chemical biomarkers of cardiac injury for nonclinical safety testing. Toxicol Pathol 2006; 34: 94–104.

167. Gaggin HK, Januzzi JL Jr. Biomarkers and diagnostics in heart failure. Biochim Biophys Acta 2013; 1832: 2442–2450.

168. Ponikowski P, Voors A, Anker SD, Bueno H, Cleland J, Coats A, Falk V, González‐Juanatey JR, Harjola V‐P, Jankowska EA. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016; 37: 2129–2200.

169. Morris PG, Chen C, Steingart R, Fleisher M, Lin N, Moy B, Come S, Sugarman S, Abbruzzi A, Lehman R, Patil S, Dickler M, McArthur HL, Winer E, Norton L, Hudis CA, Dang CT. Troponin I and C‐reactive protein are commonly detected in patients with breast cancer treated with dose‐dense chemotherapy incorporating trastuzumab and lapatinib. Clin Cancer Res 2011; 17: 3490–3499.

170. Onitilo AA, Engel JM, Stankowski RV, Liang H, Berg RL, Doi SA. High‐sensitivity C‐reactive protein (hs‐CRP) as a biomarker for trastuzumab‐induced cardiotoxicity in HER2‐positive early‐stage breast cancer: a pilot study. Breast Cancer Res Treat 2012; 134: 291–298.

171. Gullo G, Eustace AJ, Canonici A, Collins DM, Kennedy MJ, Grogan L, Reathnah BO, McCaffrey J, Keane M, Martin MJ, Gupta R, Leonard G, O'Connor M, Calvert PM, Donnellan P, Walshe J, McDermott E, Scott K, Hernando A, Parker I, Murray DW, O'Farrell A, Maratha A, Dicker P, Rafferty M, Murphy V, O'Donovan N, Gallagher WM, Ky B, Tryfonopoulos D, Moulton B, Byrne A, Crown J. Pilot study of bevacizumab in combination with docetaxel and cyclophosphamide as adjuvant treatment for patients with early stage HER‐2 negative breast cancer, including analysis of candidate circulating markers of cardiac toxicity: ICORG 08–10 trial. Ther Adv Med Oncol 2019; 11: 1–9.

172. Bulten BF, Verberne HJ, Bellersen L, Oyen WJ, Sabaté‐Llobera A, Mavinkurve‐Groothuis AM, Kapusta L, van Laarhoven HW, de Geus‐Oei LF. Relationship of promising methods in the detection of anthracycline‐induced cardiotoxicity in breast cancer patients. Cancer Chemother Pharmacol 2015; 76: 957–967.

173. Horacek JM, Jebavy L, Vasatova M, Pudil R, Tichy M, Jakl M, Maly J. Glycogen phosphorylase BB as a potential marker of cardiac toxicity in patients treated with anthracyclines for acute leukemia. Bratisl Lek Listy 2013; 114: 708–710.

174. Horacek JM, Vasatova M, Tichy M, Pudil R, Jebavy L, Maly J. The use of cardiac biomarkers in detection of cardiotoxicity associated with conventional and high‐dose chemotherapy for acute leukemia. Exp Oncol 2010; 32: 97–99.

175. Zver S, Zadnik V, Černelč P, Koželj M. Cardiac toxicity of high‐dose cyclophosphamide and melphalan in patients with multiple myeloma treated with tandem autologous hematopoietic stem cell transplantation. Int J Hematol 2008; 88: 227–236.

176. Rigaud VO, Ferreira LR, Ayub‐Ferreira SM, Ávila MS, Brandão SM, Cruz FD, Santos MH, Cruz CB, Alves MS, Issa VS, Guimarães GV, Cunha‐Neto E, Bocchi EA. Circulating miR‐1 as a potential biomarker of doxorubicin‐induced cardiotoxicity in breast cancer patients. Oncotarget 2017; 8: 6994–7002.

177. Qin X, Chang F, Wang Z, Jiang W. Correlation of circulating pro‐angiogenic miRNAs with cardiotoxicity induced by epirubicin/cyclophosphamide followed by docetaxel in patients with breast cancer. Cancer Biomark 2018; 23: 473–484.

178. Koutova L, Sterbova M, Pazourkova E, Pospisilova S, Svobodova I, Horinek A, Lysak D, Korabecna M. The impact of standard chemotherapy on miRNA signature in plasma in AML patients. Leuk Res 2015; 39: 1389–1395.

179. Horie T, Ono K, Nishi H, Nagao K, Kinoshita M, Watanabe S, Kuwabara Y, Nakashima Y, Takanabe‐Mori R, Nishi E, Hasegawa K, Kita T, Kimura T. Acute doxorubicin cardiotoxicity is associated with miR‐146a‐induced inhibition of the neuregulin‐ErbB pathway. Cardiovasc Res 2010; 87: 656–664.

180. Ruggeri C, Gioffré S, Achilli F, Colombo GI, D'Alessandra Y. Role of microRNAs in doxorubicin‐induced cardiotoxicity: an overview of preclinical models and cancer patients. Heart Fail Rev 2018; 23: 109–122.

181. Gioffré S, Ricci V, Vavassori C, Ruggeri C, Chiesa M, Alfieri I, Zorzan S, Buzzetti M, Milano G, Scopece A, Castiglioni L, Sironi L, Pompilio G, Colombo GI, D'Alessandra Y. Plasmatic and chamber‐specific modulation of cardiac microRNAs in an acute model of DOX‐induced cardiotoxicity. Biomed Pharmacother 2019; 110: 1–8.

182. Wang J, Martin JF. Macro advances in microRNAs and myocardial regeneration. Curr Opin Cardiol 2014; 29: 207–213.

183. Jayawardena TM, Egemnazarov B, Finch EA, Zhang L, Payne JA, Pandya K, Zhang Z, Rosenberg P, Mirotsou M, Dzau VJ. MicroRNA‐mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res 2012; 110: 1465–1473.

184. Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature 2011; 469: 336–342.

185. Desai VG, Kwekel JC, Vijay V, Moland CL, Herman EH, Lee T, Han T, Lewis SM, Davis KJ, Muskhelishvili L, Kerr S, Fuscoe JC. Early biomarkers of doxorubicin‐induced heart injury in a mouse model. Toxicol Appl Pharmacol 2014; 281: 221–229.

186. Hertz DL, McLeod HL. Use of pharmacogenetics for predicting cancer prognosis and treatment exposure, response and toxicity. J Hum Genet 2013; 58: 346–352.

187. Lipshultz SE, Lipsitz SR, Sallan SE, Dalton VM, Mone SM, Gelber RD, Colan SD. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J ClinOncol 2005; 23: 2629–2636.

188. Megias‐Vericat JE, Martinez‐Cuadron D, Herrero MJ, Alino SF, Poveda JL, Sanz MA, Montesinos P. Pharmacogenetics of metabolic genes of anthracyclines in acute myeloid leukemia. Curr Drug Metab 2018; 19: 55–74.

189. Villanueva S, Zhang W, Zecchinati F, Mottino A, Vore M. ABC transporters in extrahepatic tissues: pharmacological regulation in heart and intestine. Curr Med Chem 2019; 26: 1155–1184.

190. Tian C, Ambrosone CB, Darcy KM, Krivak TC, Armstrong DK, Bookman MA, Davis W, Zhao H, Moysich K, Gallion H, DeLoia JA. Common variants in ABCB1, ABCC2 and ABCG2 genes and clinical outcomes among women with advanced stage ovarian cancer treated with platinum and taxane‐based chemotherapy: a Gynecologic Oncology Group study. Gynecol Oncol 2012; 124: 575–581.

191. Visscher H, Ross CJ, Rassekh SR, Barhdadi A, Dubé MP, Al‐Saloos H, Sandor GS, Caron HN, van Dalen EC, Kremer LC, van der Pal HJ, Brown AM, Rogers PC, Phillips MS, Rieder MJ, Carleton BC, Hayden MR. Canadian pharmacogenomics network for drug safety consortium pharmacogenomic prediction of anthracycline‐induced cardiotoxicity in children. J ClinOncol 2012; 30: 1422–1428.

192. Visscher H, Ross CJ, Rassekh SR, Sandor GS, Caron HN, van Dalen EC, Kremer LC, van der Pal HJ, Rogers PC, Rieder MJ, Carleton BC, Hayden MR. CPNDS consortium validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline‐induced cardiotoxicity in children. Pediatr Blood Cancer 2013; 60: 1375–1381.

193. Vulsteke C, Pfeil AM, Maggen C, Schwenkglenks M, Pettengell R, Szucs TD, Lambrechts D, Diudonné AS, Hatse S, Neven P, Paridaens R, Wildiers H. Clinical and genetic risk factors for epirubicin‐induced cardiac toxicity in early breast cancer patients. Breast Cancer Res Treat 2015; 152: 67–76.

194. Bray J, Sludden J, Griffin MJ, Cole M, Verrill M, Jamieson D, Boddy AV. Influence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide. Br J Cancer 2010; 102: 1003–1009.

195. Megías‐Vericat JE, Montesinos P, Herrero MJ, Moscardó F, Bosó V, Rojas L, Martínez‐Cuadrón D, Hervás D, Boluda B, García‐Robles A, Rodríguez‐Veiga R, Martín‐Cerezuela M, Cervera J, Sendra L, Sanz J, Miguel A, Lorenzo I, Poveda JL, Sanz MÁ, Aliño SF. Impact of ABC single nucleotide polymorphisms upon the efficacy and toxicity of induction chemotherapy in acute myeloid leukemia. Leuk Lymphoma 2017; 58: 1197–1206.

196. Koene RJ, Prizment AE, Blaes A, Konety SH. Shared risk factors in cardiovascular disease and cancer. Circulation 2016; 133: 1104–1114.

197. Writing Group Members , Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB. American Heart Association Statistics Committee; Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics‐2016 Update: A Report From the American Heart Association. Circulation 2016; 133: 38–360.

198. Howell A, Anderson AS, Clarke RB, Duffy SW, Evans DG, Garcia‐Closas M, Gescher AJ, Key TJ, Saxton JM, Harvie MN. Risk determination and prevention of breast cancer. Breast Cancer Res 2014; 16: 446.

199. Vaduganathan M, Hirji SA, Qamar A, Bajaj N, Gupta A, Zaha V, Chandra A, Haykowsky M, Ky B, Moslehi J, Nohria A, Butler J, Pandey A. Efficacy of neurohormonal therapies in preventing cardiotoxicity in patients with cancer undergoing chemotherapy. JACC Cardio Oncol 2019; 1: 54–65.

200. Avila MS, Ayub‐Ferreira SM, de Barros Wanderley MR, das Dores Cruz F, Gonçalves Brandão SM, Rigaud VO, Higuchi‐dos‐Santos MH, Hajjar LA, Kalil Filho R, Hoff PM, Sahade M. Carvedilol for prevention of chemotherapy‐related cardiotoxicity: the CECCY trial. J Am Coll Cardiol 2018; 71: 2281–2290.

201. Seicean S, Seicean A, Plana JC, Budd GT, Marwick TH. Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: an observational clinical cohort study. J Am Coll Cardiol 2012; 60: 2384–2390.

202. Jones LW, Habel LA, Weltzien E, Castillo A, Gupta D, Kroenke CH, Kwan ML, Quesenberry CP Jr, Scott J, Sternfeld B, Yu A, Kushi LH, Caan BJ. Exercise and risk of cardiovascular events in women with nonmetastatic breast cancer. J Clin Oncol 2016; 34: 2743–2749.

203. Irwin ML, Smith AW, McTiernan A, Ballard‐Barbash R, Cronin K, Gilliland FD, Baumgartner RN, Baumgartner KB, Bernstein L. Influence of pre‐and postdiagnosis physical activity on mortality in breast cancer survivors: the health, eating, activity, and lifestyle study. J Clin Oncol 2008; 26: 3958.

204. Gilchrist SC, Barac A, Ades PA, Alfano CM, Franklin BA, Jones LW, La Gerche A, Ligibel JA, Lopez G, Madan K, Oeffinger KC, Salamone J, Scott JM, Squires RW, Thomas RJ, Treat‐Jacobson DJ, Wright JS, American Heart Association Exercise, Cardiac Rehabilitation, and Secondary Prevention Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; and Council on Peripheral Vascular Disease . Cardio‐oncology rehabilitation to manage cardiovascular outcomes in cancer patients and survivors: a scientific statement from the American Heart Association. Circulation 2019; 139: e997–e1012.

205. Michel L, Mincu RI, Mahabadi AA, Settelmeier S, Al‐Rashid F, Rassaf T, Totzeck M. Troponins and brain natriuretic peptides for the prediction of cardiotoxicity in cancer patients: a meta‐analysis. Eur J Heart Fail 2020; 22: 350–361.