Introduction

In women in the United States, breast cancer is the most common cancer and the second leading cause of cancer-related death.¹ Improved therapies have increased cure rates and helped patients live longer with incurable disease, such that the 5-year relative survival rate is now 91 percent.¹ However, some of these treatments (e.g., radiation and certain chemotherapies) can cause serious side effects, including those that affect the cardiovascular (CV) system.^2,3 Acute manifestations of cardiac damage from radiation or chemotherapy include pericarditis and pericardial effusion, and late and long-term manifestations include congestive heart failure (HF), coronary artery disease (CAD), cardiomyopathy, valvular disease, myocardial fibrosis, and conduction abnormalities (sometimes manifesting years after the causal oncologic therapy).^2-4 These complications can cause significant morbidity or mortality. Table 1 contains information about the presumed pathophysiologic mechanisms that underlie therapy-induced cardiovascular disease (CVD) in survivors of breast cancer.

Table 1: Pathophysiology of CV Toxicities Observed With Breast Cancer Treatment^5-8

Treatment	Pathophysiology of Cardiac Toxicity
Radiation	Free radicals and oxidative stress due to irradiation lead to DNA damage, transcriptional changes, and pro-inflammatory state. This damages the micro-and macro-vasculature and leads to fibrin deposition and fibrosis. This facilitates the development of atherosclerotic disease. Fibrosis can affect the valves and conduction system as well.
Trastuzumab	Not well understood; likely related to the effects of HER2 signaling on cardiac development, myocyte survival, and protection from cardiotoxins. HER2-blockade interferes with the ligand-binding-induced cardioprotective pathways that are obligatory to recover from cardiac injury pathways. It is thought that trastuzumab leads to loss of contractility due to cellular stunning rather than myocyte death.
Anthracycline	Uncertain mechanism. One hypothesis is that the drug-DNA complex triggers cell death. Anthracyclines target topoisomerase II. The drug-topoisomerase II complexes induce DNA double strand breaks, transcriptome changes, and subsequent cell death when the damage is not repaired. Alternatively or in addition, reactive oxygen species and oxidative stress may lead to DNA damage, lipid peroxidation of membranes (especially cardiolipin), and subsequent irreversible damage and fibrosis. The dilated cardiomyopathy observed with anthracycline usage is thought to be due to myocardial necrosis.
Endocrine Therapy	Estrogen's cardioprotective effects are likely due to its influence on lipoproteins, hemostasis, carbohydrate metabolism, and vessel wall tone and reactivity. Selective estrogen receptor modulators act as estrogen agonists in some systems, inhibiting either the oxidation of low-density lipoprotein or lipid peroxidation in cell membranes, which are required for triggering atherosclerosis. Aromatase inhibitors reduce circulating estrogens in postmenopausal women and therefore are associated with slightly increased CV event rates compared with tamoxifen.

Radiation Therapy

Radiation therapy has contributed significantly to the reduction of local recurrence and improved survival of patients with early stage breast cancer.^9,10 Breast radiation (often including certain regional nodal fields) has traditionally been recommended routinely after lumpectomy, though recent data suggest that some patients who are older than 70 with low-risk tumors may safely omit radiation.¹¹ After mastectomy, patients with large and/or node-positive disease may also benefit from chest wall and regional nodal radiation. Radiation is also occasionally used to manage symptoms (e.g., pain) in patients with stage 4 (incurable) cancers. When the heart and its structures are included even partially in the radiation field, potential CV side effects can include congestive HF, restrictive cardiomyopathy, ischemic heart disease, valvular heart disease, and constrictive pericarditis and pericardial effusion.^12,13 In a recent study comparing CVD risk between the general population and more than 70,000 patients with breast cancer, radiation therapy was associated with an increased risk of the listed manifestations of radiation-induced heart disease.¹³

The risk of cardiotoxicity from radiation therapy is related to the total dose of radiation administered, dose per fraction, and volume of heart irradiated² and, thus, differs depending on whether the left or right breast/chest wall undergoes radiation treatment.^14-16 Newer techniques (e.g., three-dimensional planning, conformal blocking, deep-inspiration breath hold, and prone positioning) aim to reduce exposure of healthy tissue to radiation damage,^17-21 but most patients who receive left-sided radiation still receive at least 2 Gy to the heart.²² Boekel and colleagues reported that the incidence of ischemic heart disease but not overall CVD was slightly increased after left- versus right-sided radiation therapy for breast cancer.¹³ The increase is proportional to the mean dose to the heart, begins within a few years after exposure, and continues for at least 20 years.¹² In addition, CV side effects are more likely in patients with a known history of cardiac disease.^2,23 CAD and cerebrovascular disease are common, as are diabetes, smoking, hypertension, high cholesterol, lack of physical activity, and poor nutrition. Although these comorbidities are typically associated with older age, younger age at treatment actually seems to increase the risk of radiation-induced cardiotoxicity as well.^13,24

Trastuzumab

Trastuzumab is a monoclonal antibody that targets the human epidermal growth factor receptor 2 (HER2). Since its discovery, trastuzumab has dramatically improved the survival of the 15-20% of patients with breast cancer whose tumors overexpress HER2.²⁵ However, this antibody is associated with a risk for asymptomatic decrease in left ventricular ejection fraction (LVEF) and, rarely, clinical HF.^26,27

Trastuzumab-related cardiotoxicity is more likely in patients who have used anthracyclines previously or concomitantly.^28,29 However, concurrent treatment with trastuzumab and radiation is safe.^30,31 Pre-existing cardiac dysfunction such as decreased LVEF, older age (age greater than 50 years), obesity, and anti-hypertensive therapy are risk factors.^32,33 Diabetes, valvular disease, and CAD are not consistently associated with increased risk,^34-36 though diabetes appeared to be a risk factor in one cohort of elderly women.³⁷

Trastuzumab-related cardiotoxicity does not depend on cumulative dose. Moreover, re-challenge is often tolerated after recovery.³⁷ Use of dual HER2 blockade by adding pertuzumab or lapatinib (other drugs that target the same pathway) does not seem to increase the risk of cardiomyopathy over trastuzumab alone.^38,39

Anthracycline-Based Chemotherapy

Prolonged treatment with anthracyclines (e.g., doxorubicin and daunorubicin) has been associated with cardiotoxicity in the form of cardiomyopathy and HF.^40,41 Acute/subacute cardiotoxicity can be seen any time between treatment initiation and months after treatment cessation, but chronic cardiotoxicity (manifesting as clinical HF or subclinical decline in myocardial function) can take years to develop.^42-44 Chronic cardiomyopathy often presents as asymptomatic diastolic or systolic dysfunction and progresses to HF, which may be fatal.

The strongest risk factor for anthracycline-induced cardiotoxicity is cumulative dose.⁴⁵ Age at the time of exposure, co-administration of other cardiotoxic agents, chest irradiation, preexisting CVD, hypertension, diabetes, and peripheral vascular disease have been associated with anthracycline-related cardiotoxicity. Cardiac function has been shown to decrease up to 30 years after initial treatment,⁴⁵ though it can be difficult to identify the contribution of anthracycline exposure versus other age-related comorbidities in some very late cases of cardiac dysfunction. As more patients live decades after the diagnosis and treatment of early stage breast cancer, more will have time to develop cardiac compromise. Additional research is needed to better understand the significant individual variability in susceptibility to anthracycline-induced cardiotoxicity. Genetic factors such as polymorphisms in the HAS3 gene may be at play.⁴⁶

Endocrine Therapies

Endocrine therapy with selective estrogen receptor modulators (e.g., tamoxifen) and aromatase inhibitors improves survival for patients with hormone receptor-positive breast cancer.^47,48 Aromatase inhibitors have slightly better antineoplastic efficacy than tamoxifen in postmenopausal patients, but rates of CVD are slightly higher after treatment with aromatase inhibitors than after tamoxifen.⁴⁹ In a recent study of over 13,000 women, aromatase inhibitor-only users had a similar risk of cardiac ischemia and stroke as tamoxifen-only users, but dysrhythmia, valvular dysfunction, and pericarditis were more prevalent with use of aromatase inhibitors.⁵⁰ For premenopausal patients, ovarian function suppression is sometimes administered in combination with tamoxifen and always administered if aromatase inhibitor therapy is to be used.⁵¹ However, the long-term CV effects of ovarian function suppression remain uncertain.

Detection of CV Toxicity

Baseline history and physical exam with attention to signs and symptoms of CV compromise is recommended for all patients who will undergo potentially cardiotoxic breast cancer treatment. Echocardiography (preferably three dimensional or two dimensional with contrast) is typically used to monitor cardiac function before and during trastuzumab (to identify reversible subclinical declines in ejection fraction) in patients with early-stage breast cancer. Whether there is value to echocardiographic monitoring in patients with metastatic disease (who may receive many years of treatment), and at what frequency if so, is uncertain.^52,53 The utility of repeated echocardiography is also controversial in patients with early-stage cancer who are at relatively low risk of chronic HF due to young age and no receipt of anthracycline. Patients who receive anthracycline have traditionally been assessed by echocardiography only at baseline, but the 2015 National Comprehensive Cancer Network Survivorship guideline added a recommendation to consider post-anthracycline echocardiography in certain groups at high risk of cardiotoxicity (Table 2).⁵⁴ The American Society of Echocardiography issued two consensus statements on cardiac monitoring during chemotherapy and after radiation therapy, which are meant to serve as a reference for cardiology and cardio-oncology providers.^55,56 More research is warranted to identify which patients do and do not benefit from intensive monitoring and preventative strategies.

Table 2: Criteria for Consideration of Post-Anthracycline Echocardiography According to National Comprehensive Cancer Network Guidelines⁵⁴

Age over 65

Underlying CV risk factors such as hypertension, dyslipidemia, diabetes mellitus, and family history of cardiomyopathy

History of other CV comorbidities (e.g., atrial fibrillation, known CAD, or structural heart disease)

Treatment with a high cumulative anthracycline dose (>300 mg/m2 doxorubicin)

Low-normal LVEF (50-54%) at baseline

Symptoms of HF

How Can We Prevent Cardiotoxicity?

It is important to take cardiac risks into account during the decision-making process about chemotherapy. For some patients who are at increased risk of cardiotoxicity due to age or comorbidities, the estimated risk/benefit ratio may weigh in favor of a non-anthracycline-containing regimen or no chemotherapy at all. For others, there may be a role for heart-protective medications concurrent with anthracycline use.^57,58 A number of medications have been tested and tried as reviewed elsewhere.⁵⁸ The most recent of the randomized controlled cohort studies is the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial, which used a 2 x 2 randomization to assign 130 women with early-stage breast cancer and no serious comorbidity to the angiotensin receptor blocker candesartan cilexetil, the beta-blocker metoprolol succinate, or matching placebos in parallel with adjuvant anthracycline-based chemotherapy. The overall decline in LVEF was 2.6% in the placebo group and 0.8% in the candesartan group in the intention-to-treat analysis. Ejection fraction declines did not differ between metoprolol and placebo.⁵⁹ Indeed, there does not seem to be a class effect for beta-blockers, and only carvedilol and nebivolol have documented cardioprotective properties in the setting of anthracycline therapy. On the contrary, there does seem to be a class effect for angiotensin-converting enzyme (ACE) inhibitors and possibly angiotensin-receptor blockers; of note, spironolactone seems to be protective against anthracycline cardiotoxicity as well. One small-sized randomized controlled study outlined the cardioprotective properties of atorvastatin. Currently, the PREVENT (Preventing Anthracycline Cardiovascular Toxicity With Statins) study is enrolling patients with early-stage breast cancer and patients with lymphoma to receive a statin medication or placebo before and during anthracycline therapy to assess if cardiac function is protected by simvastatin. Dexrazoxane is an expensive and potentially toxic medication that is proven to decrease CV toxicity from anthracyclines, but due to adverse effects such as leukemia, the Food and Drug Administration has limited the use of dexrazoxane to women with metastatic breast cancer who have received a cumulative dose of 300 mg/m² doxorubicin and who will continue to receive doxorubicin to maintain tumor control.⁶⁰

For radiation-induced heart disease, no preventive effort other than reduction of exposure is effective. Patients with CV risk factors including age >65 years and history of CAD and myocardial infarction should be appropriately counseled on the risk of coronary/cardiac events.¹²

Treatment Options

Patients demonstrating signs of cardiac dysfunction should be referred for a cardiology consultation prior to receiving any additional cardiotoxic therapy. Cessation of a cardiotoxic drug can reverse or limit toxicity in some cases. When acute cardiotoxicity is identified in a patient receiving anthracycline, a change in regimen to a non-anthracycline-containing combination (or cessation of chemotherapy entirely depending on the clinical situation) is warranted. Cardinale and colleagues found that 42% of patients with asymptomatic ejection fracture declines after anthracycline therapy experienced complete ejection fracture recovery after treatment with a beta-blocker and ACE inhibitor, but there was no placebo in this study to clarify if there would have been improvement with anthracycline cessation alone.⁶¹ Randomized clinical trial data regarding optimal drugs for treatment of cardiotoxicity in patients with breast cancer are needed. Current best practices include use of beta-blockers and ACE inhibitors, lifestyle modifications (smoking cessation and exercise), and management of other comorbidities (e.g., diabetes, hypertension, and hypercholesterolemia).

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Keywords: Cardiotoxicity, Breast Neoplasms, Anthracyclines, Antineoplastic Agents, Aromatase Inhibitors, Aromatase, Atrial Fibrillation, Cardiomyopathies, Cardiotoxins, Coronary Artery Disease, Diabetes Mellitus, Doxorubicin, Dyslipidemias, Echocardiography, Hypertension, Pericarditis, Peripheral Vascular Diseases, Postmenopause, Risk Factors, Selective Estrogen Receptor Modulators, Stroke, Tamoxifen, Adrenergic beta-Antagonists, Angiotensin-Converting Enzyme Inhibitors, Hypercholesterolemia, Smoking Cessation, Smoking Cessation, Carbazoles, Leukemia, Lymphoma, Myocardial Infarction, Heart Failure

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