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Cancer Therapy–Induced Cardiac Toxicity in Early Breast Cancer

Addressing the Unresolved Issues
Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.112.100560Circulation. 2012;126:2749–2763

    Introduction

    The landscape of early breast cancer has changed dramatically with significant advancements in early screening and diagnosis and curative-intent therapies. Indeed, breast cancer–specific survival has improved by 20% during the past 30 years, and 5-year survival is now 98% for early-stage disease.1 As a consequence, the risk and nature of adjuvant therapy–induced immediate and late-occurring cardiovascular injury have similarly evolved. In women with early breast cancer, particularly those >65 years of age, cardiovascular disease (CVD) is now the predominant cause of mortality as indicated by Surveillance, Epidemiology, and End Results (SEER)–Medicare linked data.2 Additionally, these women are also at increased risk of CVD compared with age-matched women without a history of breast cancer.3

    Significant cardiac safety concerns about anticancer therapy were first described by Von Hoff and colleagues,4 identifying dose-dependent and progressive left ventricular (LV) dysfunction manifesting as symptomatic heart failure in patients receiving anthracyclines. From this work and others,5,6 anthracycline-induced cardiac toxicity7,8 is now a well-recognized adverse side effect. More recently, randomized trials have demonstrated that human epidermal growth factor receptor 2 (HER2)–directed monoclonal antibodies (ie, trastuzumab) and newer multitargeted small-molecule inhibitors interfere with molecular pathways crucial to normal cardiac homeostasis,9 resulting in relatively high incidences of subclinical and overt cardiac toxicity.10 Although cardiac toxicity with newer therapies has demonstrated reversibility,11 recovery of LV function after treatment cessation is uncertain at this time.12 Thus, to identify those individuals at high risk of cardiac toxicity, baseline measurement of LV ejection fraction (LVEF) is recommended by the American College of Cardiology (ACC) and American Heart Association (AHA) as standard of care for all breast cancer patients being considered for potentially cardiac-toxic treatment regimens.13,14 In addition, measurement of LVEF is Food and Drug Administration (FDA) mandated in all registrational breast cancer adjuvant trials involving an anthracycline- or a trastuzumab-containing regimen. Finally, use of endocrine therapy (eg, tamoxifen and aromatase inhibitors) in women with hormone receptor–positive breast cancer may also increase the risk of cardiovascular complications.15

    Despite the rapidly changing landscape of breast cancer management and the resultant changes in cardiovascular safety, several critical issues in the emerging field of “cardio-oncology” remain unresolved. To ensure that this field keeps pace, a full understanding of the incidence, magnitude, and consequences of cardiovascular side effects of adjuvant therapy is an essential first step in optimizing early breast cancer management. Against this background, the purpose of this article is to comprehensively review several pivotal unaddressed issues concerning the definition, incidence, detection, and clinical importance of cardiac toxicity in early breast cancer. The evidence supporting the efficacy of preventive and treatment strategies is also discussed.

    In this article, we use the term cardiac toxicity to refer to myocardial injury related to anticancer pharmacological therapies. The principal manifestations of myocardial injury, LV dysfunction and heart failure, are the primary focus of our review. Additional cardiovascular toxicities associated with anticancer therapies, including sequelae of vascular injury (ie, myocardial ischemia/infarction and stroke), are also considered in discussions of CVD events. Finally, the range of potential cardiovascular effects of currently approved adjuvant breast cancer systemic therapies is summarized and highlighted by class of agent in Table 1.

    Table 1. Potential Cardiovascular Effects of Adjuvant Breast Cancer Systemic Therapy

    Adjuvant TherapyShort-Term EffectsLong-Term Effects
    Polychemotherapy
        AnthracyclinesAtrial and ventricular arrhythmiasProgressive decline in left ventricular function, may lead to overt heart failure
    Pericarditis/myocarditis
    Left ventricular dysfunction, dilated cardiomyopathy, sudden cardiac death
    Alkylating agents
        CisplatinMyocardial ischemia/infarction
    Hypertension
    Heart failure
    Arrhythmias
    Heart block
    Endocardial fibrosis
    Venous thromboembolism
        CyclophosphamidePericarditis/myocarditis
    Heart failure
    Atrial ectopy
    Bradycardia
    Microtubule-targeting drugs
        TaxanesBradycardia/atrioventricular block
    Atrial and ventricular arrhythmias
    Heart failure
    Myocardial ischemia
    Antimetabolites
        FluorouracilHeart failure
    Atrial or ventricular ectopy
    Myocardial ischemia/infarction
        CapecitabineHeart failure
    Atrial or ventricular ectopy
    Myocardial ischemia/infarction
        MethotrexateArrhythmias
    Myocardial ischemia/infarction
    Radiotherapy
    AnginaCoronary artery disease
    DyspneaPericardial constriction
    Heart failureAtherosclerosis
    Diffuse intimal hyperplasia of coronary arteries/left main stenosisMediastinal fibrosis
    Pericardial effusionCarotid lesions
    Sudden deathValvular heart disease
    Endocrine therapy
        TamoxifenVenous thromboembolism
    Stroke
        Aromatase inhibitorsUnknown at this time
            Anastrozole
            Letrozole
            Exemastane
    HER2-directed therapies*
        TrastuzumabLeft ventricular dysfunction
        PertuzumabHeart failure
        Lapatinib

    *The time course (early versus late) of cardiovascular effects associated with HER2-directed therapies has not been established. Adapted from Jones et al.16 with permission from the publisher.

    Definition and Clinical Importance

    Several oncology and cardiology organizations provide definitions for cardiac toxicity that encompass overt clinical events and subclinical injury (Table 2), although there is no universally accepted definition or clinical cut points. In registrational oncology trials, the most widely adopted criteria for adjudicating cardiovascular events is the Common Terminology Criteria for Adverse Events, developed by the National Cancer Institute.17,18 The Common Terminology Criteria for Adverse Events (version 4.03)18 recognize a broad array of cardiovascular events and subclinical laboratory and imaging-based functional changes. In clinical trials and routine practice, cardiac function is typically determined by measuring resting LVEF, with cardiac toxicity defined as >10% LVEF decline from baseline to <55%, ≥10% LVEF decline from baseline to <50%, ≥20% or >15% LVEF decline from baseline but remaining ≥50%, or any LVEF decline to <50%. However, because of varying application of safety surveillance protocols, differing LVEF parameters (and measurement methodologies), differences in patient eligibility criteria, and short duration of follow-up, accurate assessment of the frequency and magnitude of LV dysfunction is challenging (Table 3); furthermore, the real-world incidence is essentially unknown, but higher rates of dysfunction are expected.23

    Table 2. Different Classification Schemes for Cardiac Toxicity and Heart Failure

    Classification SystemSeverity
    LowHigh
    Oncology derived
        CTCAE, version 3.0, LV systolic dysfunction17Grade 1 (mild); asymptomatic; resting EF <60%–50%; SF <30%–24%Grade 2 (moderate); asymptomatic; resting EF <50%–40%; SF <30%–24%Grade 3 (severe); symptomatic HF responsive to intervention; EF <40%–20%; SF <15%Grade 4 (life threatening); refractory or poorly controlled HF; EF <20%; intervention such as LVAD, ventricular reduction surgery, or heart transplantation indicatedGrade 5 (death)
        CTCAE, version 4.03, LV systolic dysfunction18Symptomatic as a result of a drop in EF; responsive to interventionRefractory or poorly controlled HF owing to EF drop; intervention such as LVAD, IV vasopressor support, or heart transplantation indicatedDeath
        CTCAE, version 4.03, heart failure18Asymptomatic with laboratory (eg, BNP) or cardiac imaging abnormalitiesSymptoms with mild to moderate activity or exertionSevere with symptoms at rest or with minimal activity or exertion; intervention indicatedLife-threatening consequences; urgent intervention indicated (eg, continuous IV therapy or mechanical hemodynamic support)Death
        CTCAE, version 4.03, ejection fraction decreased18 (investigations)Resting EF, 50%–40%; 10%–19% drop from baselineResting EF, 39%–20%; >20% drop from baselineResting EF, <20%
        Cardiac Review and Evaluation Committee 19Any of 4 criteria confirms cardiac dysfunction: cardiomyopathy, reduced LVEF (global or more severe in the septum); symptoms of HF; signs associated with HF (S3 gallop and/or tachycardia); and decrease in LVEF from baseline ≥5% to <55% with accompanying signs or symptoms of HF or decline in LVEF ≥10% to <55% without accompanying signs or symptoms of HF
    Cardiology derived
        ACC/AHA heart failure stage14Stage A, at risk (eg, patients receiving cardiotoxins) but without structural heart disease or symptomsStage B, structural heart disease (hypertrophy, low EF, valve disease) but without signs or symptomsStage C, structural heart disease with prior or current symptomsStage D, refractory HF requiring specialized interventions
        NYHA symptom classificationGrade I, no limitation of activityGrade II, mild limitation of activity; grade III, marked limitation of activityGrade IV, confined to bed or chair

    ACC/AHA indicates American College of Cardiology/American Heart Association; BNP, brain natriuretic peptide; CTCAE, Common Terminology Criteria for Adverse Events; EF, ejection fraction; HF, heart failure; IV, intravenous; LVAD, left ventricular assist device; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; and SF, shortening fraction.

    Table 3. Incidence of Cardiac Toxicity and Heart Failure With Common Early Breast Cancer Therapies

    DrugStudy (Study Type)Surveillance MethodSurveillance Time PointsLVEF Cardiac Toxicity CriteriaTreatment RegimennIncidence of LVEF Cardiac Toxicity, %Incidence of HF Symptoms, %
    DoxorubicinVon Hoff, et al4 (retrospective; multiple cancer diagnoses)RNA0 to 231 d (posttherapy period during which HF noted)By doxorubicin dose:
    <400 mg/m23190
    ≥400 mg/m25633
    ≥550 mg/m21857
    ≥700 mg/m23318
    Total39412.2
    Swain, et al5 (retrospective meta-analysis; 3 trials: 2 breast, 1 small-cell lung carcinoma)RNABaselineAsymptomatic LVEF decline from baseline: (1) ≥20%, or (2) 10% to below LLN from postbaseline: (3) ≥5% to below LLNBy doxorubicin dose:
    150 mg/m2;≥400 mg/m25
    300 mg/m2;≥550 mg/m226
    400 mg/m2;≥700 mg/m248
    500 mg/m2;
    >500 mg/m2
    Total63018.65.1
    Trastuzumab with or without doxorubicinNSABP B-3120 (RCT)RNABaseline;Asymptomatic LVEF decline from baseline:AC→T8140.5
    3, 6, 9, 18 m(1) >15% orAC→T+H85014.34.1
    (2) 10%–15% to below LLN
    NCCT N-983121 (RCT)RNA/echoBaseline;Asymptomatic LVEF decline from baseline:AC→T6644–5.10
    3, 6, 9, 18 m(1) >15% orAC→T→ H7104–7.82.5
    (2) 10%–15% to below LLNAC→TH5705.8–10.43.3
    BCIRG 00622 (RCT)RNA/echoBaseline;7 times over study durationAsymptomatic, relative LVEF decline >10% from baselineAC→T AC→T+H TCH1014 1042 103011.2 18.6 9.40.7 2.0 0.4

    AC indicates doxorubicin/cyclophosphamide; D, docetaxel; H, trastuzumab; HF, heart failure; LLN, lower limit of normal; LVEF, left ventricular ejection fraction; RCT, randomized, controlled trial; RNA, radionuclide angiography; T, paclitaxel or docetaxel; TCH, docetaxel/carboplatin/trastuzumab; →, sequential; and +, additional. Studies typically allowed the LLN to be determined at participating institutions. For most institutions, the LLN for LVEF was 50% to 55%.

    Despite widespread use, the clinical importance of current definitions of cardiac toxicity is unknown, as is the long-term natural history of LVEF during and after therapy cessation in any cancer population.24 The incidence of overt cardiac toxicity in modern anthracycline- and anthracycline-trastuzumab–containing regimens is typically <5%; however, a significantly larger proportion experience asymptomatic reductions in LVEF (>5%–15%) but remain >50% (Table 3). The prognostic value of an asymptomatic decline in LVEF (that remains >50%) for cardiovascular-related or all-cause mortality in women with early-stage breast cancer is not presently known.

    However, CVD is now the major cause of competing mortality in women with early breast cancer, and women with breast cancer have excess CVD risk relative to age-matched women without a history of breast cancer. For example, Hooning et al3 found that early breast cancer patients had an overall 30% increased standardized incidence ratio of CVD events, particularly heart failure, leading to an excess of 62.9 events per 10 000 patient-years compared with women from the general population. The excess CVD risk is potentially a consequence of the adverse effects of anticancer therapy on components of the cardiovascular system.16 For instance, anthracyclines cause irreversible cardiomyocyte cell death with characteristic ultrastructural changes, including vacuolar degeneration and myofibrillar loss.7,8 Epidemiological evidence suggests that, even without an overt decline in EF at the time of treatment, receiving anthracycline-based adjuvant chemotherapy carries a substantial long-term risk of HF, especially for women >65 years of age.25 HER2-directed agents also cause cardiomyocyte dysfunction and augment anthracycline injury;26,27 elegant preclinical studies have demonstrated that HER2 is essential for cardiomyocyte survival and stress adaptation, whereas deletion or mutation of this gene leads to dilated cardiomyopathy.28,29 In terms of endocrine therapy, the newer third generation of aromatase inhibitor agents is associated with more CVD events than standard tamoxifen therapy.30,31 In conjunction with therapy-related adverse cardiovascular effects, almost two thirds of breast cancer patients are either overweight or obese,32 and 36% are sedentary.33 During adjuvant therapy, early breast cancer patients decrease physical activity levels,34 and a significant proportion gain fat mass with a concomitant loss of lean mass.32 Collectively, these multiple hits combine to reduce cardiovascular reserve capacity.16,35 Cardiovascular reserve capacity is a strong predictor of cardiovascular and all-cause mortality in noncancer clinical populations,36,37 although the prognostic importance in patients with early-stage breast cancer is not known. These parameters can be integrated into a comprehensive conceptual model to explain the accelerated development of CVD/overt heart failure in early breast cancer (see the red row labeled “disease progression” in Figure 1).

    Figure 1.

    Figure 1. Cardiovascular disease detection, prevention, and treatment in early breast cancer. A schematic representation describing the continuum of breast cancer treatment, cardiac toxicity, and eventual development of cardiovascular disease, in particular heart failure. Cancer occurs in the setting of the patient's baseline health and risk factors profile. With the administration of potentially cardiac toxic therapies, surveillance diagnostic strategies may be adopted; others have proposed primordial preventive treatment of all patients. A number of biomarker strategies have been assessed to detect subclinical cardiac toxicity; primary preventive treatment has also been proposed. Once there is clear clinical evidence of cardiac toxicity (ie, American College of Cardiology/American Heart Association [ACC/AHA] stage B heart failure), imaging and biomarkers may help to guide treatment; secondary prevention is recommended to prevent the development of symptomatic heart failure and cardiovascular disease. Finally, in those with overt heart failure, standard heart failure treatment is needed to reduce cardiovascular mortality. ACE indicates angiotensin-converting enzyme; CV, cardiovascular; and LVEF, left ventricular ejection fraction.

    Underlying Mechanisms of Cardiovascular Events

    For a comprehensive overview of all the potential anticancer agents and mechanisms of cardiovascular toxicity, the reader is referred to prior excellent reviews.3842 A brief overview is provided here.

    Anthracyclines

    Suggested mechanisms of anticancer effects include intercalation into DNA, preventing macromolecule synthesis; generation of reactive oxygen species, leading to DNA damage or lipid peroxidation; and topoisomerase II inhibition, inducing DNA damage and apoptosis.38,39 Anthracycline-induced generation of reactive oxygen species is a central mediator of numerous direct adverse myocardial consequences (Figure 2).38,39 For instance, anthracyclines both accelerate myofilament apoptosis via activation of the tumor suppressor protein p5344,45 and suppress sarcomere protein synthesis through depletion of GATA-4–dependent gene expression46,47 and cardiac progenitor cells.48,49 This imbalance between sarcomere synthesis and degradation results in impaired myocyte turnover, accumulation of senescent cells, and eventually the onset of myocardial dysfunction.50 Reactive oxygen species also stimulate cardiomyocyte calcium release and inhibit sarcoplasmic reticulum calcium reuptake, with the resulting cytosolic calcium overload leading to systolic (contractile) and diastolic (lusitropic) dysfunction.5052 Anthracycline induction of inducible nitric oxide synthase and the generation of peroxynitrite, a reactive oxidant produced from the reaction of nitric oxide and superoxide anion, in the myocardium may trigger cell death and contribute to myocardial dysfunction.5355 Finally, anthracyclines decrease AMP-activated protein kinase expression, triggering perturbations in mitochondrial substrate use and a decrease in ATP production.56 Collectively, these molecular mechanisms contribute to the pathogenesis of myocardial dysfunction and heart failure.

    Figure 2.

    Figure 2. Mechanisms underlying anthracycline-induced cardiac toxicity. Anthracycline-induced generation of oxidative stress is a central mediator of accelerated myofilament apoptosis via upregulation of the p53 pathway and inducible nitric oxide synthase (iNOS), suppression of myofilament protein synthesis via inhibition of cardiac progenitor cells (CPCs) and GATA-4, calcium overload resulting in ultrastructural changes to myocytes, and alterations in cardiac energy metabolism via downregulation of AMP-activated protein kinase (AMPK). These changes lead to myocardial dysfunction and ultimately heart failure. Adapted from Scott et al.43

    Molecularly Targeted Therapeutics

    Receptor tyrosine kinases are enzymes that act as critical mediators of normal cellular signal transduction and regulate diverse cellular processes, including cell cycle progression, metabolism, transcription, and apoptosis.57 Strategies for the prevention or interception of malignant-induced deregulated receptor tyrosine kinase signaling include the development of selective agents that target either the extracellular ligand-binding domain or the intracellular tyrosine kinase–binding region.58 HER2-directed therapies are receptor tyrosine kinase agents approved by the FDA for adjuvant treatment of early breast cancer that may have adverse myocardial consequences.59,60

    Of clinical importance, trastuzumab, the first FDA-approved anti-HER2 therapy, and pertuzumab, a newer agent undergoing phase II clinical trials, are associated with significant ventricular systolic dysfunction,20,21,61,62 whereas lapatinib may be associated with a lower incidence of decline in EF.63 In the normal heart, neuregulin-1β binds to HER (also known as ErbB) receptors on cardiomyocytes, leading to activation of the PI3K/Akt pathway promoting protein synthesis, cell survival, and protein hypertrophy and reducing protein degradation (Figure 3).27 Extracellular HER2-directed agents (ie, trastuzumab and pertuzumab) inhibit neuregulin-1β release,64 leading to a marked decrease in both total and phosphorylated Akt,65 thus limiting cardiomyocyte cell hypertrophy and survival and protein regulation.6669 However, lapatinib, a small-molecule intracellular HER2 antagonist, may not affect neuregulin-1β–mediated Akt activation in cardiomyocytes while still exerting antiproliferative effects in HER2-amplified tumor cells through Akt inhibition.70,71

    Figure 3.

    Figure 3. Mechanisms underlying molecularly targeted therapeutics-induced cardiac toxicity. Inhibition of neuregulin-1β (Nrg1)/ErbB receptors with human epidermal growth factor receptor 2 (HER2)–directed therapies affects numerous signaling pathways, resulting in suppression of myofilament protein synthesis via the PI3K-Akt pathway, suppression of protein hypertrophy via the mitogen-activated protein kinase (MAPK) pathway, suppression of cell survival via the Src/Fak pathway, and upregulation of protein degradation via FOXO signaling. Fak indicates focal adhesion kinase; NO, nitric oxide; and PI3K, phosphatidylinositol 3-kinase.

    Endocrine Therapies

    The underlying mechanisms of cardiovascular toxicity remain to be elucidated; however, a brief overview of the potential cardiovascular consequences of endocrine therapies is provided. Traditional endocrine therapy (tamoxifen, oophorectomy) for women with hormone receptor–positive breast cancer has not been clearly associated with cardiovascular injury. Although controversial, as a selective estrogen receptor antagonist/agonist, tamoxifen may have protective properties against myocardial infarction and ischemic heart disease72 related to a generally beneficial impact on serum lipids.73,74 However, these favorable benefits may be offset by a higher incidence of vascular events, particularly venous thromboembolism72,75 and stroke.75,76 The marked reduction in serum estrogen associated with the newer third generation of aromatase inhibitor therapy and the unfavorable changes in lipoprotein profiles raise concerns about the adverse cardiovascular effects of these agents. Compared with tamoxifen, aromatase inhibitor therapy has been associated with a slight increase in CVD events,30,31 although the incidence of thromboembolism was significantly lower.31,7779 No significant differences in the incidence of CVD events have been observed between aromatase inhibitor therapy and placebo.80 Long-term follow-up is required to fully assess the associated cardiovascular risks, if any, with aromatase inhibitor therapy.

    Detection of Cardiac Toxicity

    Several excellent articles have comprehensively reviewed strategies of detection in the oncology setting.81,82 Thus, a brief overview and comparison of detection modalities (Table 4) are provided here.

    Table 4. Relative Advantages and Disadvantages of Detection Methods for Cancer Therapy–Related Cardiac Toxicity

    Echocardiography
    RNAcMRBlood Biomarkers
    2D3DStrainTroponinNatriuretic Peptides
    Target(s)LVEF; volumesLVEF; volumesMyocardial deformationLVEF; volumesLVEF; volumes; myocardial damage/deformationMyocardial injuryMyocardial stretch/stress
    Availability++++++++++++++++++++++
    CostLowMediumMediumLow
    Reproducibility++++++++++++++++++++++++
    Cardiac structure*
        Temporal resolution++++++++--
        Spatial resolution++++++--
    Myocardial function
        Systolic++++++(+)++++++++++++--
        Diastolic+++++++++-++--
    Tissue characterization+---++++--
    Potential to detect subclinical cardiac toxicityLowLowModerate–highLowModerateHighUnknown

    cMR indicates cardiac magnetic resonance; LVEF, left ventricular ejection fraction; RNA, radionuclide angiogram; 2D, 2-dimensional; and 3D, 3-dimensional.

    *Cardiac structure includes visualization and quantification of cardiac chambers (dimension), myocardium (thickness), and valves (mobility, regurgitation, stenosis).

    Myocardial function includes visualization and quantification of systolic function (eg, LVEF, strain, strain rate, stroke volume) and diastolic function (eg, diastolic grade/pattern).

    Conventional Approaches

    Current methods to assess cardiac function are insensitive measures of early (subclinical) cardiac injury. Resting LVEF assessments, by either echocardiography or nuclear blood pool scanning (radionuclide angiography), do not detect chemotherapy-induced early myocyte damage83 and are poor predictors of cardiac risk,84 including symptomatic heart failure,5,6,85 particularly when LVEF is normal or mildly impaired. As a consequence, the decrease in LVEF becomes evident only once significant myocardial damage has already occurred; this magnitude of injury may be irreversible.6 There are also few established guidelines on the specific timing and frequency of initial and serial LVEF assessments.86,87 The majority of centers adhere to the FDA package insert for baseline and serial monitoring of LVEF in patients receiving trastuzumab88; however, considerable variability likely exists in clinical trials and practice, ranging from no testing to regular repeated testing.89

    New Approaches

    Several groups have started to investigate the predictive ability of blood and imaging biomarkers for the detection of early cardiac injury (see the blue row labeled “diagnostic testing” in Figure 1).

    Blood Biomarkers

    The consistent relationship between elevations in a variety of cardiac troponin assessments (troponin I, troponin T, regular, and highly sensitive) and LVEF decline indicates that these factors are likely useful biomarkers of early cardiac injury. For example, a transient rise in cardiac troponin I has been demonstrated to predict the occurrence90 and the magnitude of LVEF decline9193 in patients with hematologic and solid malignancies receiving high-dose anthracyclines. In women receiving anthracycline-trastuzumab–containing therapy, detectable troponin I levels (>0.08 ng/mL) were associated with a 23-fold increased risk of cardiotoxicity (LVEF decline >10% to <50%) and an ≈ 3-fold increased risk of LVEF irreversibility after drug discontinuation.94 Troponin T predicts LV diastolic dysfunction.95 High-sensitivity troponin I measurements demonstrated predictive value in 43 breast cancer patients receiving anthracyclines and trastuzumab.96 However, the clinical utility of troponin measurements is not established for other chemotherapeutic regimens.97 The family of natriuretic peptides (eg, brain natriuretic peptide, N-terminal pro-brain natriuretic peptide, and N-terminal proatrial natriuretic peptide) appears to be less reliable than troponins in predicting LVEF decline in the oncology setting, with studies reporting contradictory findings.98101

    Overall, the studies of troponins and natriuretic peptides have notable limitations. The predictive role of these biomarkers has been investigated in small studies with heterogeneous cancer populations receiving multiple types of cytotoxic therapies; the timing of biomarker assessment also varied considerably.102 Although promising, further research is required to determine the optimal blood-based approach (type of test, timing, and frequency), including the initiation of adequately powered, randomized trials to determine whether biomarker-directed preventive therapy mitigates and/or abrogates the subsequent development of LV dysfunction in breast cancer patients receiving conventional therapies. Furthermore, although developed to evaluate biomarkers of treatment efficacy, the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) may provide an excellent framework for the evaluation and reporting of biomarkers of cardiac toxicity.103

    Cardiac Imaging Modalities

    Tissue Doppler imaging (TDI) uses Doppler measurements of the myocardium to assess myocardial velocity, deformation (strain), and rate of deformation (strain rate). TDI-derived parameters, particularly strain and strain rate, are more sensitive for detecting altered myocardial performance beyond LVEF104 and, in the case of strain rate, less susceptible to alterations in loading conditions compared with LVEF.105 Few studies to date have explored the utility of TDI in the detection of cancer therapy–induced cardiac toxicity. In mice treated with doxorubicin, TDI-derived myocardial velocities and strain rate detected myocardial dysfunction before alterations in conventional echocardiographic indexes of LV function.106 In clinical studies, reduced TDI strain and strain rate revealed impaired myocardial function before LVEF decline107109 and heart failure symptoms110 in patients treated with anthracycline-containing therapy; the predictive value of these parameters was not evaluated. Two-dimensional speckle-tracking strain echocardiography has technical advantages compared with TDI-measured strain, but few studies have assessed the sensitivity or specificity of this technique to predict LV dysfunction in the oncology setting. Sawaya et al96 found, however, that reduced global longitudinal strain at 3 months predicted LVEF decline at 6 months in 43 patients receiving anthracycline-trastuzumab therapy. Optimal timing for echocardiographic myocardial deformation assessments remains undetermined, but emerging evidence suggests that it has a potential role for predicting therapy-related cardiac toxicity that merits further investigation.

    Cardiovascular magnetic resonance imaging is emerging as the gold standard for LVEF assessment, and early studies show promise for its use in the oncology setting.111,112 For example, in a pilot study of 22 patients receiving anthracyclines, an increase in myocardial contrast enhancement of >5 relative to skeletal muscle from baseline to day 3 of chemotherapy predicted LVEF decline.113 Serial measures of gadolinium signal intensity by cardiovascular magnetic resonance in mice receiving anthracyclines also predict LV dysfunction.114 Finally, a significant increase in aortic stiffness detected by cardiovascular magnetic resonance early after receipt of anthracyclines may be associated with vascular injury and a higher risk of future cardiovascular events.115 Targeted nuclear imaging techniques with radiolabeling of fatty acids and molecularly directed anticancer drugs have also demonstrated promise in this context.116 However, although these novel tracers are emergent, this remains an area of research that has not been translated to clinical practice.

    Cardiopulmonary Exercise Tolerance Testing

    All conventional and forthcoming detection strategies in the oncology setting focus almost exclusively on the heart and do not provide a measure of global, integrative cardiopulmonary function. Incremental exercise tolerance tests to symptom limitation provide an accurate evaluation of global cardiopulmonary reserve (aerobic capacity).117 Work from our group indicates that breast cancer patients have significant and marked impairments in aerobic capacity with V̇o2peak being, on average, ≈30% below that of age-matched sedentary healthy women despite normal cardiac function (resting LVEF ≥50%).35 Thus, cancer therapy–induced cardiac injury may occur in conjunction with, or is even preceded by, concomitant injury to other steps in oxygen transport (lungs, blood, vascular) and/or use (skeletal muscle function)—injury that is not evaluated by existing techniques. Large cross-sectional and prospective cohort studies are now required to fully characterize the level and mechanisms of exercise intolerance in breast cancer survivors and its relationship to cardiovascular risk, long-term prognosis after cancer, and competing causes of mortality.

    Management of Cardiac Toxicity

    Strategies to prevent and/or treat cardiac toxicity must be congruent with the degree of risk and/or extent of CVD (see green row labeled “Prevention and Treatment” in Figure 1). Accordingly, possible management strategies are divided into 4 distinct categories: (1) primordial prevention (prophylactic therapy given before or during adjuvant therapy to prevent anticipated injury), (2) primary prevention (therapy provided to selected patients with early signs of myocardial damage but with normal LVEF to treat injury and prevent progression), (3) secondary prevention (therapy provided after the detection of LVEF decline to treat impairment), and (4) treatment of clinical symptoms and overt heart failure.

    Primordial Prevention

    Several small, randomized trials have investigated the efficacy of various standard cardiovascular medications (eg, angiotensin-converting enzyme [ACE] inhibitors,118 angiotensin receptor blockers,119,120 β-blockers,118,121 and statins122), most often as prophylactic strategies to prevent anthracycline-induced LV dysfunction and heart failure (Table 5). Carvedilol121 significantly reduced the incidence of systolic dysfunction (ie, LVEF decline to <50%), as did atorvastatin122 in preliminary data from a recent study. Nakamae et al119 found that prophylactic valsartan attenuated pathological LV remodeling and diastolic dysfunction in 20 patients receiving anthracyclines. Ongoing clinical trials are evaluating whether prophylactic ACE inhibitors and β-blockers can prevent cancer therapy–induced LV remodeling and systolic dysfunction in patients with HER2-positive breast cancer126 and hematologic malignancies.127 Endurance exercise training not only attenuates anthracycline-induced cardiac injury in mouse models but also has the added advantage, compared with current pharmacological approaches, to simultaneously augment the reserve capacity of the other components of O2 transport that govern global cardiovascular function.43 Finally, dexrazoxane has been shown to mitigate cardiac toxicity in breast cancer patients;128 however, it currently is approved by the FDA only in the metastatic (advanced) setting and in patients receiving cumulative doxorubicin dose ≥300 mg/m2129 and is not routinely used in clinical practice, likely because of concerns about reduced efficacy of conventional antitumor agents.130 However, a recent meta-analysis including studies among patients with advanced breast cancer demonstrated dexrazoxane cardioprotection without a decrease in antitumor therapeutic efficacy,131 suggesting the need to reinvestigate the use of dexrazoxane during initial treatment in women with breast cancer.

    Table 5. Comparison of Therapies for Prevention of Cancer Therapy–Related Cardiac Toxicity

    ReferencePatient PopulationTreatmentCV Therapy IndicationGroupsNDoseΔLVEF, %Incidence of
    Therapy Prevented (P Significant)
    LVEF<50%, %Heart Failure, %Mortality, %
    Cardiovascular medications
        Georgakopoulos et al118Hodgkin and non-Hodgkin lymphomaABVD orProphylaxisMetoprolol4288.8 mg/d−2.40.8
    R-CHOP(chemo onset)Enalapril4311 mg/d−1.31.6
    Control40−12.4
        Nakamae et al119Non-Hodgkin lymphomaCHOPProphylaxisValsartan2080 mg/d↑BNP
    (chemo onset)Control20↑LVEDD
    ↑QT interval
        Cadeddu et al120Multiple diagnosesEpirubicinProphylaxisTelmisartan2540 mg/d4↓TDI strain rate
    (chemo onset)Placebo240Diastolic dysfunction
    ↑IL-6, ↑ROS
        Kalay et al121Multiple diagnosesAnthracyclinesProphylaxisCarvedilol2512.5 mg/d−0.8404↓LVEF
    (chemo onset)Control25−16.620416LV dilation
    Diastolic dysfunction
        Acar et al122Multiple diagnosesAdriamycin or IdarubicinProphylaxisAtorvastatin2040 mg/d1.35↓LVEF
    (chemo onset)Control20−7.925LV dilation
    ↑CRP
        Cardinale et al123Multiple diagnosesHigh-dose chemotherapycTnI+Enalapril5620 mg/d0.5000↓LVEF
    Control58−14.543243LV dilation
    Heart failure
    Arrhythmia
    Cardiac events
    Exercise
        Haykowsky et al124HER2+TrastuzumabProphylaxisAerobic training173 times/wk−5No effect on LV dilation, ↓LVEF, or V̇o2peak
    Breast(chemo onset)At 60%–85% V̇o2peak
        Jones et al125BreastACProphylaxisAerobic training103 times/wk1ΔV̇o2peak of
    (chemo onset)At 60%–100% V̇o2peak4.1 mL·kg−1·min−1 favoring AT
    AC only102No ΔLVEF

    ABVD indicates doxorubicin/bleomycin/vinblastine/dacarbazine; AC, doxorubicin and cyclophosphamide; AT, aerobic training; BNP, brain natriuretic peptide; cTnI, cardiac troponin I; CRP, C-reactive protein; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; (R)-CHOP, (Rituximab)-cyclophosphamide/doxorubicin/vincristine/prednisone; ROS, reactive oxygen species; and TDI, tissue Doppler imaging.

    Primary Prevention

    Use of biomarker positivity to guide treatment is promising and has the appeal of limiting therapy to only those patients at greatest risk. Cardinale et al123 used detectable levels of troponin I assessed 1 month after the completion of high-dose chemotherapy to select 114 patients with various malignancies for randomization to placebo versus enalapril 20 mg/d for 1 year. LVEF declines below 50% and heart failure were observed only in untreated patients. Enalapril also attenuated a significant increase in LV volumes. Biomarker-driven therapy warrants further investigation because current data are limited and the optimal blood and/or imaging biomarker on which to base early intervention remains to be determined.

    Secondary Prevention

    ACC/AHA guidelines emphasize the importance of preemptive treatment of asymptomatic LVEF decline (ie, stage B heart failure)14; however, randomized trial data are limited in early-stage heart failure from any cause. Thus, the broad Class I indication to treat with a β-blocker and ACE inhibitor or angiotensin receptor blockers is based on limited evidence in stage B patients from the general population.132,133 Guidelines for treatment in patients affected by cancer therapy–induced LV dysfunction have been published,14,129 although specific details on the timing of initiation and duration are not provided. In addition, the continuous nature of the myocardial insult from cytotoxic therapy likely warrants special consideration.

    Symptomatic Heart Failure

    Heart failure is a progressive clinical syndrome in which symptoms of congestion typically occur late in the course of disease. The ACC/AHA recommendations for the treatment of symptomatic (stage C and D) heart failure include routine use of ACE inhibitors or angiotensin receptor blockers and β-blockers with diuretics added for symptomatic congestion.14 Few studies have assessed optimal treatment in the oncology setting, and no standard of care exists on specific interventions for cancer therapy–induced heart failure. Jensen et al6 prospectively studied 120 women with advanced breast cancer. Among 10 patients developing heart failure after anthracyclines, treatment with enalapril or ramipril improved symptoms to New York Heart Association functional class I in 7 patients and class II in 3 patients. Moreover, ACE inhibition also reversed an LVEF decline (defined by relative LVEF increase ≥15%) in 7 of 8 patients compared with only 1 of 33 untreated patients. Notably, discontinuation of ACE inhibitors resulted in an LVEF decline of ≥10% after 4 to 5 months. In 201 patients with anthracycline-induced cardiomyopathy (LVEF ≤45%), enalapril, frequently used in combination with carvedilol, resulted in reduced cardiac events, including heart failure hospitalizations, and a complete LVEF recovery when therapy was instituted within 6 months of detection of LV systolic dysfunction.134

    Few studies have directly compared the relative efficacy of ≥2 pharmacological agents or different prevention/management strategies in any cancer setting. Current state-of-the-art treatment for symptomatic cytotoxic therapy–induced heart failure is ACE inhibitors and β-blockers. This recommendation, however, is based on limited data and guidelines derived from findings in noncancer heart failure.14 ACE inhibitors and β-blockers may reduce cytotoxic therapy–induced myocardial injury and dysfunction through biomechanical effects proven to mitigate systolic heart failure in noncancer patients135 and possess antioxidant properties against anthracyclines.136138 Statins also possess antioxidant properties.139,140 However, all these agents are also well-established pleiotropic therapies; hence, the relative cardioprotective contribution of antioxidant or other mechanisms against cytotoxic therapy– induced cardiac toxicity is undetermined. Preclinical studies have demonstrated that other cardiovascular agents (eg, amlodipine,141 sildenafil,142 and bosentan143) with the potential to reduce oxidative stress may prevent or reduce anthracycline-induced cardiac toxicity, but the clinical efficacy of these agents remains unknown at present. Future strategies to treat and prevent anti-cancer therapy–induced cardiac toxicity are likely to include personalized approaches that tailor patients to specific therapies using -omic(s)–based approaches.144 Gene polymorphisms may explain, in part, the observed heterogeneity in the incidence rates of cardiac toxicity and may contribute to myocardial injury from trastuzumab145 and anthracyclines by altering pharmacodynamics,146 transport,147 and reactive oxygen species generation via NADPH oxidase.148,149 Recently, breast cancer susceptibility gene 2 (BRCA2) deficiency has also been demonstrated to increase anthracycline-induced DNA damage, apoptosis, and risk of cardiac failure in mouse models.150 To comprehensively assess pharmacological and nonpharmacological interventions at each stage of disease progression, both translational studies and multicenter, randomized, controlled trials in patients receiving conventional and/or novel adjuvant therapies are required.

    Future Directions

    We hope that this review has provided persuasive information for the investigation of several questions to define and map the clinical trajectory of cytotoxic therapy–associated cardiac toxicity in early breast cancer and to provide strategies for its detection, prevention, and management. These have been noted throughout the text and are summarized in Table 6.

    Table 6. Future Directions in Cardio-Oncology Research

    Definition
        Establish a comprehensive and universal definition of cancer-related cardiac toxicity recognized by the cardiology and oncology fields
        Incorporate this definition in all breast cancer trials
        Perform mechanistically driven translational studies to elucidate mechanisms of cardiac injury
    Clinical importance
        Delineate the short- and long-term natural history of positive blood and imaging biomarkers and relationship with clinical events
        Delineate the short- and long-term natural history of asymptomatic LVEF declines and relationship with clinical events
    Detection
        Determine the optimal strategy (type of test, timing, and frequency) for detection of early subclinical myocardial dysfunction in patients receiving conventional and/or novel adjuvant therapies
        Stipulate that biomarkers to detect cardiac toxicity adhere to REMARK criteria for biomarkers that evaluate cancer treatment efficacy
        Perform adequately powered multicenter RCTs comparing efficacy of different strategies to individualize breast cancer drug therapy and to prevent the development of LVEF decline and symptomatic heart failure
    Prevention/management
        Compare different medications, varying doses, and combinations of pharmacological therapies for use in preventive strategies
        Determine the relative efficacy, safety, and cost-effectiveness of primordial, primary, and secondary prevention strategies
        Perform adequately powered multicenter RCTs of both pharmacological and nonpharmacological interventions at each stage in disease progression
        Evaluate cardiovascular interventions in patients receiving conventional and/or novel adjuvant therapies
        Compare different medications, varying doses, and combinations of pharmacological therapies for treatment in symptomatic heart failure owing to cardiac toxicity of chemotherapeutic agents
        Perform mechanistically driven translational studies to elucidate mechanisms of heart failure treatment

    LVEF indicates left ventricular ejection fraction; RCT, randomized, controlled trial; and REMARK, Reporting Recommendations for Tumor Marker Prognostic Studies.

    Conclusions

    Advances in curative-intent cancer therapies, in conjunction with the rapidly aging, deconditioned, and at-risk women being diagnosed with early breast cancer, have swiftly propelled cardiac toxicity as a major public health problem. The heart has become the victim of the success of modern breast cancer adjuvant therapy; the short- and long-term consequences of cardiac toxicity on treatment risk-to-benefit ratio, survivorship issues, and competing causes of mortality are beginning to be increasingly acknowledged. As reviewed here, there are several important unresolved issues in the emerging field of cardio-oncology. Immediate work is now required to minimize, or optimally to eliminate, myocardial injury in breast cancer management. Such endeavors will require significant investment from government and industry and continued lobbying from the cancer community. These studies will inform policy, evidence-based guidelines, and day-to-day clinical care and will identify new therapeutic strategies to improve health, quality of life, and longevity after a diagnosis of early breast cancer.

    Sources of Funding

    Dr Jones is supported by National Institutes of Health grants CA143254, CA142566, CA138634, and CA133895 and funds from George and Susan Beischer. Dr Scherrer-Crosbie is supported by a Susan G. Komen Investigator Initiated Grant.

    Disclosures

    None.

    Footnotes

    *Drs Douglas and Jones contributed equally.

    Correspondence to Lee W. Jones, PhD,
    Duke Cancer Institute, Box 3085, Durham, NC 27710
    . E-mail

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