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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Circulation. Author manuscript; available in PMC 2013 December 4.
Published in final edited form as:
PMCID: PMC3667651
NIHMSID: NIHMS424679

Cancer Therapy-Induced Cardiac Toxicity in Early Breast Cancer: Addressing the Unresolved Issues

Introduction

The landscape of early breast cancer has changed dramatically with significant advancements in early screening/diagnosis and curative-intent therapies. Indeed, during the past 30 years, breast cancer specific survival has improved by 20% and 5-year survival is now 98% for early-stage disease. 1 As a consequence, the risk and nature of adjuvant therapy-induced acute and late-occurring cardiovascular injury has similarly evolved. In women with early breast cancer, particularly those over age 65, cardiovascular disease (CVD) is now the predominant cause of mortality based on 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 regarding anti-cancer therapy were first described by Von Hoff and colleagues identifying dose-dependent and progressive left ventricular (LV) dysfunction manifesting as symptomatic heart failure in patients receiving anthracyclines. 4 Based on this work, and that of others,5, 6 anthracycline-induced cardiac toxicity7, 8 is now a well-recognized adverse side-effect. More recently, randomized trials demonstrate that HER2-directed monoclonal antibodies (i.e., trastuzumab) and newer multi-targeted 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 following treatment cessation is uncertain at this time. 12 As such, to identify those individuals at high-risk of cardiac toxicity, baseline measurement of left ventricular ejection fraction (LVEF) is recommended by the ACC and 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 FDA-mandated in all registrational breast cancer adjuvant trials involving an anthracycline- or trastuzumab-containing regimen. Finally, use of endocrine therapy (e.g., 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 resultant changes in cardiovascular safety, several critical issues in the emerging field of ‘cardio-oncology’ remain unresolved. To ensure 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 paper 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 will also be discussed.

In this paper, 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 (i.e., myocardial ischemia/infarction and stroke) are also considered when discussing CVD events. Finally, the range of potential CV effects of currently approved adjuvant breast cancer systemic therapies are summarized and highlighted by class of agent in Table 1.

Table 1
Potential Cardiovascular Effects of Adjuvant Breast Cancer Systemic Therapy

Definition and Clinical Importance

Several oncology and cardiology organizations provide definitions for cardiac toxicity that encompass overt clinical events as well as 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 (CTCAE), developed by the National Cancer Institute (NCI). 17, 18 CTCAE (v.4.03) 18 recognizes a broad array of cardiovascular events as well as 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 either: (1) > 10% LVEF decline from baseline, to < 55%, (2) ≥ 10% LVEF decline from baseline, to < 50%, (3) ≥ 20% or > 15% LVEF decline from baseline, but remains ≥ 50%, or (4) 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
Table 3
Incidence of Cardiac Toxicity and Heart Failure with Common Early Breast Cancer Therapies

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 following therapy cessation in any cancer population. 24 The incidence of overt cardiac toxicity in modern anthracycline- and anthracycline-trastuzumab containing regimens is typically less than 5%, however, a significantly larger proportion experience asymptomatic reductions in LVEF (> 5 to 15 percentage points) but remain > 50% (Table 3). The prognostic value of an asymptomatic decline in LVEF (that remains > 50%) for CV-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 al. 3 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 to 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 ultra-structural changes including vacuolar degeneration and myofibrillar loss. 7, 8 Epidemiologic evidence suggests that, even without an overt decline in ejection fraction at the time of treatment, receiving anthracycline-based adjuvant chemotherapy carries a substantial long-term risk of HF, especially for women older than 65 years of age. 25 Human epidermal growth factor receptor 2 (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 (AI) agents is associated with more CVD events than standard tamoxifen therapy. 30, 31 In conjunction with therapy-related adverse CV 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 (CVRC). 16, 35 CVRC is a strong predictor of cardiovascular and all-cause mortality in non-cancer 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 colored row labeled ‘disease progression’ in 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 ...

Underlying Mechanisms of Cardiovascular Events

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

Anthracyclines

Suggested mechanisms of anti-cancer effects include intercalation into DNA preventing macromolecule synthesis, generation of reactive oxygen species (ROS) 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 (ROS) 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, p53, 44, 45 and suppress sarcomere protein synthesis through depletion of GATA-4 dependent gene expression 46, 47 and cardiac progenitor cells (CPCs). 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 ROS 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 (iNOS) and the generation of peroxynitrite, a reactive oxidant produced from the reaction of NO and superoxide anion, in the myocardium may trigger cell death and contribute to myocardial dysfunction. 5355 Finally, anthracyclines decrease AMP-activated protein kinase (AMPK) expression triggering perturbations in mitochondrial substrate utilization and a decrease in ATP production. 56 Collectively, these molecular mechanisms contribute to the pathogenesis of myocardial dysfunction and heart failure.

Figure 2
Mechanisms underlying anthracycline-induced cardiac toxicity. Anthracycline-induced generation of oxidative stress is a central mediator of: 1) accelerated myofilament apoptosis via upregulation of p53 pathway and iNOS, 2) suppression of myofilament protein ...

Molecularly Targeted Therapeutics

Receptor tyrosine kinases (RTK) 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 RTK signaling include the development of selective agents that target either the extracellular ligand-binding domain or the intracellular tyrosine kinase binding region. 58 Human epidermal growth factor receptor 2 (HER2)-directed therapies are RTK agents FDA-approved 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 ejection fraction. 63 In the normal heart, neuregulin-1β (Nrg1) binds to HER (also known as ErbB) receptors on cardiomyocytes leading to activation of the PI3K/Akt pathway promoting protein synthesis, cell survival, protein hypertrophy, and reducing protein degradation (Figure 3). 27 Extracellular HER2-directed agents (i.e., trastuzumab and pertuzumab) inhibit Nrg1 release 64 leading to a marked decrease in both total and phosphorylated Akt, 65 thus limiting cardiomyocyte cell hypertrophy, survival and protein regulation. 6669 However, lapatinib, a small molecule intracellular HER2 antagonist, may not affect Nrg1-mediated Akt activation in cardiomyocytes while still exerting anti-proliferative effects in HER2-amplified tumor cells through Akt inhibition. 70, 71

Figure 3
Mechanisms underlying molecularly targeted therapeutics-induced cardiac toxicity. Inhibition of Nrg1/ErbB receptors with HER2-directed therapies impacts numerous signaling pathways resulting in 1) suppression of myofilament protein synthesis via the PI3K-Akt ...

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 disease 72 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 (AI) therapy as well as the unfavorable changes in lipoprotein profiles, raise concerns about the adverse cardiovascular effects of these agents. In comparison with tamoxifen, AI 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 AI therapy and placebo. 80 Long-term follow up is required to fully assess the associated cardiovascular risks, if any, with AI therapy.

Detection of Cardiac Toxicity

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

Table 4
Relative Advantages and Disadvantages of Detection Methods for Cancer Therapy-related Cardiac Toxicity

Conventional Approaches

Current methods to assess cardiac function are insensitive measures of early (subclinical) cardiac injury. Resting LVEF assessments, either by echocardiography or nuclear blood pool scanning (RNA), do not detect chemotherapy-induced early myocyte damage 83 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 only becomes evident once significant myocardial damage has already occurred; this magnitude of injury may be irreversible. 6 There are also few established guidelines regarding 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 trastuzumab, 88 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 colored row labeled ‘diagnostic testing’ in Figure 1).

Blood Biomarkers

The consistent relationship between elevations in a variety of cardiac troponin assessments (I, T, regular and highly sensitive) and LVEF decline indicate 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 occurrence 90 as well as the magnitude of LVEF decline 9193 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 a ~3-fold increased risk of LVEF irreversibility following 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 (e.g., brain natriuretic peptide (BNP), N-terminal pro-BNP, and N-terminal pro-atrial 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 do 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 While 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 subsequent development of LV dysfunction in breast cancer patients receiving conventional therapies. Further, 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, in particular strain and strain rate, are more sensitive for detecting altered myocardial performance beyond LVEF 104 and, in the case of strain rate, less susceptible to alterations in loading conditions compared to LVEF. 105 Few studies to date have explored the utility of TDI-imaging in the detection of cancer therapy-induced cardiac toxicity. In mice treated with doxorubicin, TDI-derived myocardial velocities and strain rate detected myocardial dysfunction prior to alterations in conventional echocardiographic indices of LV function. 106 In clinical studies, reduced TDI strain and strain rate revealed impaired myocardial function prior to LVEF decline 107109 and heart failure symptoms 110 in patients treated with anthracycline-containing therapy; the predictive value of these parameters was not evaluated. Two-dimensional speckle-tracking strain echocardiography (2D SE) has technical advantages compared to 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 al. 96 did, however, find 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 it has a potential role for predicting therapy-related cardiac toxicity that merits further investigation.

Cardiovascular magnetic resonance (cMR) 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 cMR in mice receiving anthracyclines also predict LV dysfunction. 114 Finally, a significant increase in aortic stiffness detected by cMR 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 radiolabelling of fatty acids and molecularly directed anticancer drugs have also demonstrated promise in this context. 116 However, while 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 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 VO2peak, on average, being ~30% below that of age-matched sedentary healthy women, despite normal cardiac function (resting LVEF ≥ 50%). 35 As such, 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 utilization (skeletal muscle function) – injury that is not evaluated by existing techniques. Establishment of large cross-sectional and prospective cohort studies are now required to fully characterize the level and mechanisms of exercise intolerance in breast cancer survivors as well as its relationship with CV risk, long-term prognosis from 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 cardiovascular disease (see green colored row labeled ‘Prevention and Treatment’ in Figure 1). Accordingly, possible management strategies are divided into four 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 [e.g., angiotensin converting enzyme (ACE) inhibitors, 118 angiotensin receptor blockers (ARB), 119, 120 beta blockers, 118, 121 and statins 122], most often as prophylactic strategies to prevent anthracycline-induced LV dysfunction and heart failure (Table 5). Carvedilol 121 significantly reduced the incidence of systolic dysfunction (i.e., LVEF decline to < 50%), as did atorvastatin 122 in preliminary data from a recent study. Nakamae et al. 119 found that prophylactic valsartan attenuated pathologic LV remodeling and diastolic dysfunction in 20 patients receiving anthracyclines. Ongoing clinical trials are evaluating whether prophylactic ACE inhibitors and beta-blockers can prevent cancer therapy-induced LV remodeling and systolic dysfunction in patients with HER2 positive breast cancer 126 and hematologic malignancies. 127 Endurance exercise training not only attenuates anthracycline-induced cardiac injury in mouse models, but also has the added advantage, in comparison with current pharmacologic 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 is only currently FDA approved in the metastatic (advanced) setting, in patients receiving cumulative doxorubicin dose ≥ 300 mg/m2 129 and is not routinely used in clinical practice, likely because of concerns surrounding 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 re-investigate use of dexrazoxane during initial treatment in women with breast cancer.

Table 5
Comparison of Therapies for Prevention of Cancer Therapy-related Cardiac Toxicity

Primary Prevention

Use of biomarker positivity to guide treatment is promising and has the appeal of limiting therapy only to those patients at greatest risk. Cardinale et al. 123 used detectable levels of troponin I assessed one month after the completion of high dose chemotherapy to select 114 patients with various malignancies for randomization to placebo vs. enalapril 20 mg daily for one year. LVEF declines below 50%, heart failure and arrhythmias were observed only in untreated patients. Enalapril also attenuated a significant increase in LV volumes. Biomarker-driven therapy warrants further investigation since current data is 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 (i.e., stage B heart failure); 14 however, randomized trial data is limited in early stage heart failure from any cause. Thus, the broad class I indication to treat with a beta-blocker and ACE inhibitor or ARB 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 regarding 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 (ARB) and beta blockers, with diuretics added for symptomatic congestion. 14 Few studies have assessed optimal treatment in the oncology setting and no standard of care exists regarding specific interventions for cancer therapy-induced heart failure. Jensen et al. 6 prospectively studied 120 women with advanced breast cancer. Among 10 patients developing heart failure after anthracyclines, treatment with enalapril or ramipril improved symptoms to NYHA functional class I in 7 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 to only 1 of 33 untreated patients. Notably, discontinuation of ACE inhibitors resulted in a LVEF decline of ≥ 10% after 4–5 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 detecting LV systolic dysfunction. 134

Few studies have directly compared the relative efficacy of two or more pharmacologic 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 beta-blockers. This recommendation, however, is based on limited data and guidelines derived from findings in non-cancer heart failure. 14 ACE inhibitors and beta-blockers may reduce cytotoxic therapy-induced myocardial injury and dysfunction through biomechanical effects proven to mitigate systolic heart failure in non-cancer patients, 135 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 cardio-protective contribution of antioxidant or other mechanisms against cytotoxic therapy-induced cardiac toxicity is undetermined. Preclinical studies have demonstrated other cardiovascular agents (e.g., amlodipine, 141 sildenafil, 142 and bosentan 143), 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 anticancer 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, observed heterogeneity in the incidence rates of cardiac toxicity and may contribute to myocardial injury from trastuzumab 145 and anthracyclines by altering pharmacodynamics, 146 transport, 147 and ROS 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 In order to comprehensively assess pharmacologic and non-pharmacologic interventions at each stage of disease progression, both translational studies and multi-center randomized controlled trials in patients receiving conventional and/or novel adjuvant therapies are required.

Future Directions

It is hoped that this review has provided persuasive information for 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 summarized in Table 6.

Table 6
Future Directions in Cardio-Oncology Research

Conclusion

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 acute 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 eliminate, myocardial injury in breast cancer management. Such endeavors will require significant investment from government and industry as well as continued lobbying from the cancer community. These studies will inform policy, evidence-based guidelines, and day-to-day clinical care, as well as identify new therapeutic strategies to improve health, quality of life, and longevity following a diagnosis of early breast cancer.

Acknowledgments

Funding Sources: LWJ is supported by NIH CA143254, CA142566, CA138634, CA133895 and funds from George and Susan Beischer. MSC is supported by a Susan G. Komen Investigator Initiated Grant.

Footnotes

Conflict of Interest Disclosures: None.

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