Cardio-Oncology Considerations for Breast Cancer: Risk Stratification, Monitoring, and Treatment

The authors

Introduction

Advancements in the detection and treatment of breast cancer have led to a significant improvement in long-term outcomes.^1,2 More than 4 million women in the US have had a prior diagnosis of breast cancer, and many are now cancer free.³As patients live longer after receiving a breast cancer diagnosis, competing risks of death from non–cancer-related conditions become increasingly significant.⁴

The most frequent cause of non–cancer-related deaths in this population is cardiovascular disease (CVD).^5,6 In one large cohort of patients with breast cancer and age-matched control patients, the risk of CVD death was almost 2-fold higher among the survivors of breast cancer than in those without the disease. This increase in risk was evident as early as 7 years after diagnosis, and it was higher among those who received chemotherapy.⁷ Results of a recent meta-analysis highlighted CVD-specific increased risk of heart failure and atrial fibrillation among survivors of breast cancer.⁸

There are several causes of increased CVD risk observed among patients with a history of breast cancer. Breast cancer and CVD share many similar risk factors. Age, increased body mass index, decreased physical activity, and alcohol use all increase risk for both diseases.^9-14 Those with underlying CVD may be more likely to develop cancer, and there is recent evidence that incident CVD may accelerate existing breast cancer progression.^15,16

Breast cancer treatment is often based on the location and extent of the disease, as well as immunohistochemical testing, which identifies the expression of specific receptors that cancer treatments can target, including estrogen receptors (ERs), progesterone receptors (PRs), and HER2.¹⁷ Importantly, many types of breast cancer therapy are implicated in the development of CVD.

Cancer therapy–related cardiac dysfunction (CTRCD) is a primary cardiotoxicity of many breast cancer therapies. CTRCD is a form of cardiomyopathy traditionally defined as a decline in left ventricular ejection fraction (LVEF) of at least 10% to an LVEF below the lower limit of normal (ie, less than 53%, according to prior American Society of Echocardiography and European Association of Cardiovascular Imaging Guidelines).¹⁸ In the 2022 European Society of Cardiology (ESC) cardio-oncology guidelines, a consensus definition for CTRCD was proposed to harmonize the broad spectrum of cancer therapy–related cardiotoxicities, including cardiac injury, cardiomyopathy, and heart failure.¹⁹ Symptomatic CTRCD was categorized by clinical severity of heart failure symptoms, and asymptomatic CTRCD was categorized based on LVEF, global longitudinal strain (GLS), and biomarker criteria.¹⁹ Other treatment-related CV complications include ischemic disease, pericardial disease, arrhythmia, and valvular disease.^20-22 In this review, we will discuss: (1) the causes of treatment-related cardiotoxicity, (2) tools for CV risk stratification, (3) monitoring of patients during and after treatment, and (4) strategies for prevention and management of treatment-related cardiotoxicity.

Treatment-Specific Cardiotoxicities

Anthracyclines

Anthracycline-based chemotherapy regimens for breast cancer have been used for more than 40 years, and clinical trial data continue to support the use of anthracyclines for many types of breast cancer.²³ Anthracyclines induce breaks in cancer DNA and inhibit DNA and RNA synthesis by inhibiting topoisomerase II.^24,25 Despite their effectiveness, anthracyclines are associated with the risk of cardiomyopathy and heart failure.²⁶ The proposed mechanism of anthracycline-induced cardiotoxicity includes inhibition of topoisomerase IIβ, resulting in oxidative stress and cell death pathways, which leads to direct cardiomyocyte toxicity.^27-29

Early data demonstrated that a higher cumulative dose of anthracycline chemotherapy increases the risk of CTRCD (Figure 1).^30,31 Other common risk factors include older age; a history of decreased LVEF; CV comorbidities such as hyperlipidemia, hypertension, and smoking; and other cancer therapies associated with cardiotoxicity, such as trastuzumab and radiation.^32-34 The typical dose of anthracycline chemotherapy used in the adjuvant or neoadjuvant treatment of breast cancer is a doxorubicin equivalent of 240 mg/m², a moderate- range dose, but it can be much higher in the metastatic setting.³⁵

HER2-Targeted Therapies

Approximately 15% of breast cancers overexpress HER2 and have a more aggressive phenotype.³⁶ Current guidelines, including those of the American Society of Clinical Oncology, recommend HER2-targeted therapy with agents such as trastuzumab or pertuzumab together with chemotherapy, depending on specific tumor characteristics.³⁷ Trastuzumab and pertuzumab are monoclonal antibodies that target HER2 and block downstream intracellular signaling pathways, thereby arresting cell growth and preventing proliferation.³⁸ Trastuzumab therapy is associated with a 3% to 7% risk of CTRCD when used as monotherapy; however, that risk significantly increases when trastuzumab is administered in combination with anthracycline chemotherapy (Figure 1).^39,40 In contrast to the mechanism associated with anthracycline chemotherapy, HER2 cardiomyopathy is hypothesized to be related to disruption of HER2 protective functions in the heart and may be reversible upon discontinuation of treatment.^41-43 Newer regimens such as HER2-targeting antibody-drug conjugates for breast cancer are typically nonanthracycline based, with similar efficacy and lower rates of cardiotoxicity.⁴⁴ The 2022 ESC guidelines recommend a baseline electrocardiogram (ECG) and baseline transthoracic echocardiogram (TTE), along with follow-up TTEs every 3 months during HER2-targeted therapy.¹⁹

Endocrine Therapies

Endocrine therapies are an important class of treatment for hormone receptor–positive cancers and can be divided into selective ER modulators (SERMs; eg, tamoxifen) and aromatase inhibitors (AIs; eg, letrozole, anastrozole, exemestane). More than 80% of breast cancers are hormone receptor–positive, for which these treatments are indicated.³⁶ ER modulators are a common treatment for patients with breast cancer. They are used in the adjuvant setting for early-stage disease or as first-line therapy for advanced or metastatic breast cancer.

AIs have been associated with increased risk of dyslipidemia, metabolic syndrome, hypertension, and myocardial infarction (Figure 1).⁴⁵ The Arimidex and Tamoxifen Alone or in Combination (ATAC) trial demonstrated that patients with a history of preexisting coronary artery disease treated with anastrozole experienced more CV events and higher serum cholesterol levels than those treated with tamoxifen.⁴⁶ Additionally, tamoxifen had been historically associated with elevated venous thromboembolic risk, and it should be used with caution in patients with baselineelevated clotting risk.⁴⁷ However, a recent meta-analysis of randomized controlled trials showed no increase in CV risk with AI vs placebo, but a 19% increased CV risk with AIs vs tamoxifen.⁴⁸ Tamoxifen was associated with a 33% decreased CV risk vs placebo.⁴⁸ This suggests that the historically increased risk of AI compared with tamoxifen may be attributable to the favorable cardiometabolic profile of tamoxifen.

FIGURE 1. Cardiovascular Toxicities of Anticancer Therapies

Radiation Therapy

Adjuvant radiation therapy improves breast cancer survival for many patients. However, radiation increases the risk of pericardial disease, heart failure, ischemic disease, arrhythmias, and valvular disease (Figure 1).^49,50 The CV risk from radiation therapy is both dose and location dependent. Radiation-associated coronary artery disease is more than twice as likely to occur with radiation to the left breast than with radiation to the right breast, and the risk increases with mean radiation dose.^51-53 Although radiation may induce direct damage and fibrotic changes to the myocardium, chronic inflammatory changes and oxidative stress may also contribute to observed cardiac toxicities.⁵⁴ Newer radiation techniques, including improved contouring of the dose distribution and respiratory management of delivery, have allowed for decreased incidental radiation exposure to the heart.⁵⁵ The ongoing RADCOMP trial (NCT02603341) is investigating whether proton therapy, instead of photon therapy, may further reduce the risk of adverse CV effects by reducing the radiation dose to the heart.⁵⁶

CDK4/6 Inhibitors

CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib are used in combination with endocrine therapy to manage hormone receptor–positive/HER2-negative metastatic breast cancer and improve patients’ progression-free and overall survival.⁵⁷ Although CDK4/6 inhibitors have a spectrum of noncardiac secondary adverse effects, the most common cardiac-specific effect of this class of medication is QT-segment prolongation (Figure 1). The risk of QT prolongation is highest with ribociclib, which occurs in 3% to 4% of patients who are taking both ribociclib and letrozole.⁵⁸ 

Other Therapies

Other therapies used for the treatment of breast cancer that have been associated with CV toxicity include 5-fluorouracil (5FU), immune checkpoint inhibitors (ICIs), and PARP inhibitors. Capecitabine is an oral prodrug of 5FU that has been associated with angina, hypertension, takotsubo cardiomyopathy, and myocardial infarction, even in patients without coronary artery disease.^59,60 Pembrolizumab, a monoclonal antibody ICI that interacts with the PD-1 receptor, was shown to improve rates of pathological complete response and event-free survival for patients with previously untreated stage II or III triple-negative breast cancer when added to neoadjuvant paclitaxel and carboplatin as part of the phase 3 KEYNOTE-522 trial (NCT03036488).⁶¹ ICI-related toxicity includes aberrant immune activity against many organs, including the heart. Although relatively rare, severe CV manifestations of ICI-related adverse effects include fulminant myocarditis, cardiogenic shock, and malignant tachyarrhythmias or bradyarrhythmias.^62,63

Olaparib is a PARP inhibitor with a highly selective mechanism of action against tumor cells with dysfunctional homologous recombination pathways. It has been commonly associated with hypertension and more rarely with thromboembolism, including pulmonary embolism.⁶⁴

Risk Stratification

Optimization of patient-specific CV risk factors is a key strategy to mitigate the risk of treatment-related cardiotoxicity (Table 1). In recent years, risk assessment tools have emerged to guide this individualized risk stratification and inform the appropriate therapy selection.

TABLE 1. Association of Patient-Specific CV Risk Stratification for Breast Cancer Treatments

Several non–cancer-specific CV risk assessment calculators have been endorsed by the 2022 ESC cardio-oncology guidelines to evaluate baseline risk in patients with cancer and include theSMART (Second manifestations of arterial disease) risk score, ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation) risk score, SCORE2 (Systematic Coronary Risk Estimation 2), SCORE2-OP (Systematic Coronary Risk Estimation 2 – Older Persons), and ASCVD (Atherosclerotic Cardiovascular Disease) risk score.¹⁹ Special consideration should be given to patients receiving therapies associated with significant cardiotoxicity, such as anthracyclines, particularly regimens with planned cumulative doxorubicin or equivalent dose exceeding 250 mg/m², given the elevated risk they pose for CV toxicity.⁶⁵

The International Cardio-Oncology Society (ICOS), in conjunction with the Cardio-Oncology Study Group of the Heart Failure Association (HFA), developed baseline CV risk stratification proformas for different cancer treatments, which take into consideration a patient’s preexisting CVD, risk factors, previous cardiotoxic cancer treatment exposure, and biomarkers (ie, troponin and natriuretic peptide).⁶⁶ These CV risk stratification proformas can help personalize approaches to mitigate risk by categorizing patients as low, medium, high, or very high risk. The HFA-ICOS risk assessment tools are based on expert opinion, and data on the use of these strategies in real-world settings are limited.^66,67

More recently, a breast cancer–specific nomogram was developed by Yu et al.⁶⁸ The nomogram uses 9 clinical variables to estimate the 1-year risk of CTRCD for patients with breast cancer on HER2-targeted therapy. This readily available tool can help clinicians navigate decision-making and opt for early referral to cardiology or cardio-oncology services to optimize and manage risk factors, as indicated.

Additional consideration should be given to emerging, nontraditional CV risk factors, many of which are specific to women, that may lead to treatment-related cardiotoxicity. These risk factors include preterm delivery, preeclampsia, autoimmune disease, depression, and gestational diabetes. Further research may help better delineate the impact of these and other nontraditional risk factors on the development of treatment-related cardiotoxicity.^69,70 

Risk stratification should occur at the time of cancer diagnosis and prior to the initiation of cancer treatment, taking into consideration individual CV risk factors, cancer type, and cancer treatment. A thorough history and clinical examination, along with complementary testing such as ECG, measurement of cardiac serum biomarkers, CV imaging such as TTE, and the use of risk stratification tools, are the basis of the baseline CV risk evaluation recommended for all patients with cancer.

Communication of the baseline evaluation with the patient and other treatment team members is crucial. Patients categorized as low risk for CV toxicity should receive scheduled anticancer therapy promptly, whereas those with moderate risk can be referred to a cardiologist for the optimization and management of preexisting CV risk factors. It is recommended that patients at high or very high risk for CV toxicity be referred to the cardiology department for consideration of cardioprotective strategies, as well as discussion of the risks and benefits of cardiotoxic anticancer treatments.¹⁹ Regardless of CV risk stratification, all patients will benefit from a focus on CV primary prevention by undergoing routine screening of blood pressure, lipids, hemoglobin A1c, and focused lifestyle modifications such as healthy diet, exercise, and smoking cessation.⁷¹

Monitoring

Careful monitoring of cardiac function is essential in patients with breast cancer receiving potentially cardiotoxic therapies, such as anthracyclines and HER2-targeted agents (Figure 2).¹⁹ Early detection of cardiotoxicity allows for timely intervention, potentially mitigating cardiac damage and improving patient outcomes. Before, during, and after cancer treatment, a team-based approach with close communication and collaboration among clinical team members, especially between the oncologist and cardiologist, is crucial for achieving the best clinical outcomes. The ESC 2022 guidelines provide comprehensive recommendations to guide clinical practice in this area.¹⁹

FIGURE 2. Surveillance Techniques Recommended for Patients With Breast Cancer¹⁹

Baseline Assessment

The ESC 2022 guidelines recommend obtaining a baseline ECG and TTE in all patients scheduled to receive anthracycline or HER2-targeted therapy. The TTE assesses LVEF, wall motion, valvular abnormalities, and diastolic function, providing a comprehensive overview of cardiac performance. The ECG detects arrhythmias and conduction abnormalities at baseline that may be exacerbated by cardiotoxic treatments.

For patients at high or very high risk for treatment-related cardiotoxicity—such as those with preexisting CVD, multiple CV risk factors, or prior exposure to cardiotoxic agents—baseline measurement of cardiac biomarkers may help estimate CV risk during cancer therapy, specifically natriuretic peptides and cardiac troponins¹⁹ Elevated levels of these biomarkers at baseline may indicate subclinical cardiac dysfunction and necessitate closer monitoring.

Monitoring During Treatment

During treatment, monitoring of a patient’s ECG, TTE, and cardiac biomarkers may be appropriate, depending on the patient’s treatment regimen and baseline risk assessment.

Periodic ECG assessments may be considered for patients with cardiac symptoms or those receiving QT-prolonging medications such as CDK4/6 inhibitors. For example, monitoring is recommended when starting a patient on ribociclib with a baseline ECG and a follow-up ECG at 14 and 28 days or with dose adjustments, and avoidance of other QT-prolonging medications such as tamoxifen is also recommended, as the combination of ribociclib and tamoxifen may increase QT prolongation.^19,72,73 

TTE is the cornerstone of cardiac function monitoring because of its noninvasive nature and comprehensive assessment capabilities. TTE should be performed at routine intervals in patients receiving anthracycline or HER2-targeted therapy.¹⁹ A reduced frequency may be appropriate in patients receiving nonanthracycline HER2-targeted treatment regimens or long-term maintenance HER2-targeted therapy. The goal of surveillance TTE is to detect early signs of CTRCD, guide initiation of cardioprotective strategies, and reduce risk for progression to clinical heart failure. Global longitudinal strain (GLS) is a simple parameter that measures the longitudinal shortening of the left ventricle during systole as a percentage of its resting dimension.⁷⁴ A relative reduction greater than 12% or 15% from baseline GLS is considered significant and may help detect subclinical left ventricular dysfunction.^18,75-77 Investigators in the SUCCOUR trial (ACTRN12614000341628) randomly assigned patients receiving anthracycline chemotherapy to a GLS- vs LVEF-guided strategy of cardioprotection; results showed no difference in change in LVEF at 3 years of follow-up.⁷⁸ Data from the SUCCOUR-MRI trial subsequently demonstrated that initiation of cardioprotective medications in patients undergoing treatment with anthracyclines with isolated GLS reduction of 12% or more was associated with a modest preservation of LVEF at 1 year compared with usual care; however, the final LVEF in both groups remained in the normal range.⁷⁹

Other noninvasive imaging modalities are also important tools for monitoring cardiotoxicity in patients with breast cancer. Cardiacmagnetic resonance imaging (CMR) can detect myocardial fibrosis through late gadolinium enhancement and may be helpful in the diagnosis of ICI-myocarditis according to the Lake Louise Criteria.⁸⁰ CMR also provides the gold standard for quantification of cardiac volumes and function because of its high spatial resolution and reproducibility; this can be of value when TTE images are suboptimal for the measurement of LVEF.⁸¹ However, CMR is not routinely used for this purpose, given its high cost, limited availability, and the relative ease with which TTE may be performed. Multigated acquisition scans are an accurate and reproducible alternative modality for measuring LVEF, but their use has declined due to efforts to reduce unnecessary radiation exposure and technological advances in TTE and CMR.

Studies that seek to understand the role of monitoring laboratory cardiac biomarkers have yielded mixed results. Cardiac troponins are highly sensitive, specific markers of myocardial injury that may identify patients at risk of developing cardiac dysfunction with cardiotoxic chemotherapy.⁸² The 2022 ESC guidelines recommend measuring troponin prior to the initiation of anthracycline chemotherapy, HER2-targeted therapy, and ICIs, especially for patients at high and very high CVD risk.¹⁹ A prespecified threshold for troponin has not been defined for patients undergoing cardiotoxic cancer treatment, and data on the efficacy of troponin-guided cardioprotection remain limited⁸³; therefore, levels should be interpreted within the clinical context of the patient. A recent meta-analysis showed that although brain natriuretic peptide (BNP)/N-terminal pro-BNP increased post treatment with anthracycline or HER2-targeted therapy, elevation did not predict LVEF.⁸⁴ Additional prospective data are needed to better elucidate the role of biomarkers to improve CV outcomes in patients undergoing cardiotoxic cancer treatment.

The frequency of monitoring should be based on the patient’s risk profile, specific therapies being administered, and presence of any cardiac symptoms. A suggested framework for monitoring during treatment is summarized in Figure 2.¹⁹

Monitoring After Treatment

Many patients with breast cancer may develop late-onset cardiac dysfunction years after treatment has concluded, especially those who received anthracycline or HER2-targeted therapy.^2,7,39,85 The risk is significantly higher than in the general population, and it may be highest in those who were diagnosed with and treated for cancer at a young age.^86,87 A repeat TTE and cardiac biomarkers within 12 months can be considered for patients treated with anthracycline and/or HER2-targeted therapy.¹⁹ For patients with a normal resting TTE with persistent exercise intolerance 12 months after cancer treatment, an exercise stress TTE or cardiopulmonary exercise test should be considered, and cardiac rehabilitation should be targeted toward patients who may benefit from it. The need for and optimal timing of long-term surveillance remains uncertain, but TTE may be considered for asymptomatic survivors of cancer beyond 1 year after completion of treatment, depending on individual risk factors.¹⁹ All patients should be educated on healthy lifestyle choices and recognition of early signs of CTRCD, and annual assessment of CV risk factors is recommended.

Left-sided breast radiation therapy is associated with risk for ischemic heart disease, especially for patients treated prior to the availability of techniques that reduce cardiac radiation exposure (eg,precise contouring, respiratory management of radiation delivery).⁸⁸ The 2022 ESC guidelines recommend noninvasive screening for coronary artery disease every 5 to 10 years for survivors of cancer who received more than 15 Gy of a mean heart dose of radiation.

Prevention and Treatment

Neurohormonal Agents

Studies investigating the prophylactic use of β-blockers, angiotensin-
converting enzyme inhibitors, and angiotensin receptor blockers have demonstrated mixed results (Table 2)^{19,84,93-95,99,100,114,118-127}. The PRADA trial (NCT02771938) was a randomized, placebo-controlled, double-blinded clinical trial that studied the prophylactic effect of metoprolol and/or candesartan in the prevention of cardiac dysfunction in patients receiving anthracycline chemotherapy with or without trastuzumab or radiation.⁸⁹ In this study, candesartan but not metoprolol appeared to confer a modest protection against the development of LVEF reduction. In contrast, the phase 3 PROACT trial (NCT03265574) showed that prophylactic enalapril did not prevent CTRCD as measured by troponin T levels in patients with breast cancer and lymphoma treated with anthracycline-based chemotherapy.⁹⁰ The phase 3 CECCY trial (NCT01724450) randomly assigned 200 patients with HER2-negative breast cancer to receive carvedilol or placebo while undergoing anthracycline chemotherapy. Although carvedilol had no significant impact on the incidence of early-onset LVEF reduction, it did reduce troponin levels and diastolic dysfunction. One randomized, placebo-controlled study of patients with HER2-positive breast cancer receiving trastuzumab and anthracyclines found that both carvedilol and lisinopril prevented LVEF reduction.⁹¹

TABLE 2. Studies of Cardioprotective Strategies for Patients With Breast Cancer Undergoing Cardiotoxic Therapy

Data from a recent single-center, randomized controlled trial demonstrated favorable effects of sacubitril/valsartan on the reduction of left ventricular GLS at 6 months in patients receiving anthracycline-based chemotherapy.⁹² These data suggest that neurohumoral interventions in the primary prevention for patients receiving anthracyclines might ameliorate subclinical left ventricular dysfunction; however, validation of these findings in larger studies of patients with other cancer treatment exposures or higher CV risk profiles is needed.

Statins

There is conflicting evidence on the role of statins in reducing the risk of cardiotoxicity during anthracycline chemotherapy in patients with breast cancer. One large double-blinded, placebo-controlled study randomly assigned patients with both breast cancer and lymphoma who had received doxorubicin (median cumulative anthracycline dose, 240 mg/m²) to either atorvastatin 40 mg or placebo over 24 months, with no difference in change in LVEF, incidence of cardiomyopathy, LV strain, LV mass, or biomarkers between the groups.⁹³ Another double-blind, placebo-controlled trial similarly randomly assigned patients with breast cancer, lymphoma, leukemia, sarcoma, or thymoma treated with anthracyclines to atorvastatin 40 mg or placebo and revealed no difference in postanthracycline LVEF or other secondary end points, including LV volumes, myocardial edema and/or fibrosis on CMR, or peak troponin and BNP level.⁹⁴ In contrast, the phase 2 STOP-CA trial (NCT02943590) results showed that atorvastatin reduced the incidence of cardiac dysfunction in patients with lymphoma treated with a median cumulative anthracycline dose of 300 mg/m².⁹⁵

Dexrazoxane

Dexrazoxane is the only FDA-approved medication for the prevention of anthracycline-induced cardiotoxicity. It was approved in 1995 for women with metastatic breast cancer who receive anthracyclines beyond a doxorubicin-equivalent dose of 300 mg/m², and it has been shown to be cardioprotective for many patients undergoing anthracycline treatment.^96-101 Potential mechanisms by which dexrazoxane prevents anthracycline-induced cardiotoxicity include iron chelation and inhibition of topoisomerase IIβ activity within cardiomyocytes.^102-104 Despite concerns that dexrazoxane may increase the risk for cancer progression or secondary tumors, data from a meta-analyses of studies involving dexrazoxane have failed to show any negative long-term cancer effects.^105-106 Larger prospective trials are needed to better evaluate the efficacy and safety of up-front dexrazoxane to reduce the risk of anthracycline cardiomyopathy.

Adjustment of Anthracycline Administration

Multiple studies dating to the 1980s have shown a significant reduction in CTRCD with continuous, slow infusion of anthracycline chemotherapy compared with rapid infusion.^107-110 Liposomal anthracycline formulations have also been shown to significantly reduce cardiotoxicity risk.¹¹¹ 2022 ESC guidelines note that liposomal anthracyclines are approved for patients with high and very high CTRCD risk or who have already received significant anthracycline doses.¹⁹

Exercise

The role of exercise in the prevention of cardiac dysfunction in patients with cancer remains unclear.¹¹² Exercise training programs may improve peak oxygen consumption in patients undergoing chemotherapy for breast cancer.¹¹³ In a clinical trial of women with stage I to III breast cancer, patients were randomly assigned to either 3 to 4 days per week of aerobic and resistance exercise training or usual care prior to beginning anthracycline-based chemotherapy. They continued this program for 1 year. Functional disability was attenuated in the exercise group at 4 months, but not at 12 months; however, exercise provided benefits in cardiac reserve and peak oxygen consumption, and postchemotherapy troponin levelsincreased less in the exercise group than in the standard-of-care group.¹¹⁴

A randomized parallel 3-group trial demonstrated that for postmenopausal women who had previously been treated for early-stage breast cancer, short-term exercise was associated with modest improvements in cardiorespiratory fitness as measured by peak oxygen consumption.¹¹⁵ Future research may help to better elucidate the role and type of exercise in the prevention of CTRCD.

Future Directions

Additional prospective data are needed to better understand the role of currently available CV pharmacotherapy in the prevention and management of cardiotoxicity related to breast cancer treatment. Studies have been generally limited by small numbers of enrollees and mixed results due to heterogeneous patient populations. Although routine use of genetic testing is not recommended for the risk assessment of CTRCD, additional research is needed to understand whether variants in cardiomyopathy-associated genes, such as mutations of clonal hematopoiesis of indeterminate potential and titin-truncating variants, may predispose patients to treatment-related cardiomyopathy, especially among those receiving anthracycline-based chemotherapies.^116,117 A more personalized approach to risk stratification could include the validation of the ICOS-HFA CV pro formas, more sensitive and specific imaging surveillance techniques, and genetic testing.

Conclusion

In summary, cardiotoxicity is a major adverse effect of contemporary breast cancer treatments, and CVD is a major competing cause of morbidity and mortality among survivors of breast cancer. Anthracyclines, HER2-targeted therapy, radiation therapy, hormonal treatment, and other forms of treatment have significant potential cardiotoxic effects. Understanding a patient’s individual risk profile can help identify those at highest risk and those who would benefit from consultation with a cardio-oncology specialist. Additional research is needed to elucidate the role of CV therapies in the prevention of cardiotoxicity.

Corresponding Author

Joseph S. Wallins, MD, MPH

T: 617-595-3256

F: 646-962-0495

Email: edd9050@nyp.org

Funding

Research at Memorial Sloan Kettering Cancer Center (MSK) is supported in part by a National Institutes of Health (NIH)/National Cancer Institute (NCI) Cancer Center support grant (P30 CA008748). A.F.Y. is supported in part by an NIH/NCI grant (R37CA273923).

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