Cardiovascular disease (CVD) is the leading cause of death globally, and breast cancer is one of the top five causes of cancer-related death worldwide.1 Women who have been diagnosed with CVD and breast cancer have an exponentially higher risk of death compared with patients without CVD.1 CVD progression can affect cancer outcomes and cancer treatments can worsen CVD through the biologic effects of cancer and treatment-related toxicities. Breast cancer and CVD are inexorably intertwined, creating substantial demand for the field of cardio-oncology. This field developed in part from the necessity to administer cancer treatments while actively mitigating cardiac injury and optimizing cardiovascular health.

Revolutionary advancements in treatment have been made for patients with human epidermal growth factor 2 (HER2) receptor-positive breast cancer through targeted therapies. Trastuzumab is a HER2-targeted therapy that has reduced breast cancer recurrence by 50% and mortality by 33%.2 However, trastuzumab exposure is associated with an increased risk of heart failure.2 Generally, trastuzumab-related cardiomyopathy is reversible, at least to a certain degree, by stopping treatment and initiating cardioprotective therapy such as beta-blockers.3

Anthracyclines are used in treatment regimens for multiple types of cancer, including lymphoma, melanoma, breast cancer, and uterine cancer.4 Breast cancer mortality has decreased significantly with the use of anthracycline-based chemotherapies.3 However, anthracyclines have been shown to cause irreversible left ventricular (LV) dysfunction through chemotherapeutic interaction with DNA, causing myocyte cell death.3 The exact mechanisms for cardiotoxicity are not well understood. Some proposed mechanisms include myocardial oxidative stress, topoisomerase binding causing cardiomyocyte apoptosis, and calcium dysregulation.4,5

The clinical manifestation of anthracycline- or anti-HER2 therapy-induced cardiotoxicity is LV dysfunction or cardiomyopathy. This myocardial damage, if severe enough, can lead to clinical heart failure, as demonstrated in the case of a patient with breast cancer who presented to urgent care (Table 1). Cancer therapy-related cardiac dysfunction has varying definitions, the commonality being a decline in LV ejection fraction (LVEF), although the specific criterion for percentage of decline varies. Generally, asymptomatic LV dysfunction is characterized by a reduction in LVEF by greater than 10% to an LVEF less than the widely accepted normal of 55%. Symptomatic dysfunction is characterized by a reduction in LVEF by greater than 5% with symptoms of heart failure.2

A 48-year-old woman presented to the urgent care center with progressive dyspnea on exertion, orthopnea, and mild lower extremity edema for the past 6 months.

   History Three years earlier, the patient was diagnosed with stage II triple-negative breast cancer and underwent left breast lumpectomy and adjuvant chemotherapy with doxorubicin (standard dose of 240 mg/m2), cyclophosphamide, and paclitaxel. She had a history of hypertension and hyperlipidemia. She denied chest pain, dizziness, palpitations, diaphoresis, or syncope. Her medications included amlodipine 5 mg daily for hypertension and rosuvastatin 10 mg daily for hyperlipidemia. She denied any previous cardiac history. She had no family history of coronary artery disease (CAD) or stroke. She had no history of tobacco or illicit drug use. She drank one to two glasses of wine several times per month. Upon further discussion, the patient stated that she missed her scheduled 6-month follow-up echocardiogram because of the COVID-19 pandemic. She denied any recent hospitalization, illness, or sick contacts.

   Physical examination The patient's vital signs were stable and within normal limits. She was in no acute distress. Her physical examination was notable for bibasilar crackles, jugular venous distension, and trace pitting edema. No murmurs, gallops, or rubs were noted on cardiac examination. No abdominal distension was noted. The remainder of the physical examination was unremarkable.

   Diagnostic testing Pertinent laboratory results included B-type natriuretic peptide (BNP) of 900 pg/mL (normal range, 0 to 100 pg/mL) and troponin levels 0.03-0.04-0.03 ng/mL measured every 8 hours (normal range, less than 0.02 ng/mL). An ECG revealed normal sinus rhythm with nonspecific ST-segment and T-wave abnormalities. A transthoracic echocardiogram (TTE) revealed an LVEF of 30% to 35% with severe global hypokinesia of the LV. Compared with a previous study from 3 years earlier, new severe LV dysfunction was noted.

   Outcome Given her cardiac risk factors of hypertension and hyperlipidemia, the patient was referred for a pharmacologic nuclear stress test that revealed an LVEF of 35% with no evidence of ischemia or infarct. The overall findings for this patient were consistent with nonischemic cardiomyopathy. No infectious source was identified. Her final diagnosis was anthracycline-related cardiomyopathy. Her volume status significantly improved with IV furosemide. She was started on guideline-directed medical therapy for heart failure with lisinopril 5 mg daily, carvedilol 6.25 mg twice a day, and furosemide 20 mg daily as needed.

The specific incidence of cardiac dysfunction shifts depending on whether trastuzumab, anthracyclines, or both were used for treatment; the specific order in which they were given if both were used; and the cumulative doses. A large, multicenter cohort study of 10,209 participants concluded that exposure to anthracyclines and trastuzumab was associated with subsequent heart failure.6 The risk of heart failure was increased when the patient was exposed to anthracycline-based chemotherapy before trastuzumab.6 Risk of cardiotoxicity due to trastuzumab was increased in the first few years and decreased as time progressed; anthracycline-associated heart failure increased with higher cumulative doses.6 The standard dose for breast cancer treatment varies by the number of cycles, with a base dose of doxorubicin 60 mg/m2 per cycle and up to 550 mg/m2 as the widely accepted maximum cumulative dose.6 The risk for toxicity is dose-dependent, with a high-dose range considered to be greater than or equal to 250 mg/m2.5,7 Consequently, a patient with breast cancer may develop cardiotoxicity after having completed half of the cumulative recommended chemotherapy dose. The combination of the two potentially cardiotoxic chemotherapies in succession posed the highest risk of adverse reactions; the incidence of cardiotoxicity in these cases was 26% to 28%.2,6

Box 1

The incidence of cardiomyopathy related to trastuzumab exposure alone varies from 7% to 21%.6 Trastuzumab-related heart failure often is reversible; however, one-third of patients who develop cardiomyopathy after treatment with trastuzumab had long-term cardiac dysfunction.8 Cardiovascular risk factors that increase the risk for developing cardiomyopathy after trastuzumab include advanced age, low LVEF, hypertension, hyperlipidemia, smoking, and diabetes.2 Anthracycline-based chemotherapies are known to cause irreversible myocardial damage, with the highest risk of heart failure within the first 2 years after exposure and decreasing thereafter.8 Strikingly, women who are exposed to trastuzumab have a fourfold increased risk of cardiomyopathy compared with those not exposed to trastuzumab.8 Patients exposed to anthracyclines plus trastuzumab have a sevenfold increased risk for cardiomyopathy.6 The 10-year combined cumulative risk of heart failure after treatment with both anthracyclines and trastuzumab is 4.8%.8

DISCUSSION

Before patients with breast cancer start potentially cardiotoxic treatment, they should be risk-stratified from a cardiac perspective and evaluated by a cardio-oncology team. When evaluating patients, cardio-oncology teams should consider treatment-related risk factors and patient-related risk factors. Treatment-related risks include the choice of treatment (anthracycline-based regimen or non-anthracycline), previous chest radiation, and previous cancer treatment-induced cardiotoxicity.2 Patient-related risk factors include demographics (such as age); lifestyle factors (including exercise, smoking, and alcohol history); and the CVD risk factors of hypertension, hyperlipidemia, diabetes, obesity, and smoking history.2,9 Advanced age, specifically, has been shown to be a predictor of LV dysfunction in patients receiving cardiotoxic chemotherapy; as age increases, so does the burden of comorbidities.9 The challenge clinicians face is how to appropriately predict where their patients fall on the risk scale before patients receive cardiotoxic chemotherapies that could compromise outcomes. CVD risk factors increase patients' likelihood of developing cancer therapy-related cardiomyopathy; therefore, perform a baseline risk assessment and modify cardiovascular risk factors before beginning treatment.

Managing CVD risk factors in patients after breast cancer treatment is vital to preventing heart disease. Guidelines from the American Cancer Society and the American Society of Clinical Oncology recommend surveillance for cancer recurrence, health promotion, and managing late and long-term effects of breast cancer treatment in survivors.10 Primary care clinicians should focus on monitoring and managing cardiovascular risk factors and providing patient education. The ABCDE steps can be used to guide heart disease prevention in patients who have survived breast cancer:

Awareness of the risks of heart disease and recognition of signs and symptoms of coronary artery disease and heart failure are critical, and patients should be educated accordingly.

BP/Cholesterol management and Cigarette cessation are important risk factors for heart disease.

Factors such as Diet and Diabetes management play a large role in reducing the incidence of heart disease. Every patient should be screened for diabetes. The Dose of chemotherapy a patient received will increase the likelihood of cardiotoxic effects.

Exercise has been shown to reduce BP, weight, and lipid levels. Lastly, screening with an Echocardiogram can be used to detect structural changes such as decline in ejection fraction.11

Monitoring strategies

Diagnostic imaging and biomarker surveillance can help identify patient risk of cardiotoxicity as early as possible. LVEF can be measured using echocardiography or cardiac MRI to identify patients with cardiotoxicity; however, change in LVEF is considered a late manifestation of cardiac damage.3 The myocardial damage from cardiotoxicity can be permanent; thus, the goal is to use techniques such as global longitudinal strain via echocardiography, a sensitive marker to predict subclinical LV dysfunction before sufficient myocardial damage occurs. Myocardial strain measures LV contractility. An expert consensus document included global longitudinal strain in the evaluation of cardiotoxicity and defined a relative drop in this parameter by 15% as a measure of subclinical LV dysfunction.12 Change in global longitudinal strain measurement can precede change in LVEF, making it a useful predictor of impending myocardial damage.3 Studies have shown that an absolute global longitudinal strain value of less than 17.2% taken 6 months after anthracycline therapy was predictive of abnormal global longitudinal strain at 1-year follow-up.3 Similarly, global longitudinal strain has been shown to be an early predictor of LV dysfunction in patients treated with trastuzumab.3 Current recommendations based on expert consensus for patients receiving anthracycline-based therapies are echo imaging with global longitudinal strain measurement at baseline, at completion, and 6 months following completion of treatment.13 Recommendations for patients receiving trastuzumab-based regimens are echo imaging with global longitudinal strain measurement at baseline and every 3 months.13

Echo imaging with strain is less expensive and does not expose the patient to added radiation compared with multigated acquisition scan.3 However, cardiac MRI is considered the gold standard for assessing LVEF because of its increased accuracy and superior intra- and interobserver reproducibility.13 Current expert consensus recommendations are to use cardiac MRI in place of echocardiography if the acoustic window is poor and the estimation of LVEF is thought to be unreliable, or in situations where discontinuation of cancer treatment is being entertained secondary to cancer therapy-related cardiac dysfunction.13

Biomarker surveillance

Unlike imaging recommendations, there are no agreed-upon guidelines for the use of circulating biomarkers and monitoring strategies for cardiotoxicity. The most attractive and possibly most reliable biomarker is troponin because of its consistent measure of cardiac myocyte integrity.13 Troponin I and troponin T have optimal sensitivity and specificity for cardiac damage and are used for diagnosis and risk stratification for acute coronary syndrome. Troponin is shown to increase following exposure to anthracyclines, with peak values after 120 days, aligning with peak LVEF decline between 100 and 150 days.13 High-sensitivity troponin T may lend itself nicely to prediction of cardiotoxicity, with incremental change from baseline value to integration value being a more accurate parameter than absolute value. Troponin I can be used for prognosis and risk stratification, because persistent incremental increase in value was associated with cardiac events, while risk remained low for patients without troponin I elevation.13 More specifically, elevated troponin I or T before trastuzumab therapy is linked to increased risk for trastuzumab-induced cardiac dysfunction in patients pretreated with anthracyclines.13

Brain-type natriuretic peptide (BNP) and its amino-terminal fragment (NT-proBNP) are cardiac biomarkers used as markers of cardiac decompensation in the diagnosis and follow-up of patients with heart failure.14 Studies remain equivocal for the use of BNP or NT-proBNP for reliable association with cardiotoxicity.13,14 The lack of a well-established elevation threshold prevents a direct connection between these biomarkers and cardiotoxicity; however, higher increases from baseline were seen in patients with trastuzumab-associated cardiotoxicity.14

Imaging combined with cardiac biomarkers could be used in tandem to detect early signs of cardiotoxicity before development of cardiomyopathy. One study revealed that a change in global longitudinal strain and troponin I at 3 months after anthracycline therapy predicted cardiotoxicity at the 6-month follow-up.3,15 Another study suggested that the combination of a 10% decrease in global longitudinal strain with elevation in troponin I was 97% specific in predicting cardiotoxicity after doxorubicin therapy.3,16

OPTIMIZING OUTCOMES

Management of cancer therapy-related cardiac dysfunction generally follows the American College of Cardiology/American Heart Association heart failure management guidelines. Ongoing randomized controlled trials have evaluated the role of exercise in patients with breast cancer and preventive cardiac medications for patients considered high-risk for cardiac complications.3,17

Though numerous primary prevention trials have investigated initiating cardiac medications during breast cancer treatment, results are mixed because of the varying endpoints and small study sizes. For example, some randomized controlled trials have shown significant benefit for patients started on prophylactic beta-blocker therapy with carvedilol or nebivolol.3 Specifically, these trials have shown that in patients with structurally normal hearts, starting a prophylactic beta-blocker during treatment with anthracyclines or trastuzumab resulted in a lower incidence of new heart failure events.3

A particularly significant randomized, controlled, double-blind trial evaluated the outcome of candesartan, an angiotensin-receptor blocker (ARB), in combination with metoprolol succinate or placebo in patients receiving adjuvant chemotherapy (5-FU, epirubicin, and cyclophosphamide).18 The primary endpoint was change in LVEF as evaluated by cardiac MRI.18 A clinically significant reduction in LV dysfunction was found in the group receiving candesartan; no effect overall was found in the patients receiving metoprolol succinate.18

In contrast, observational studies have suggested that the long-term use of beta-blockers in women with operable breast cancer had reduced metastasis and tumor recurrence at 10-year follow-up.3 Beta-blockers have been linked to recovery of LV function in patients who developed trastuzumab-related cardiac dysfunction.

Angiotensin-converting enzyme (ACE) inhibitors and spironolactone also have been evaluated on a small scale in patients with breast cancer and treatment-related LV dysfunction. The combined use of an ACE inhibitor and beta-blocker was associated with LVEF recovery in 3 to 12 months in patients with trastuzumab-induced cardiomyopathy.3,19 This suggests that ACE inhibitors and beta-blockers are beneficial in cardiac recovery.3 Spironolactone used during anthracycline-based treatments was shown to attenuate decline in LVEF as well as stabilize diastolic function.3 In summation, these studies support the use of traditional guideline-directed medical therapy for managing cancer therapy-related cardiac dysfunction.

LIMITATIONS

Larger clinical trials are needed for further evaluation of predictive risk assessment tools, initiation of protective cardiac medications, and determining the role of exercise for patients undergoing breast cancer treatment with potentially cardiotoxic regimens. The Heart Failure Association/International Cardio-Oncology Society risk score may be valuable to cardio-oncologists if studied further.9 Promising data support the benefit of using beta-blockers, ACE inhibitors, ARBs, and spironolactone prophylactically in high-risk patients with breast cancer, but larger trials could expand on these data further.

CONCLUSION

Patients with breast cancer should be monitored diligently by a multidisciplinary team from diagnosis throughout treatment and survivorship. Patients with CVD risk factors should not be limited in their treatment options because of their increased risk of cardiomyopathy; instead, their risks should be optimized before treatment and supported throughout treatment with serial imaging, biomarker surveillance, and prophylactic cardiac medications as appropriate. Specific guidelines for serial cardiac imaging are not well-defined, and research is ongoing to define the best monitoring guidelines for patient-specific cardiovascular risk factors and regimen-specific cardiotoxicity risks. The intersection of cardiovascular health and oncology is evolving, and to maximize curative treatment while minimizing cardiotoxic events, cardio-oncology teams must be involved to optimize patient care.

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