Breast Cancer and Heart Disease: What is the Connection?

This article was written in collaboration with Dr. Ramey Marshell, Arkansas Cardiology, Baptist Health Heart Institute.

Advances in screening and treatment have improved survival for patients with breast cancer. There are currently over 3 million breast cancer survivors and they are projected to be over 5 million by 2030. On average, women with breast cancer have a 90% chance to survive at 5 years. This takes a team approach that includes a primary care physician, an oncologist, a radiation oncologist, a pharmaco-oncologist, and in many instances, a cardio-oncologist. The goal of the team in the Cardio-Oncology program is to ensure patients can receive the most appropriate cancer therapy while minimizing their risk of heart complications and treating any heart conditions that may ensue from the cancer treatment. The cardio-oncologist evaluates and treats heart conditions before, during, and after cancer treatment as needed.

Which Breast Cancer Patients Are at Risk of Cardiac Problems?

In the general population, cardiovascular disease (CVD) is the leading cause of mortality in women and men. However, patients with breast cancer have an even higher rate of CVD compared to age-matched control. This is likely due to shared risk factors for breast cancer and CVD as well as cancer-related therapies. Importantly, taking care of cardiovascular risk factors and comorbidities not only lowers cardiovascular morbidity and mortality but improves breast cancer survival.

Determinants of risk for cardiac complications in breast cancer patients can be divided into patient-related risk factors and medication-related risks. 

Women that are older than 60 years of age, hypertension, diabetes mellitus, Obesity, High cholesterol, cigarette smoking, coronary artery or peripheral artery disease, heart failure or cardiomyopathy, atrial fibrillation, prior treatment with anthracycline or chest radiation are related to increased risk of cardiac events. 

Medication-related risk can be divided into high risk: Anthracyclines, Cyclophosphamide, Herceptin, Ifosfamide, and Clofarabine. 

Intermediate-risk medications include Pertuzumab, Docetaxel, Sunitinib, and Sorafenib. 

Finally, low-risk medications include Bevacizumab, Dasatinib, Imatinib, Lapatinib, Rituximab. 

Radiation treatment to the left breast can also increase the risk for cardiotoxicity.

What Are the Most Common Cardiovascular Problems Associated With Breast Cancer Treatment?

One of the most important cardiac complications is the development of cardiomyopathy and systolic heart failure in patients treated with chemotherapy such as anthracycline (Doxorubicin or Epirubicin). Anthracycline is known to increase oxidative stress, damage to the mitochondria, apoptosis, and inhibition of the topoisomerase. This can manifest as an asymptomatic reduction of the heart function (Ejection Fraction) and can progress to systolic heart failure. This risk is increased exponentially with the cumulative dose of anthracycline: 6% incidence with a dose of 250 mg/m2, 14% with 300 mg/m2, and 33% with 400 mg/m2. The risk is also increased when given in combination with cyclophosphamide. 

Patients with HER2-positive breast cancer are treated also with HER2-targeted therapies such as monoclonal antibodies trastuzumab (Herceptin) and pertuzumab. HER2 receptors are also present in the heart muscle. These antibodies can disrupt cardiac repair and result in a transient and reversible reduction of heart function (EF) and systolic heart failure. This is particularly important when Herceptin treatment is given after anthracycline chemotherapy. Rates of heart failure have been reported as high as 30-40% in women greater than 65 yo after the treatment combination. 

Immune checkpoint Inhibitors such as Pembrolizumab (Keytruda) have been used more and more in cancer treatment and allow our “T” cells to kill cancer cells. On rare occasions ( approx 1%) it can cause fulminant myocarditis with severe inflammation of the heart muscle cell with an increased risk of dying (>25% risk).  It tends to occur early into treatment and can be subtle at the beginning (minor changes on the ECG, some elevation of the troponin cardiac enzyme with preserved heart function (normal EF)). 

Other targeted oral chemotherapy such as Lapatinib, a tyrosine kinase inhibitor, can also cause a reduction of heart function.

In postmenopausal women with estrogen receptor-positive breast cancer, aromatase inhibitors have been used to prevent the recurrence of cancer. Some of the side effects include elevation of blood pressure. Myocardial infarction has been reported in 1-10%. 

Finally, Radiation therapy, particularly when localized to the left breast, has been associated with damage to the inner lining of the coronary arteries, development of coronary artery disease, myocardial infarction, and heart failure. Long-term effects on the mitral and aortic valves include narrowing as well as insufficiency of the valves. Those risks increase as a function of the radiation exposure particularly at doses >30 Gy or >2 Gy/day, if the patient is younger than 50 years of age, concomitant with anthracycline or pre-existing coronary disease.

How Do We Mitigate the Risk?

One of the most important factors in preventing cardiac complications following breast cancer treatment is adopting a healthy lifestyle. Exercising at least 5 days per week with 30-45 minutes of aerobic-type activities such as brisk walking, swimming, cycling, interspersed with stretching, yoga, and strength training. Eating a healthy diet that includes green leafy vegetables, fruits and discouraging processed meat and refined sugar. Treatment of diabetes mellitus, hypertension, and hyperlipidemia as well as smoking cessation are crucial interventions to prevent coronary artery disease. 

Clinical prediction models have been developed based on the initial heart function (EF), age and medication-related risk and patient-related risk factors have been studied for the use of anthracycline and trastuzumab. Heart failure can develop in up to 16% of patients at relatively low risk and 40% for patients at high risk. 

When a patient is at higher risk, it can be helpful to limit the dose of anthracycline and/or to administer chemotherapy by continuous infusion. Anthracycline analogs or liposomal anthracycline have been used as well. Dexaroazoxane can reduce the toxicity of anthracycline as well by reducing free radical formation and damage to the heart muscle. Multiple trials have been conducted using ace inhibitors or angiotensin receptor blockers and beta-blockers such as bisoprolol and carvedilol. Meta-Analysis of 14 studies in breast cancer patients showed a lesser decline in left ventricular function. The Prevent trial studied the use of statin to reduce oxidative stress and improve survival in patients with triple-negative breast cancer patients.

Careful monitoring of the left ventricular function (EF) with echocardiogram during and after cancer treatment allows for early detection of cardiotoxicity, even if asymptomatic. Patients with decreased EF have a 5 fold increased risk of heart failure and death. This allows also for early institution of medical treatment for heart failure.

Certain techniques have been used to reduce the risk of cardiotoxicity of radiation therapy that include: CT-guided radiation treatment, deep inspiration, and breath-holding during radiation treatment and in certain centers, Proton radiation therapy.

What Is the Treatment When the Heart Starts to Fail and the Ejection Fraction (EF) is Lower?

Within days or weeks after instituting anthracycline chemotherapy, myocardial cell injury occurs and can result in myocardial deformation and subtle abnormalities of the left ventricular function detected by echo and that we call Global Longitudinal Strain (GLS). GLS measures the maximal shortening of the length of the left ventricle when the heart contracts. Reduced GLS may reflect an early sign of cardiotoxicity even before the loss of ejection fraction becomes apparent and the patient remains asymptomatic. Medical therapy that includes ace inhibitors (enalapril) and possibly a beta-blocker like carvedilol may prevent the further deterioration of LV function. 

Within a few months of anthracycline, a decrease in left ventricular function can be measured by a reduction of ejection fraction (<60% or >10% reduction compared to baseline). Despite the fact that it may be asymptomatic, it is usually treated with a combination of ace inhibitors and beta-blockers. Overt cardiotoxicity can occur years after treatment and can manifest itself as symptoms of shortness of breath, fatigue, and ankle swelling accompanied by a lower ejection fraction. The treatment consists usually of a combination of ace inhibitors, beta-blockers, and diuretics. More contemporary treatments that include Sacubitril/Valsartan or Entresto and SGLT2 antagonists are also used as a therapy for heart failure.

Trastuzumab is used after anthracycline treatment for patients with HER2-positive breast cancer. Prospective studies have shown that this combination can result in a decreased ejection fraction is up to 40% of patients and that partial recovery can be expected after stopping trastuzumab.  

This article was written in collaboration with Dr. Ramey Marshell, Arkansas Cardiology, Baptist Health Heart Institute.

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