Cardio-Oncology: Breast Cancer Treatment and Your Heart

Finding out that you have breast cancer can be overwhelming. As a person newly diagnosed with the condition, you may have several questions. A common concern relates to cancer treatments and their side effects: How will they impact your life over the following days, months and years?

Breast cancer treatment depends on the type of breast cancer you have as well as the stage, or progression, of the disease. Often, breast cancer treatment will involve a combination of different therapies:

• Surgery
• Radiation therapy
• Chemotherapy
• Hormonal therapy
• Targeted therapies

About 20% of patients diagnosed with breast cancer will have a specific type of tumor called HER2-positive breast cancer (breast tumors with high levels of a protein called human epidermal growth factor 2, or HER2). Treatment of HER2-positive breast cancer involves medications that target HER2, also called HER2-targeted therapies.

Ask your provider about the HER2 status of your tumor and whether HER2-targeted therapy is an option for you. Use this condition center to learn more about targeted therapy for breast cancer and how it can affect your heart.

HER2-Targeted Therapies

Overview

What is HER2-positive breast cancer? HER2-positive breast cancers are breast tumors with high levels of a protein called human epidermal growth factor 2 (HER2). HER2 is a protein that functions as a receptor outside of breast cancer cells. When HER2 receives an activating signal from the body, it promotes cell growth and multiplication. As such, HER2-positive breast cancers may grow quickly and have a high chance of spreading to other parts of the body (metastasis).

The good news is that the outlook for patients with HER2-positive breast cancers has improved greatly over the past decade with new therapies that target HER2.

In many ways, treatment of HER2-positive breast cancer is similar to treatment of HER2-negative breast cancer. It often involves a combination of surgery, chemotherapy and radiation therapy, but with the addition of HER2-targeted therapy.

Most HER2-targeted therapies block HER2 receptors from receiving signals that tell the cells to grow and multiply. These targeted therapies can be given before, during or after chemotherapy. They generally don’t cause the side effects common with chemotherapy such as nausea, vomiting or hair loss. However, HER2-targeted therapies have unique side effects. A possible side effect involves the heart and is called cardiotoxicity. If you are prescribed a HER2-targeted therapy, ask your provider about its potential side effects.

What is Cardiotoxicity?

Cardiotoxicity is the term used for heart damage caused by medications. The form cardiotoxicity takes can range from temporary changes in heart function that you might not notice to more serious conditions such as heart failure. It also can be life threatening.

Most cases of cardiotoxicity from HER2-targeted therapies are without symptoms and last for a short time. However, more serious reactions can occur.

Why do HER2-Targeted Therapies Cause Cardiotoxicity?

HER2-targeted therapies block HER2 receptors from receiving signals that tell the cells to grow and multiply. Blocking HER2 on cancer cells is good because it stops the message telling tumor cells to grow and spread. However, HER2 receptors are also on healthy cells, such as heart muscle cells. In the heart, HER2 activation is important for cell survival, particularly during stressful situations, and thus blocking HER2 may cause heart damage.

What Increases Your Risk of Harm to Your Heart

The rate of cardiotoxicity from HER2-targeted therapy varies according to the agent used, other treatments given and some characteristics unique to the patient. The most important factors that make patients receiving HER2-targeted therapy more likely to experience cardiotoxicity are the following:

• Cancer treatments given at the same time that also can affect the heart, including anthracyclines or radiation.
• Older age. The risk of cardiotoxicity rises with increasing age, especially if you are 60 or older.
• Existing heart disease or risk factors for heart disease.

If you already have some form of heart disease, you are more prone to have heart damage from cardiotoxic medications. For example if you have:

• Heart failure
• Abnormal heart function (low ejection fraction)
• Coronary heart disease
• Atrial fibrillation
• High blood pressure
• High cholesterol
• Diabetes
• Abnormal kidney function
• Obesity(BMI of 30 or greater)

You are at higher risk for cardiotoxicity likely because your heart’s ability to tolerate stress is lower. Occasionally, providers may choose not to give HER2-targeted therapies if the risk of heart damage is too great. This might occur for patients with an abnormal heart function or who have heart failure. In these circumstances and for most patients with heart disease, talking to a cardio-oncologist or cardiologist might be recommended.

Patients and providers are encouraged to engage in a discussion about risks and benefits and decide together which is the right treatment plan for you, the patient. In some cases, the HER2-targeted therapies may be given with careful monitoring if the benefits are seen to outweigh the risks. They may also be given with heart medications, which may act to protect the heart from damage.

Risks Linked With Specific Treatments

This section covers the different types of HER2-targeted therapies and concerns associated with them.

Trastuzumab (Herceptin®): The oldest and most widely studied HER2-targeted therapy is trastuzumab. Trastuzumab was first approved for use in patients with metastatic HER2-positive breast cancer in 1998 and is used to treat various stages of HER2-positive breast cancer. Trastuzumab may reduce the risk of death or slow the progress of breast cancer by up to 50%. Cardiotoxicity from trastuzumab is uncommon when it is used in young and healthy patients, without other heart risk factors (for example, high blood pressure, high cholesterol or diabetes), and who are not receiving other cardiotoxic drugs. However, cardiotoxicity from trastuzumab may occur at much higher rates (20% to 40% of patients) when used in combination with cardiotoxic chemotherapy (especially those containing agents called anthracyclines), in patients who are older, have several heart risk factors or already have heart disease.

Pertuzumab (Perjeta®): The combination of pertuzumab and trastuzumab with chemotherapy is most often used in patients with metastatic HER2-positive disease, or before surgery for patients with earlier stages of HER2-positive breast cancer. The addition of pertuzumab to trastuzumab does not appear to increase the risk of cardiotoxicity beyond that linked with trastuzumab alone.

Lapatinib (Tykerb®): Lapatinib is an oral HER2-targeted therapy sometimes used in patients with metastatic HER2-positive breast cancer that continues to grow and spread despite treatment with therapies including trastuzumab. In this setting, adding lapatinib may prevent the cancer from spreading. The impact of lapatinib on the heart has been studied less than trastuzumab; however, the available data suggest lapatinib has a low risk of cardiotoxicity.

Ado-trastuzumab emtansine (Kadcyla®): Ado-trastuzumab emtansine is a combination of trastuzumab and a chemotherapy called emtansine. It is approved for use in patients with metastatic breast cancer who have had tumor growth despite treatment with therapies including trastuzumab. As is the case for lapatinib, ado-trastuzumab emtansine appears to cause less cardiotoxicity than trastuzumab. However, its effects on the heart have been less studied than trastuzumab.

Neratinib (Nerlynx®): Neratinib is a recently approved oral HER2-targeted treatment that can be used in patients with early breast cancer who have completed one year of trastuzumab. It helps lower the chance the cancer will return. Neratinib does not appear to be cardiotoxic.

Other Cardiotoxic Medications

The risk of cardiotoxicity from HER2-targeted therapies is greatest when it is used with anthracyclines. Two major drugs are in this class: doxorubicin and epirubicin. Anthracyclines are effective in treating breast cancer. Unfortunately, they also can cause cardiotoxicity. The risk is greater when high doses are given (>250 mg/m2 of doxorubicin or >600 mg/m2 of epirubicin). The use of trastuzumab at the same time or after anthracyclines increases the risk of poor heart function or development of heart failure.

Today, anthracyclines usually are given in low doses or aren’t given at the same time as HER2-targeted therapy to reduce the risk of heart damage. Radiotherapy may also be linked with heart damage, although more research is needed to find out how much risk is added when used with HER2-targeted therapy.

Signs and Symptoms

In most cases of cardiotoxicity from HER2-targeted therapies, a decline in heart function will be found during routine monitoring with the patient having no symptoms or vague symptoms, such as fatigue. In some cases, however, the decrease in heart function will be accompanied by symptoms of heart failure.

In heart failure, the heart isn’t pumping as well as it should, which leads to fluid buildup in the lungs and eventually in the legs. Patients may experience:

• Shortness of breath, especially with exertion.
• Swelling of the ankles, legs and sometimes abdomen.
• Chest pressure or shortness of breath when lying flat.
• Waking up with severe shortness of breath.
• Rapid changes in weight.
• Heart palpitations.
• Extreme fatigue.
• Decreased appetite.

If you develop any of these symptoms, talk to your doctor at once.

Exams and Tests

Most cancer centers perform routine monitoring of heart function during treatment with HER2-targeted therapies. The method used for monitoring and the frequency of tests depends on each case.

Imaging of the heart will take place before therapy begins to ensure a normal heart function and will be repeated every three months after the HER2-targeted agent is started. Over time, you may have the test done less often, and no monitoring is required after therapy is completed. That is because the risk of cardiotoxicity is greatest during HER2-targeted therapies and lower once these cancer treatments are stopped. More testing may be done if you develop symptoms that suggest heart failure.

Here are the tests most commonly used to monitor heart function and cardiotoxicity:

• Echocardiogram:An ultrasound of the heart is used to calculate ejection fraction, a measure of how well your heart is pumping. Also, echocardiograms provide information on heart size, the relaxation of the heart, and the function of heart valves. The test is widely available and does not involve any radiation exposure.
• Multigated acquisition (MUGA) scan:This test involves your receiving a radioactive solution through a vein and then having an X-ray. A MUGA is commonly used to assess ejection fraction.
• Cardiac Magnetic Resonance Imaging (MRI):Cardiac MRI provides detailed information on heart size and function. It is usually reserved for cases when the images from the echocardiogram are not good enough or more information is needed.
• Blood tests:Some providers also may monitor markers present in your blood to measure heart injury. This is not done routinely and is more likely to occur in patients with increased risk of cardiotoxicity from HER2-targeted therapies and may help to detect heart damage early. Commonly measured blood markers are cardiac troponin (TnI, TnT) or natriuretic peptides (BNP, NT-proBNP).

Prevention

• You can take several steps to help lower your risk of developing heart damage during treatment with cardiotoxic medications.

· Be Heart-Healthy

• Anything you can do to keep your heart as healthy as possible will reduce your risk of cardiotoxicity. Studies suggest that people who are overweight or obeseare at increased risk of developing heart damage during cancer treatment. Similarly, data show that most patients decrease their levels of physical activity and gain weight after being diagnosed with cancer, both of which are associated with higher risk of heart disease. To find out whether you are above your ideal weight, calculate your body mass index (BMI). A BMI between 25 and 29.9 indicates you are overweight, and BMI of 30 or greater means that you have obesity.If you are overweight or obese, try to lose weight. Try to eat a heart-healthy diet that is low in salt and saturated fats and rich in whole grains, fruits and vegetables. The DASH diet is a good one to try.

  Similarly, it is important to stay active. Current guidelines recommend engaging in no less than 75 minutes per week of intense exercise or 150 minutes per week of moderate or intense exercise. But any physical activity is better than nothing.

  Smoking increases the risk of heart attacks and heart damage. If you smoke, work with your provider on strategies to quit. If you don’t smoke, don’t start!

Know Your Numbers!

• Most studies suggest that having an elevated blood pressure, diabetesor high cholesterol increases the risk of cardiotoxicity. These also are risk factors for heart disease and put stress on your heart. The more stress on your heart, the higher your chance of developing heart damage. Follow up with either your primary care provider or cardiologist to ensure these conditions are well controlled.

What if You Have Heart Disease

• If you have a history of poor heart function (low ejection fraction), heart failure, coronary artery disease(if you had a heart attack or received a stent), or an abnormal heart rhythm, you should see a cardiologist or cardio-oncologist to manage these conditions.A few studies have suggested certain medications may help prevent cardiotoxicity from HER2-targeted therapies. These include angiotensin converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs) and beta blockers. Most providers will not routinely start these medications for this purpose if there is no history of heart disease or heart risk factors. More research is needed and currently in progress.

  However, if you already have heart disease, you may benefit from being on one or more of these medicines when you receive HER2-targeted therapy.

Living With Cardiotoxicity

• What should you expect if you develop cardiotoxicity? Here is the good news: Cardiotoxicity from HER2-targeted therapies tends to be temporary and reversible. For most patients, their heart function will return to normal.
• If you have a significant decline in your heart function detected by routine tests or because of symptoms, your provider may recommend you stop HER2-targeted therapies for a short time. Typically, therapy is put on hold for about four weeks and then tests are repeated. In most cases, the heart function returns to normal, and HER2-targeted therapy can start again with close monitoring.If the heart function does not return to normal, your provider may recommend you stop the medication completely. However, this type of decision is made on an individual basis and in close consultation with your team of health providers, including your oncologist and cardiologist or cardio-oncologist, paired with a careful discussion of what you prefer and value.
• Also, heart medicines (noted in the Prevention section) can help the heart recover, and these may also be started.