In the JournalsPerspective

CVD risk may increase with breast cancer treatment

Laxmi S. Mehta

Current breast cancer treatment negatively affects CV health and may lead to CVD, including HF and left ventricular dysfunction, according to a scientific statement from the American Heart Association published in Circulation.

In the United States, breast cancer affects an estimated 3.32 million women, and an estimated 47.8 million women are affected by CVD, according to the scientific statement.

“The important takeaways are to understand that there are some risk factors that are similar between heart disease and breast cancer,” Laxmi S. Mehta, MD, FAHA, director of the women’s cardiovascular health program and associate professor of medicine at Wexner Medical Center at The Ohio State University in Columbus and chair of the writing group, told Cardiology Today. “Several of them are really lifestyle factors that patients can follow for both disease conditions. It’s important to understand that cancer therapies have evolved and, fortunately, resulted in increased breast cancer survivors, but it’s also imperative to understand that there are some side effects from cancer treatment that can impact the heart, which may sometimes alter their cancer treatment or require some heart treatments to be done first.”

More women are surviving breast cancer through successful screening and treatment. Many survivors are aged at least 65 years, and the leading cause of mortality in this group is CVD, with the second cause being breast cancer.

“The identification and management of cardiovascular risk factors in this population is important because CVD, if not recognized and treated, can pose a greater health risk than the cancer itself,” Mehta and colleagues wrote. “The expanding role of primary care physicians, oncologists, cardiologists and allied health care providers in survivorship programs is essential to optimize the management of comorbidities to realize the gains seen in breast cancer treatment.”

#
Breast cancer treatment may lead to early or delayed cardiotoxicity, including HF, LV dysfunction, arrhythmias, hypertension, valvular disease, myocardial ischemia, pulmonary hypertension, thromboembolic disease and pericarditis.
Photo Credit: Shutterstock

Risk factors

CVD and breast cancer have some common risk factors that can be modified through physical activity, promoting a healthy diet, maintaining a healthy weight, BP control, smoking cessation, a good lipid profile and diabetes management.

A healthy diet that is high in poultry, fruits, vegetables, whole grains, low-dairy products and fish have been shown to reduce CV mortality, although data are less consistent in breast cancer, as the association between diet and breast cancer may depend on the tumor type.

Weight and diet influence blood plasma lipid levels, which have been linked to breast cancer risk, according to the scientific statement.

Low to moderate alcohol intake may decrease the risk for CHD, and modest drinking has not been shown to have cancer-related benefits, although it is a modifiable risk factor for breast cancer. The association between cigarette smoking and breast cancer is inconclusive.

Meat consumption in relation to breast cancer has also not been well-understood.

“Collectively, the evidence for the influence of diet on breast cancer and CVD risk is mixed,” Mehta and colleagues wrote. “The results of epidemiological studies must be interpreted cautiously because these studies cannot determine causation.”

Physical activity has been shown to decrease CVD and breast cancer risk, especially in pre- and postmenopausal women. A sedentary lifestyle also is linked to breast cancer and CVD. Those with sedentary behavior are more likely to have high breast density, which is an independent risk factor for breast cancer. Obesity increases the risk for CVD and breast cancer, especially in postmenopausal women.

As women age, the incidence of breast cancer increases until menopause. The risk for CVD also increases with age, but the incidence is steeper after menopause.

The age of menarche and menopause can also affect CVD and breast cancer risk. Early menarche is associated with CVD and breast cancer, although early menopause is only linked to an increased risk for CVD.

Other risk factors, including hormone use and genetics, play a role in the increased risk for breast cancer and CVD.

“Knowledge and understanding of the risk factors for CVD and breast cancer will contribute to a better understanding of how best to prevent both diseases,” Mehta and colleagues wrote.

Effects of treatment on CVD

Breast cancer treatment may lead to early or delayed cardiotoxicity, including HF, LV dysfunction, arrhythmias, hypertension, valvular disease, myocardial ischemia, CAD, pulmonary hypertension, thromboembolic disease and pericarditis.

“The absence of a clear consensus in definitions of cardiotoxicity makes it difficult to compare results of cardiac endpoints between clinical trials and, furthermore, makes the applicability of these findings in the real world challenging at best,” Mehta and colleagues wrote.

There are several chemotherapeutic agents that lead to cardiotoxicity. Anthracyclines may cause significant irreversible LV dysfunction, which is shown early or late after exposure. Alkylating agents can damage DNA and result in myocyte death and cytotoxicity. Treatment with taxanes can result in bradycardia, asymptomatic left bundle-branch block and nonsustained ventricular tachycardia. Antimetabolite drugs used to distort RNA and DNA synthesis can cause chest pain, HF, MI and arrhythmias.

Women with estrogen or progesterone receptor breast cancer are often treated with endocrine therapy. Tamoxifen, the agent mostly used for premenopausal women, has been shown to have a positive effect on the lipid profile with reduced total cholesterol and LDL levels, but no significant changes in HDL. The protective effect on CV endpoints has not been shown in long-term data from clinical trials.

Aromatase inhibitors are effective in the primary prevention of breast cancer in high-risk postmenopausal women, although it may increase the risk for CVD. Ovarian suppression therapy is recommended for women who are premenopausal and have stage II or III breast cancer, as it does not increase CV-specific adverse effects.

Monoclonal antibodies, specifically trastuzumab (Herceptin, Genentech), have been shown to cause LV dysfunction, which is mostly reversible. When compared with a small-molecule tyrosine kinase inhibitor, combination therapy with trastuzumab was associated with an increased risk for serious cardiac events.

New therapies are currently being developed to overcome endocrine resistance, according to the scientific statement. Ribociclib (Kisqali, Novartis), which has been approved by the FDA, has been shown to cause prolongation of the corrected QT interval.

“Health care professionals and patients should be educated about the importance of avoiding concomitant use of other drugs that could further prolong the QT interval,” Mehta and colleagues wrote.

Cardiotoxicity caused by radiation therapy may have biological mechanisms that are secondary to pathway alterations, including fibrosis, myocyte ischemia, injury, inflammation, microvascular dysfunction and oxidative stress. The risk for morbidity and mortality caused by CVD toxicity is significantly increased with thoracic radiation therapy. This also may lead to impaired coronary flow reserve, myocardial fibrosis and myocardia ischemia.

Identifying CV toxicity early can be achieved through echocardiography, cardiac MRI or multigated acquisition scan. Cardiac damage should be diagnosed early, as the detection of LV ejection fraction changes may be a sign of a late manifestation of myocardial damage that may be irreversible.

“As such, the development of strategies for early detection of cardiotoxicity has been the focus of more recent research efforts,” Mehta and colleagues wrote.

A newer cardiac imaging technique to detect LV myocardial strain is speckle-tracking echocardiography. Although it is limited in patients with obesity and lung disease, this technique has been shown to produce similar results to cardiac MRI, less expensive, no radiation risk to the patient, less time-consuming and not nephrotoxic.

Biomarkers also be used to predict or detect cardiomyopathy. Troponin I can predict LVEF reduction, differentiate irreversible and reversible LV dysfunction, identify CV outcomes and has a negative predictive value for not developing cardiotoxicity. Data are limited or lacks consensus for natriuretic peptides and novel biomarkers. Conflicting results have been found regarding the use of biomarkers in patients undergoing radiation therapy.

Mitigating cardiotoxicity in patients undergoing cancer treatments has been shown in studies using agents such as dexrazoxane and doxorubicin infusion. Limiting radiation exposure through new techniques such as respiratory gating and proton therapy may lower complication rates, although long-term data are not available.

There are no guidelines that focus on preventing CVD in patients with breast cancer, but there are a few medications that can be used to prevent the disease, according to the scientific statement. Beta-blocker therapy has been shown to reduce new HF events and lessen the decline in LV function, but did not alter the risk for cardiotoxicity caused by trastuzumab.

Some observational studies have shown that aspirin can prevent breast cancer, whereas others have shown that it has little to no effect on cancer risk or has increased the incidence of it.

Data have not shown that statins may affect breast cancer incidence, but there are some data that show that it may favorably affect the prognosis of breast cancer.

There are limited data on the benefits of exercise on the prevention of breast cancer.

“Further clinical research is needed to determine whether exercise during cancer therapy is a feasible and effective method for the reduction of cardiovascular morbidity and mortality in breast cancer survivors,” Mehta and colleagues wrote.

The survivorship stage of breast cancer should involve the risk calculation for CVD, and individualized treatment recommendations should be based on the overall survival prognosis. Patients with pre-existing and ongoing CVD and those at risk for late cardiotoxicity should be monitored with transthoracic echocardiograms and cardiac MRIs, if necessary.

“We want to make sure that all breast cancer patients understand that it is imperative for them to undergo the best treatment that’s recommended by their oncologist for their breast cancer,” Mehta told Cardiology Today. “We want to make sure they’re getting the best treatment to survive breast cancer, but it also implies that depending on the type of treatment that’s personalized for them, they may require some heart monitoring before, during and after treatment.” – by Darlene Dobkowski

Disclosures: Mehta reports no relevant financial disclosures. Please see the statement for all other authors’ relevant financial disclosures.

Laxmi S. Mehta

Current breast cancer treatment negatively affects CV health and may lead to CVD, including HF and left ventricular dysfunction, according to a scientific statement from the American Heart Association published in Circulation.

In the United States, breast cancer affects an estimated 3.32 million women, and an estimated 47.8 million women are affected by CVD, according to the scientific statement.

“The important takeaways are to understand that there are some risk factors that are similar between heart disease and breast cancer,” Laxmi S. Mehta, MD, FAHA, director of the women’s cardiovascular health program and associate professor of medicine at Wexner Medical Center at The Ohio State University in Columbus and chair of the writing group, told Cardiology Today. “Several of them are really lifestyle factors that patients can follow for both disease conditions. It’s important to understand that cancer therapies have evolved and, fortunately, resulted in increased breast cancer survivors, but it’s also imperative to understand that there are some side effects from cancer treatment that can impact the heart, which may sometimes alter their cancer treatment or require some heart treatments to be done first.”

More women are surviving breast cancer through successful screening and treatment. Many survivors are aged at least 65 years, and the leading cause of mortality in this group is CVD, with the second cause being breast cancer.

“The identification and management of cardiovascular risk factors in this population is important because CVD, if not recognized and treated, can pose a greater health risk than the cancer itself,” Mehta and colleagues wrote. “The expanding role of primary care physicians, oncologists, cardiologists and allied health care providers in survivorship programs is essential to optimize the management of comorbidities to realize the gains seen in breast cancer treatment.”

#
Breast cancer treatment may lead to early or delayed cardiotoxicity, including HF, LV dysfunction, arrhythmias, hypertension, valvular disease, myocardial ischemia, pulmonary hypertension, thromboembolic disease and pericarditis.
Photo Credit: Shutterstock

Risk factors

CVD and breast cancer have some common risk factors that can be modified through physical activity, promoting a healthy diet, maintaining a healthy weight, BP control, smoking cessation, a good lipid profile and diabetes management.

PAGE BREAK

A healthy diet that is high in poultry, fruits, vegetables, whole grains, low-dairy products and fish have been shown to reduce CV mortality, although data are less consistent in breast cancer, as the association between diet and breast cancer may depend on the tumor type.

Weight and diet influence blood plasma lipid levels, which have been linked to breast cancer risk, according to the scientific statement.

Low to moderate alcohol intake may decrease the risk for CHD, and modest drinking has not been shown to have cancer-related benefits, although it is a modifiable risk factor for breast cancer. The association between cigarette smoking and breast cancer is inconclusive.

Meat consumption in relation to breast cancer has also not been well-understood.

“Collectively, the evidence for the influence of diet on breast cancer and CVD risk is mixed,” Mehta and colleagues wrote. “The results of epidemiological studies must be interpreted cautiously because these studies cannot determine causation.”

Physical activity has been shown to decrease CVD and breast cancer risk, especially in pre- and postmenopausal women. A sedentary lifestyle also is linked to breast cancer and CVD. Those with sedentary behavior are more likely to have high breast density, which is an independent risk factor for breast cancer. Obesity increases the risk for CVD and breast cancer, especially in postmenopausal women.

As women age, the incidence of breast cancer increases until menopause. The risk for CVD also increases with age, but the incidence is steeper after menopause.

The age of menarche and menopause can also affect CVD and breast cancer risk. Early menarche is associated with CVD and breast cancer, although early menopause is only linked to an increased risk for CVD.

Other risk factors, including hormone use and genetics, play a role in the increased risk for breast cancer and CVD.

“Knowledge and understanding of the risk factors for CVD and breast cancer will contribute to a better understanding of how best to prevent both diseases,” Mehta and colleagues wrote.

PAGE BREAK

Effects of treatment on CVD

Breast cancer treatment may lead to early or delayed cardiotoxicity, including HF, LV dysfunction, arrhythmias, hypertension, valvular disease, myocardial ischemia, CAD, pulmonary hypertension, thromboembolic disease and pericarditis.

“The absence of a clear consensus in definitions of cardiotoxicity makes it difficult to compare results of cardiac endpoints between clinical trials and, furthermore, makes the applicability of these findings in the real world challenging at best,” Mehta and colleagues wrote.

There are several chemotherapeutic agents that lead to cardiotoxicity. Anthracyclines may cause significant irreversible LV dysfunction, which is shown early or late after exposure. Alkylating agents can damage DNA and result in myocyte death and cytotoxicity. Treatment with taxanes can result in bradycardia, asymptomatic left bundle-branch block and nonsustained ventricular tachycardia. Antimetabolite drugs used to distort RNA and DNA synthesis can cause chest pain, HF, MI and arrhythmias.

Women with estrogen or progesterone receptor breast cancer are often treated with endocrine therapy. Tamoxifen, the agent mostly used for premenopausal women, has been shown to have a positive effect on the lipid profile with reduced total cholesterol and LDL levels, but no significant changes in HDL. The protective effect on CV endpoints has not been shown in long-term data from clinical trials.

Aromatase inhibitors are effective in the primary prevention of breast cancer in high-risk postmenopausal women, although it may increase the risk for CVD. Ovarian suppression therapy is recommended for women who are premenopausal and have stage II or III breast cancer, as it does not increase CV-specific adverse effects.

Monoclonal antibodies, specifically trastuzumab (Herceptin, Genentech), have been shown to cause LV dysfunction, which is mostly reversible. When compared with a small-molecule tyrosine kinase inhibitor, combination therapy with trastuzumab was associated with an increased risk for serious cardiac events.

New therapies are currently being developed to overcome endocrine resistance, according to the scientific statement. Ribociclib (Kisqali, Novartis), which has been approved by the FDA, has been shown to cause prolongation of the corrected QT interval.

“Health care professionals and patients should be educated about the importance of avoiding concomitant use of other drugs that could further prolong the QT interval,” Mehta and colleagues wrote.

Cardiotoxicity caused by radiation therapy may have biological mechanisms that are secondary to pathway alterations, including fibrosis, myocyte ischemia, injury, inflammation, microvascular dysfunction and oxidative stress. The risk for morbidity and mortality caused by CVD toxicity is significantly increased with thoracic radiation therapy. This also may lead to impaired coronary flow reserve, myocardial fibrosis and myocardia ischemia.

PAGE BREAK

Identifying CV toxicity early can be achieved through echocardiography, cardiac MRI or multigated acquisition scan. Cardiac damage should be diagnosed early, as the detection of LV ejection fraction changes may be a sign of a late manifestation of myocardial damage that may be irreversible.

“As such, the development of strategies for early detection of cardiotoxicity has been the focus of more recent research efforts,” Mehta and colleagues wrote.

A newer cardiac imaging technique to detect LV myocardial strain is speckle-tracking echocardiography. Although it is limited in patients with obesity and lung disease, this technique has been shown to produce similar results to cardiac MRI, less expensive, no radiation risk to the patient, less time-consuming and not nephrotoxic.

Biomarkers also be used to predict or detect cardiomyopathy. Troponin I can predict LVEF reduction, differentiate irreversible and reversible LV dysfunction, identify CV outcomes and has a negative predictive value for not developing cardiotoxicity. Data are limited or lacks consensus for natriuretic peptides and novel biomarkers. Conflicting results have been found regarding the use of biomarkers in patients undergoing radiation therapy.

Mitigating cardiotoxicity in patients undergoing cancer treatments has been shown in studies using agents such as dexrazoxane and doxorubicin infusion. Limiting radiation exposure through new techniques such as respiratory gating and proton therapy may lower complication rates, although long-term data are not available.

There are no guidelines that focus on preventing CVD in patients with breast cancer, but there are a few medications that can be used to prevent the disease, according to the scientific statement. Beta-blocker therapy has been shown to reduce new HF events and lessen the decline in LV function, but did not alter the risk for cardiotoxicity caused by trastuzumab.

Some observational studies have shown that aspirin can prevent breast cancer, whereas others have shown that it has little to no effect on cancer risk or has increased the incidence of it.

Data have not shown that statins may affect breast cancer incidence, but there are some data that show that it may favorably affect the prognosis of breast cancer.

There are limited data on the benefits of exercise on the prevention of breast cancer.

“Further clinical research is needed to determine whether exercise during cancer therapy is a feasible and effective method for the reduction of cardiovascular morbidity and mortality in breast cancer survivors,” Mehta and colleagues wrote.

The survivorship stage of breast cancer should involve the risk calculation for CVD, and individualized treatment recommendations should be based on the overall survival prognosis. Patients with pre-existing and ongoing CVD and those at risk for late cardiotoxicity should be monitored with transthoracic echocardiograms and cardiac MRIs, if necessary.

“We want to make sure that all breast cancer patients understand that it is imperative for them to undergo the best treatment that’s recommended by their oncologist for their breast cancer,” Mehta told Cardiology Today. “We want to make sure they’re getting the best treatment to survive breast cancer, but it also implies that depending on the type of treatment that’s personalized for them, they may require some heart monitoring before, during and after treatment.” – by Darlene Dobkowski

Disclosures: Mehta reports no relevant financial disclosures. Please see the statement for all other authors’ relevant financial disclosures.

    Perspective
    Javid J. Moslehi

    Javid J. Moslehi

    Dr. Mehta and colleagues should be congratulated on an excellent and thorough manuscript outlining CVD in breast cancer patients. It is great to see these experts, which include cardio-oncologists, oncologists and cardiologists who focus on women’s heart disease, come together to produce this outstanding multi-institutional document.

    One takeaway from the manuscript is the growing recognition that breast cancer patients can have heart disease as well. While some breast cancer patients may have underlying heart disease at the time of diagnosis, other breast cancer patients may develop disease due to breast cancer therapies. Breast cancer patients may be treated with anthracyclines, a type of chemotherapy that we have known for many years can cause cardiomyopathy and clinical heart failure. About 20% to 30% of the patients also receive trastuzumab and other HER-2 inhibitors, which can cause cardiomyopathy. Most patients treated with trastuzumab have routine cardiac monitoring during the course of therapy.

    Finally, many breast cancer patients are treated with radiation, which can cause a multitude of CV issues, including coronary artery and other vascular diseases. The cardiac issues associated with breast cancer therapies even extend to new therapies. For example, ribociclib, a new CDK4/6 inhibitor approved recently for a subset of patients with hormone-positive breast cancer, can cause QT prolongation and can increase the risk of arrhythmias, which is why the FDA has required monitoring with ECGs early during treatment.

    The success of many new therapies also means that breast cancer patients can become cancer survivors who may then be at risk of heart disease as they grow older. In the more than 3 million American women who are breast cancer survivors, CVD becomes much more relevant.

    Another takeaway from the document is the growing realizations that common risk factors may predispose to both breast cancer and heart disease. These include diet, exercise, genetics and high cholesterol. High cholesterol is actually a risk factor for the hormone receptor-positive breast cancer and can decrease treatment efficacy with endocrine therapies (which is a cornerstone therapy for these patients).

    A big part of the manuscript delves into steps that physicians and patients can take to decrease the risk for heart disease in women with breast cancer survivors, and the authors do a great job of addressing what these steps are. One algorithm that our program (Vanderbilt cardio-oncology program) developed several years ago is the ABCDE steps (Montazeri K, et al. Circulation. 2014;doi:10.1161/CIRCULATIONAHA.114.008820) that women can take that can decrease heart disease in all patients with cancer, but specifically patients with breast cancer. This ABCDE algorithm can be a simple checklist that physicians and patients can remember. “A” is awareness of disease. Many women don’t recognize that they are at risk of heart disease. “A” also stands for aspirin (which high-risk individuals may benefit from). A big part of the Vanderbilt ABCDE paradigm is cardiac risk factor stratification in all women and where “B” (blood pressure), “C” (cigarette smoking), “C” (also stands for cholesterol), “D” (diabetes), “D” (diet) and “E” (exercise activity) are assessed in all women and treated appropriately. “D” also stands for dose of chemotherapy, and all breast cancer survivors need to know dose of radiation and anthracyclines received during the course of therapy. In breast cancer women who receive cardiotoxic therapies, “E” also stands for echocardiogram, which should be performed following treatment in patients at risk. I am glad to report that this ABCDE algorithm will be incorporated into guidelines from the National Comprehensive Cancer Network in the coming year and will become a fundamental aspect of care for the more than 16 million American cancer survivors, including breast cancer survivors. The interesting thing to realize is that these steps may not only prevent heart disease in breast cancer survivors, but may also prevent cancer recurrence, given the shared risk factors between cancer and heart disease.

    Finally, the manuscript addresses big knowledge gaps in the field. For example, one area is the lack of studies focusing specifically on breast cancer patients. Many recommendations in cardio-oncology are essentially extrapolations from general cardiology studies. However, the breast cancer patients may have unique issues. That is something we really need to work as a collaborative network to address and to include CV studies, which include breast cancer patients. Another area is to gain a more molecular and mechanistic understanding of the mechanisms of cardiotoxicity, especially with the newer drugs. There has been some dogma that has been introduced to the field of cardio-oncology, often with very little scientific basis. As an example, there has been a ludicrous notion that cardiomyopathy from breast cancer therapies fall into type I (which is irreversible) and type II (reversible) categories. While this idea may have been “sexy” in 2005 (when it was first proposed), 13 years later, we have no understanding for the scientific underpinnings for this ridiculous classification. We as a community need to get more rigorous and become more scientific. We need to understand the precise mechanisms of heart disease in breast cancer patients so that we can make more rational preventive and treatment strategies.

    • Javid J. Moslehi, MD
    • Cardiology Today Editorial Board Member Director, Cardio-Oncology Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee

    Disclosures: Moslehi reports he has been an unpaid consultant for the FDA and receives research grants from Bristol-Myers Squibb and Pfizer.