Guideline: American Heart Association examines the challenges of cardiovascular disease and breast cancer

IN-DEPTH REVIEW OF RESEARCH

Study background:

The American Heart Association issued its first statement on cardiovascular disease and breast cancer in February 2018. This statement reviews the frequency of these diseases, their common risks, the impact of cancer therapy on heart function and ways to treat and prevent cardiovascular disease in breast cancer patients.

The focus of this statement is:

the intersection between cardiovascular disease (CVD) and breast cancer. CVD includes heart failure, myocardial ischemia (reduced blood flow to the heart) and hypertension. This review highlights the need for interdisciplinary care that combines cardiology and oncology.

Statement findings:  

1. There is a significant overlap of cardiovascular disease and breast cancer. 
   • CVD is the leading cause of death in women. CDC data shows that 47.8 million women in the United States had CVD in 2014, resulting in 1 in 3.3 deaths. Breast cancer affects 3.32 million women, resulting in 1 in 31.5 deaths annually. CVD is notably higher in older, postmenopausal breast cancer survivors than in postmenopausal women without breast cancer. This is partially due to the detrimental impact of some breast cancer treatments on heart health.
2. Cardiovascular disease and breast cancer have overlapping risk factors.
   • More than 80% of cardiovascular disease is thought to be preventable by modifying risk factors, although to what extent is unknown.  CVD and breast cancer share several major risk factors, including diet, alcohol intake, physical activity, sedentary lifestyle, weight, age and use of postmenopausal HRT. While several genetic risk factors for breast cancer have been identified, no major gene mutations account for the majority of cardiovascular disease.
3. Known factors that affect risk for both conditions include:
   • A healthy diet protects against CVD and breast cancer. 
     • In the Nurses’ Health Study (NHS), participants who maintained a diet that was high in vegetables, fruits, poultry, fish, low-fat dairy and whole grains were compared to those who had a predominantly "Western diet" that was high in red or processed meats, refined grains, sweets and high-fat dairy.
   • Alcohol intake may increase breast cancer risk and, in moderation, may slightly decrease cardiovascular disease risk.
     • Less than 1 drink per day decreases the risk for CVD.
     • Any alcohol consumption increases the risk for breast cancer.
   • A sedentary lifestyle can impact CVD, breast cancer risk and overall health.
     • About 150 minutes of moderate exercise per week is recommended for all Americans. Physical activity provides numerous health benefits, including reduced risks of CVD and breast cancer—an increased level of exercise reduces CVD risk even further. Studies also show that moderate to vigorous physical activity is associated with decreased breast cancer risk. People who report high lifetime physical activity have significantly fewer deaths from breast cancer. Consistent exercise is also important for young previvors: the Nurses’ Health Study showed that physical activity at 14-17 years of age correlated to a 15% lower risk of premenopausal breast cancer.
     • A sedentary lifestyle—sitting or lying down with limited whole body movement for more than 10 hours a day, whether or not you also engage in moderate to vigorous physical activity in the remainder of your day—is detrimental to overall health. Sedentary behavior is associated with an 18% increased risk of CVD and an 80% increased risk of breast cancer, even in people who otherwise engage in moderate to vigorous activity. Simply exercising sufficiently is not enough.
     • Reducing sedentary behavior and increasing physical activity reduce the risk of breast cancer.
   • Weight
     • Being overweight or obese is a clear CVD risk factor at all ages.
     • The relationship between weight and breast cancer risk is more complex—higher weight early in life is more protective and late in life it is more detrimental:
     • In childhood or adolescence, higher body fat is associated with a lifetime decrease in breast cancer risk of 20-50% regardless of menopausal status.
     • At 18 years of age, a high (overweight to obese) body mass index (BMI) in women is associated with a 24% decrease in breast cancer risk.
     • Every 10-pound increase in adult weight correlates to an 11% increase in breast cancer risk in postmenopausal women.
     • In women, especially just prior to menopause, short-term weight increases are associated with a 20% increase in breast cancer risk (38% premenopausal, 10% postmenopausal).
     • Being overweight or obese early in life may be somewhat protective against breast cancer but increases the risk of CVD. Either condition also increases the later-in-life risk of both breast cancer and CVD.
   • Age
     • As a person ages, the risks of breast cancer and CVD increase, especially for women who begin menstruating early.
     • Early menopause decreases the risk of breast cancer and increases risk of CVD. After menopause, breast cancer risk slows, while the risk of CVD continues to increase.
   • Postmenopausal Hormone Replacement Therapy (HRT)
     • Postmenopausal Hormone Replacement Therapy (HRT) is associated with increased risk of both breast cancer and CVD:
     • Breast cancer risk is 1.2-2 times greater among HRT users of 5 years or more compared to non-users.
     • CVD risk is 1.29 times greater among HRT users compared to non-users, according to a study of more than 16,000 women.
4. Cancer treatment can lead to early or delayed cardiotoxicity. Severe cardiovascular disease can lead to heart failure.

   • The most common form of cardiotoxicity is left ventricular dysfunction, which can be observed as decreased Left Ventricular Ejection Fraction (LVEF). An LVEF of less than 50% (less than 50% of the blood in the left ventricle is pumped out with each heartbeat) is considered dysfunctional.

   • Arrhythmia (abnormal heart rhythm) is observed with some chemotherapy and radiation treatment.

   • A prolonged corrected QT interval, a severely abnormal rhythm associated with sudden death, can occur when treating with certain chemotherapy drugs.

5. Different therapies have varying impacts on cardiovascular health.
   • Anthracyclines
     • Anthracyclines include doxorubicin and epirubicin. All doses of anthracyclines cause cardiotoxicity (damage to the heart muscle). The risk of cardiotoxicity rises as the dose increases: from 5% after 400 mg/m2 to 25% after 550 mg/m2 and to 48% after 700 mg/m2. Overall, however, the amount of cardiotoxicity is modest—averaging a 4% decrease in LVEF from baseline (>50% LVEF) 3 years after treatment. Anthracycline associated cardiotoxicity can occur early during treatment or after treatment is completed. Doxorubin can also affect the heart, although to a lesser degree: 2.6% of patients treated with doxorubicin have arrhythmias (compared to 1.0% of patients who are treated without doxorubin) and 2-10% have atrial fibrillations. Thus, monitoring heart function is important during treatment with anthracyclines.
   • Hormonal therapy
     • Endocrine therapy is used for early-stage, hormone receptor-positive breast cancer. Endocrine therapy drugs decrease cancer recurrence and greatly improve survival. They include hormonal agents (e.g., tamoxifen) and aromatase inhibitors.
     • Tamoxifen does not detrimentally impact heart function and by itself does not lead to LVEF decline. However, it is associated with increased risk of blood clots in the veins and lungs (pulmonary embolism). Therefore, a person's history of stroke should be considered before treating with tamoxifen.
     • Aromatase inhibitors (e.g., anastrozole, letrozole and exemestane) are used as primary therapy for breast cancer or as chemotherapy following tamoxifen therapy. AIs are associated with an increased risk for high cholesterol that is 2.3 times greater compared to patients who are not treated with AIs. In meta-analyses of multiple clinical trials, AIs were shown to increase the risk of CVD compared to treatment with tamoxifen alone.
   • Her2 therapies
     • Two FDA-approved antibodies are used to inhibit HER2-positive tumors: trastuzumab (brand name Herceptin) and pertuzumab.
     • Herceptin treatment of HER-positive, early-stage breast cancer reduces the risk of recurrence by 50% and decreases mortality by 33%. Heart dysfunction was observed in multiple trials of Herceptin—it is associated with both LVEF decline and heart failure; however, these effects are mostly reversible. A large follow-up study showed low overall cardiotoxicity with Herceptin; only 4.1% of participants exhibited cardiotoxicity. In the SEER program study of 9,535 women with an average age of 71, heart failure was observed in 29.4% who were treated with Herceptin compared to 18.9% in women who were not. The risk is greatest for patients who are older than age 80 with prior heart disease, hypertension or continued Herceptin therapy.
   • Radiation therapy
     • Radiation to the chest carries a significant risk of CVD toxicity that increases mortality and limits use of radiation therapy for cancer treatment. Breast cancer survivors can observe heart effects as early as 5 years post-radiation treatment and up to 30 years afterward. The increase in heart events is 7.4% for each 1 gray increase in radiation to the heart region. The National Cancer Institute’s SEER program study of mortality among 558,871 women found that women who had left-sided (heart-sided) radiation treatment for breast cancer had a 1.19-1.90 greater risk of death due to cardiac dysfunction compared to women who received right-sided radiation for breast cancer.
6. Because the risk of cardiotoxicity is high with many cancer treatment regimens, monitoring heart functions before, during and after cancer treatment is important:
   • Measuring the left ventricular ejection fraction (LVEF): This is the fraction of blood that is pumped out of the heart’s left ventricle versus the blood remaining in that ventricle in a given beat of the heart. Monitoring the LVEF during an echocardiogram or cardiac MRI indicates how effectively the heart is pumping. Although there is no consensus about what level of LVEF change is significant or detrimental, an LVEF of less than 50% is considered to be dysfunctional. Many cancer treatments cause a modest LVEF change (e.g., 4% decrease observed with anthracycline treatment).
   • Measuring tropinin1 levels. Monitoring levels of this protein in the heart’s muscle fibers is a standard, well-established and sensitive measure for acute heart injury. It may help to distinguish between reversible and irreversible changes in heart function, such as those that occur with Herceptin. Increases in troponin1 levels indicate a decline in heart function, although some studies suggest that Herceptin treatment causes increased troponin1 levels without any subsequent heart dysfunction. It is unclear how to interpret this marker for long-term heart function.
7. No definitive guidelines exist for prevention of cardiotoxicity in breast cancer patients, because most studies have been small and difficult to compare. It is very important for cardiology and oncology practitioners to jointly determine appropriate treatment, particularly for patients with a history of cardiovascular disease or a high risk of CVD during treatment.
8. Multiple clinical practices can reduce the impact of cancer therapy on cardiotoxicity:
   • Administration of doxorubicin
     • Cumulative dose is the strongest predictor of heart dysfunction with doxorubicin. However, how this drug is administered can affect these deleterious effects.
       • Infusion versus single injection: Administering by slow infusion instead of a single injection reduces cardiotoxicity without changing the drug’s anti-tumor effects. Infusing for 6 or more hours reduces heart failure by 73% more than shorter administrations, but this approach is used infrequently because of the logistics involved and the potential need for the patient to be admitted to the hospital.
       • Liposomes: Delivering doxorubicin via liposomes (small bubbles of liquid that release the medication into the system) allows higher doses to be used with fewer cardiac side effects because the drug enters tumor tissue more easily than organ tissue, including heart tissue. Although this approach is currently used in Europe, it is used for ovarian cancer—but not for breast cancer—in the U.S.
   • Radiation techniques
     • Current research is exploring new radiation techniques that reduce cardiotoxicity, including proton therapy, breath holding and different radiation positions. However, no long-term data is available on these alternative techniques.
   • Cardiovascular medications to reduce CVD
     • One approach to reducing cardiotoxicity is to treat breast cancer patients with medications that reduce CVD in the general population. Several CV medications have been tested in combination with breast cancer treatment with promising results. Beta blockers (BB) such as carvedilol, and ACE inhibitors, such as lisinopril, are standard medications for treating heart disease. Small trials with BBs and/or ACE inhibitors and doxorubicin showed reductions in the frequency of heart events in some breast cancer cases. BB has an unclear impact on Herceptin treatment; some studies show that it helps recovery of heart function after Herceptin treatment, while others show no impact or decline in heart function (although the latter was a retrospective study with patients who were already under treatment for heart conditions, which makes interpretation difficult).
   • Exercise
     • Data on exercise preventing cardiotoxicity in breast cancer is sparse. In a prospective trial of 2,973 women who had non-metastatic breast cancer, women who exercised more than 9-10 hours per week had 23% fewer CV events, a 26% lower risk of coronary artery disease and a 29% lower risk of heart failure.
   • Survivorship programs
     • A plan to manage cardiotoxicity during survivorship can improve long-term outcomes. Breast cancer survivors at higher risk for CVD include those who have a prior history of CVD, receive more than 240 mg/m2 of doxorubicin, radiation of over 30 gray, or have radiation plus doxorubicin (or other anthracycline) or high-dose cyclophosphamide.
     • Management plans include:
       • Following AHA guidelines for managing general CV risks (high blood pressure, diabetes mellitus, high cholesterol, etc.) and behavioral risks (alcohol, diet, sedentary lifestyle, etc.) is recommended.
       • Breast cancer survivors often gain weight and have less physical activity during treatment, which ideally would be reversed for optimal cardiac health. AHA recommends moderate intensity aerobic physical activity of more than 30 minutes, 5 days per week. Recent meta-analysis of many studies shows that physical activity is associated with lower mortality and lower cancer recurrence rates.
       • Post-treatment cardiac imaging is warranted for those with pre-existing and ongoing CVD. Surveillance depends on cancer treatment agents and doses received. In low-risk survivors, heart imaging at the end of cancer treatment without follow-up may be sufficient (unless evidence of CVD is found). In higher-risk survivors, post-treatment imaging from 3-18 months is recommended, depending on the prior cancer treatment. In general, greater post-treatment surveillance is needed if anthracyclines were part of cancer therapy. For those treated with Herceptin, less post-treatment imaging is necessary if patients are asymptomatic for heart dysfunction at the end of their cancer treatment.
   • Dexrazoxane
     • Dexrazoxane is an iron-chelating agent that reduces cell damage. Trials show that dexrazoxane given with the anthracyclines doxorubicin or epirubicin reduce heart events by 65-82% with no impact on progression-free survival, overall survival or response rates. FDA approval is limited to "...women with metastatic breast cancer who have received a cumulative dose of doxorubicin of 300 mg/m2 and who will continue to receive doxorubicin."

Limitations:

At what point does concern about heart dysfunction outweigh the benefit of cancer treatment? This is an ongoing controversy in cardio-oncology. Many heart function impacts are manageable in a hospital setting with adequate monitoring. Ongoing discussion between patients and their oncologist and cardiologist are recommended before, during and after treatment.

Conclusions:

The interaction of breast cancer and cardiovascular disease is significant. Preventive strategies that modify risk factors may help breast cancer survivors decrease their risk of cardiovascular disease. Some cancer therapies have significant CVD risk as a side effect. Attention to how cancer therapies are administered, possible additional preventive measures and evaluation of ongoing impact on CV function are warranted for breast cancer patients.

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Posted 5/2/18