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Cardiovascular disease is the second leading cause of mortality in survivors of cancer, second only to disease recurrence. In the accompanying article, Kyprovides a valuable, comprehensive overview of the cardiovascular issues of survivors of breast cancer to inform rational management. The article by Kyreviews the existing data on common cardiotoxic therapies (e.g., anthracyclines and trastuzumab) and describes recent progress in cardiovascular disease detection, management, and prevention in patients with breast cancer.

The comanagement of cardiovascular disease and breast cancer can be a challenge for providers and patients. Patients with heart failure who are receiving intravenous fluids as part of their cytotoxic therapies and those who develop cardiovascular disease during or after receipt of trastuzumab or anthracycline should ideally be monitored and treated by experienced cardio-oncologists. However, smaller oncology clinics, particularly in rural areas, may not have as much access to experts in the short- and long-term effects of cancer treatments. This may increase cancer health disparities for patients treated at community hospitals and in underserved areas. It will be important to develop tools (e.g., care algorithms and/or virtual consults with cardio-oncologists) to facilitate high-quality, patient-centered, evidence-based cardiac care for all patients with cancer who would benefit from comanagement of cardiovascular disease.

In addition to discussing anthracyclines and trastuzumab as cardiotoxic therapies, Ky describes cardiac risks from radiation therapy and endocrine therapy. Left-sided chest radiation is a well-known risk factor for cardiovascular disease, with a direct correlation between risk and cardiac radiation dose, but the impact of adjuvant endocrine therapy on cardiovascular disease is more controversial. Regarding radiation, it is likely that recent technical advances (e.g., prone positioning, breath hold) and the introduction of proton beam therapy and brachytherapy are reducing cardiovascular toxicity. Regarding endocrine therapy, aromatase inhibitors seem to be associated with more cardiac events than tamoxifen in randomized trials that compare the two, but it has been hard to discern whether this is due to aromatase inhibitors causing cardiovascular disease or tamoxifen preventing cardiovascular disease. Two recent meta-analyses had somewhat contradictory findings on this issue (perhaps because one focused only on extended adjuvant endocrine therapy, while the other included both adjuvant and extended adjuvant therapy trials)., As clinical practice evolves toward longer durations of treatment and more use of ovarian function suppression–based regimens in premenopausal survivors (which might increase long-term cardiovascular disease risk), it will be critical to continue to assess how endocrine therapy selection affects cardiovascular disease incidence as well as cardiac risk factors such as obesity and hypercholesterolemia.

In fact, many important questions and controversies persist in cardio-oncology. In February 2015, the National Comprehensive Cancer Network began to recommend that clinicians consider ordering a postanthracycline echocardiogram in patients at higher risk of cardiac toxicity (including all those > 65 years), and ASCO subsequently published a similar recommendation in 2016, but oncologists and patients may be wary about this type of testing in the absence of randomized clinical trial data to show that early intervention in asymptomatic patients truly improves cardiac outcomes. Indeed, the optimal duration and frequency of imaging to assess cardiac function before, during, and after receipt of anthracycline and/or trastuzumab, especially in the setting of metastatic disease, are in need of further investigation. Should all patients, even young healthy ones, undergo echocardiography before receipt of anthracycline? How should patients with asymptomatic declines in left ventricular ejection fraction during or after treatment of breast cancer be managed?

Fortunately, various ongoing clinical trials will help answer these questions. For example, the Preventing Anthracycline Cardiovascular Toxicity With Statins (PREVENT; identifier: NCT01988571) study is randomly assigning patients to atorvastatin or placebo during and after receipt of anthracycline for breast cancer or lymphoma to assess if atorvastatin is protective against cardiovascular disease in this setting. Also, the Cardio-Oncology Breast Cancer Study (COBC; identifier: NCT02571894) is testing the utility of standard cardiac risk factors, biomarkers, and cardiac imaging to predict subsequent occurrence, frequency, and severity of clinical or subclinical cardiotoxicity among women with early breast cancer any time between start of treatment up to 10 years after the completion of chemotherapy. Another study in progress, the Prospective Study of Breast Cancer Patients With Abnormal Strain Imaging ( identifier: NCT02993198), aims to develop a risk model to predict left ventricular dysfunction in patients with early-stage breast cancer undergoing chemotherapy with anthracycline and/or trastuzumab and pertuzumab-based regimens. And the Cardiac Safety Study in Patients With HER2+ Breast Cancer (SAFE-HEaRt; identifier: NCT01904903) is evaluating the safety of human epidermal growth factor receptor 2–targeted therapies in patients with breast cancer with cardiac compromise.

In conclusion, cardiovascular disease is common and deserves additional attention in survivors of breast cancer. It will be important to continue research focusing on the pathophysiology underlying treatment-induced cardiotoxicity, who is most at risk, and what monitoring and treatment strategies improve outcomes.

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