Cancer and cardiovascular disease (CVD) are leading causes of morbidity and mortality in the United States (US) and their co-occurrence is increasingly more prevalent.1 Breast cancer is increasingly a major focus of this association. Despite evidence that mortality rates for CVD and breast cancer have declined according to the US Center for Disease Control (CDC), the disease related mortality risk among older women diagnosed with breast cancer is almost equal to the risk of mortality due to CVD.2,3 Indeed, many CVD risk factors have been associated with a primary breast cancer diagnosis including but not limited to obesity and physical inactivity. Furthermore, the improved success of screening and treating breast cancer patients has contributed to the increasingly growing number of survivors of different ages with breast cancer. Framingham study has suggested that women at 50 years of age have a 39.2% lifetime risk of CVD.4
Improved survival as well as rising costs of care and treatment continue to place an increasing burden on US economy. Multidisciplinary care involving cardiology and oncology is critical in the management of breast cancer patients as breast cancer outcomes can be influenced by cardiovascular health in different ways: breast cancer care can result in cardiovascular toxicities that could prevent or impact ongoing cancer treatment and re-existing cardiovascular health can dictate breast cancer treatment selection.5 Additionally, recent studies indicate that exercise may improve vascular endothelial function and exercise capacity in breast and prostate cancer survivors.6 In this review article we present challenges and important points to taking into consideration in patients with breast cancer and their risk of heart failure.
Pre-existing Cardiovascular Risk in Patients with Breast Cancer
i. Shared Risk Factors and Common Pathophysiological Pathways
Heart failure and cancer may have a common biological background with overlap in risk factors. To date, most studies have shown that this relationship might be indirect and through increasing the risk of stage A and B heart failure. Hypertension and metabolic syndrome have been associated with the risk of postmenopausal breast cancer.7-10 There are several molecular mechanisms that overlap in breast cancer and CVD. Patients with diabetes, obesity and metabolic syndrome can have elevated levels of carcinogenic hormonal mediators, for example, insulin like growth factor 1 (IGF-1) and estrogen.11 Additionally, patients with metabolic syndrome may have higher inflammatory burden which may increase the risk of breast cancer.12 Thus, its plausible that, hypertension, diabetes obesity and metabolic syndrome could lead to adverse cardiac and vascular modeling in the same time that they increase the risk of carcinogenesis.
ii. Relevance of pre-existing HF in patient with new breast cancer diagnosis.
Before initiation of therapy, a thorough patient history and physical examination should be taken to determine the baseline cardiovascular risk. Different adjuvant therapies for breast cancer are associated with unique and varying degrees of cardiovascular injury. Toxicity can range from transient dysfunction to permanent damage. Selection of treatment is based on a complex model, including patient factors (age, comorbidities, functional status, and patient preference) and tumor factors (lymph node involvement, histological grade, and human epidermal growth factor receptor [HER]-2 status and estrogen receptor [ER]). Often, clinical profile and pre-existing risk factors can dictate certain aspects of treatment. Depending on the severity of heart failure and other comorbidities, patients with heart failure undergoing adjuvant therapy may not receive Anthracycline, however, trustozumab can be considered for patients with mild heart failure. Patients with mild heart failure may receive more frequent surveillance and closer monitoring with consideration of discontinuation of treatment for further significant drop in ejection fraction. Finally, the effect of heart failure on breast cancer patients may exceed the duration of treatment to impact outcomes years after breast cancer diagnosis. A recent study for heart failure with breast cancer has shown that heart failure can impact survivals of breast cancer patients up to 10 years after diagnosis, impact was stronger among those with early stage cancer.13 Table 1. displays potential myocardial dysfunction risks of adjuvant breast cancer systemic therapy.
iii. Management of Pre-existing CVD Risk
Patients with breast cancer and pre-existing cardiovascular risk factors are at higher risk for left ventricular (LV) dysfunction. This was demonstrated by multiple studies showing that hypertension, smoking history, diabetes are independent predictors for cardiac toxicity associated in patients who were exposed to trustozumab and/or anthracycline use.14-16 Thus, appropriate management for these risk factors should take into account the risk of LV dysfunction to chemotherapy which may necessitate the maximization of cardiac protection among this group of patients. Current evidence suggests that angiotensin converting enzyme (ACE) inhibitors as well as beta blockers can provide protection against trustozumab related cardiac dysfunction.17,18
Heart Failure Complicating Breast Cancer Treatment
i. Common pathophysiological pathways.
Anthracyclines, such as doxorubicin, have been used successfully in the treatment of various neoplasms such as breast cancer since the 1970s, but their use can result in significant irreversible LV dysfunction. The incidence of HF in in patients receiving doxorubicin is typically between 0% and 1.6% which could increase up to 2.1% in patients receiving doxorubicin with sequential taxanes.19 Multiple studies suggest that, anthracycline-based adjuvant chemotherapy carries a substantial long-term risk of HF lasting for years, especially for women older than 65 years of age.20 Although adjuvant trials typically report only symptomatic cardiac events, recent prospective studies report frequent subclinical left ventricular dysfunction, in 10% to 50% of patients receiving anthracycline-based therapy.21 The long-term consequences of subclinical LV dysfunction are not known, although this could leaves the patient more susceptible to further adverse cardiac remodeling. Biological mechanisms underlying chemotherapy-associated cardiac dysfunction remain to be fully understood. Generation of reactive oxygen species (ROS) and induction of cardiac myocyte apoptosis are thought to play a central role. There is evidence that mitochondrial DNA alterations, superoxide, and respiratory chain dysfunction accumulate long-term in the absence of the drug which may explain later onset complication.22
ii. Breast Cancer Systemic therapies and the Risk of Cardiac Dysfunction
Anthracyclines are potent inhibitors of topoisomerase II, and thus DNA function, and for decades have been an integral component of systemic breast cancer treatment. Dose-related cardiotoxicity, presenting as asymptomatic LV systolic dysfunction or clinical HF, is a major reason for switching therapies.23-25 Indeed, studies have reported that anthracycline use in breast cancer treatment has significantly declined over time.26 There are some inconsistencies with data regarding incidence of cardiotoxicity with lower-dose anthracycline used in contemporary breast cancer regimens, thus recommendations for CV evaluation are inconsistent, overall.23,24,27
Trastuzumab is a human epidermal growth factor receptor 2 (HER2) antagonist block the overexpressed signaling pathway in HER2- positive breast cancer and have dramatically improved outcomes in patients with HER2-positive disease, in patients with metastatic HER2- positive breast cancer; the addition of trastuzumab to doxorubicin-containing chemotherapy was shown to markedly improved overall survival.28 Almost one-third (27%) of patients receiving trastuzumab and doxorubicin developed cardiomyopathy and HF.29 This has led to major safety improvement measures including separate administration of anthracyclines and trastuzumab; close LVEF surveillance with recommended treatment cessation or hold if significant (>10%) LVEF decline was identified. However, there are some discrepancies in recommendations across guidelines reflecting continuous evolution of the CV safety monitoring of trastuzumab.30
iii. Treatment selection for patients with and without LV dysfunction.
Treatment selection for subjects with and without LV dysfunction
iv. Surveillance, transient LV dysfunction vs persistent during treatment.
A comprehensive assessment, including screening for CV risk factors and an echo- cardiogram to monitor for cardiac dysfunction, is recommended in all patients planned to receive potentially cardiotoxic therapy.
Once a patient has started treatment, cardiovascular testing usually is symptoms driven. In addition, this may depend on the baseline cardiovascular risk profile, the specific cancer treatment regimen, and the development of cardiac symptoms and/or events. Left ventricular ejection fraction (LVEF) obtained by echocardiography or cardiac magnetic resonance imaging (MRI) is used to identify patients with cardiotoxicity; however, a change in LVEF could constitute a late manifestation and potentially irreversible damage. Due to variability in echocardiography assessment, and the lack of consensus on clinically significant reduction in cardiac function, the development of strategies for early detection of cardiotoxicity has been the focus of more recent research efforts. This has led us to focus on myocardial strain imaging, cardiac serum biomarkers, and their combination as more sensitive biomarkers for cardiac damage. There is evidence that changes in left ventricular (LV) strain can precede and may in fact predict cardiac dysfunction in breast cancer patients receiving chemotherapy.31
Based on the above, it seems appropriate to include strain imaging in monitoring algorithms for cardiotoxicity. After completion of therapy, reassessment is recommended at 6 and 12 months and as early as 3 months for those at highest risk.
Human epidermal growth factor receptor (HER2) antagonist (trastuzumab) has been associated with the risk of cardiac toxicity. One unique aspect with trastuzumab is the prolonged (one year) treatment duration. One may argue that recognition of abnormalities in these echocardiographic parameters should prompt initiation of effective cardiac therapies with continuation rather than suspension of cancer therapy as long as LVEF is preserved and signs and symptoms of heart failure are absent.
v. CV risk reduction and risk stratification.
Primary prevention strategies for HF in patients receiving systemic breast cancer treatment starts with treatment. There have been recent trials that demonstrated that beta blockers and angiotensin converting enzyme inhibitors are well-tolerated in patients with HER2-positive early breast cancer who received trastuzumab and protected against cancer therapy-related declines in LVEF; however, trastuzumab-mediated left ventricular remodeling-the primary outcome-was not prevented by these pharmacotherapies.18 Furthermore, other studies have demonstrated that patients treated for early breast cancer with adjuvant anthracycline-containing regimens with or without trastuzumab and radiation, concomitant treatment with candesartan provides protection against early decline in global left ventricular function.32
vi. Patients Developing Cardiac Dysfunction during Treatment
Patients developing heart failure during systemic treatment should be treated according to guidelines from the American Heart Association (AHA). Involvement of a cardio-oncologist is recommended when clinical heart failure or a decline of LVEF is noted during chemotherapy as careful decision making is required with respect to further exposure to cardiotoxic cancer treatment. Depending on the gain from further cancer therapy, it is sometimes possible to continue treatment with the support of ACE inhibition (ACEi) and β-blockade. Patients who develop decline in LVEF should be considered for guideline-based heart failure treatment either with ACEi. A recent study have found that of 226 patients who developed cardiotoxicity following anthracycline-based chemotherapy and received treatment with angiotensin convertimng enzyme inhibitor and β-blocker in combination, 11% had complete recovery of LVEF, 18% had no recovery and the remainder exhibited partial LVEF recovery to baseline over a period of 5-year echocardiographic follow-up.33,34 There is an evidence that early initiation of combined enalapril and carvedilol treatment within 6 months of anthracycline therapy are associated with greater LVEF recovery and a return to baseline in 42% of patients.33
Heart failure in Breast Cancer Survivors
The rapid development of novel oncologic therapies that improve cancer-free and overall survival, but may cause treatment-associated LV dysfunction, has transformed the cardiologist's paradigm from mere avoidance of cardiac toxicity to a new common goal of HF risk prediction, prevention, early diagnosis, and concomitant cardiac and cancer treatment to improve patient outcomes. Thus, the need for cardio-oncology team collaboration is of utmost importance in breast cancer survivors.35 Close surveillance for breast cancer survivors to monitor for heart failure or LV dysfunction is essential, especially for those who were exposed to cardiotoxic systemic chemotherapy or radiation.
There is likely a significant percentage of breast cancer survivors who may have an underlying asymptomatic or subclinical LV dysfunction, which may not be a benign condition. We have learned that mild asymptomatic decline in LV function in the community can progress to heart failure and cardiovascular mortality.36 In addition, subjects who have received anthracycline are even at higher risk, due to continued adverse cardiac remodeling which is resulted from continue oxidative injury .37 In fact, studies have shown that childhood cancer survivors receiving anthracycline chemotherapy appear to be particularly susceptible and remain at elevated risk of developing heart failure decades after therapy and cure.27 Recent oncology guidelines recommend a single echocardiogram 6 to 12 month after completion of anthracycline therapy in high-risk asymptomatic patients. Cardiology consensus statements recommend more frequent (at the completion of treatment and 6 months after) or longer follow-up (at 1 and 5 years), albeit recognizing lack of data regarding frequency and duration of LVEF monitoring in cancer survivors. 23-25