Cardiac morbidity & mortality in patients with breast cancer: A review.

Cardiovascular disease (CVD) and breast cancer cause substantial morbidity and mortality in women and are major public health concerns. Breast cancer survivors are at a greater risk for CVD-related mortality compared to women without breast cancer. Breast cancer and cardiovascular diseases share a number of common risk factors. Breast cancer treatments like anthracycline based chemotherapy, novel targeted therapy and radiation therapy can cause cardiotoxicity. With improvements in breast cancer prevention and treatment, there is a significant improvement in survival and this shifts focus from disease control to long term effects of treatment and quality of life. Assessing CVD and minimizing complications from cancer therapy are important treatment goals.

Introduction

Breast cancer is one of the most common cancers among women in India123, and its incidence is increasing4. As compared to developed countries, in India, breast cancer occurs at a younger age3. Early detection and advances in treatment have decreased mortality in patients with early-stage breast cancer significantly1, and an increase in the number of breast cancer survivors is also now documented in the developed countries5. Cardiovascular disease (CVD), which is a leading cause of mortality in the general population globally, and also in India67 is an important non-cancer risk for death in certain breast cancer survivors891011. There is a paucity of cardiac morbidity and mortality data among breast cancer survivors in India.

Surgery, radiation therapy (RT), chemotherapy, endocrine and targeted therapies are the main modalities of treatment for breast cancer. The cardiotoxic effects of breast cancer treatment modalities are well documented12. According to the multiple hit hypotheses, patients with cancer are exposed to multiple serial or concurrent treatment-related risks which may lead to decrease in cardiovascular (CV) reserve, CVD and death13. This risk is multiplied further if the patient has underlying CVD risk factors or CVD. Cardiac complications during breast cancer treatment can lead to suboptimal treatment, impact morbidity and overall survival and also limit therapeutic options in case of a relapse. Prevention and management of cardiac complications during and after cancer treatment are a major challenge for clinicians managing breast cancer patients.

In this review, we discuss the CVD risk, cardiotoxicities of the commonly used anti-neoplastic drugs for breast cancer and radiation-induced heart disease. The early detection and prevention strategies as published in the literature are reviewed and some of the challenges pertaining to the Indian population are also highlighted.

Cardiovascular disease (CVD) in breast cancer

In postmenopausal women with hormone receptor-positive early breast cancer, the predicted 10-year CVD risk was found to be equivalent to or higher than the breast cancer recurrence risk14. The risk of CVD in women with breast cancer with low Framingham risk score was reportedly higher as compared to women without breast cancer15. The risk of CVD was also high in older women who were survivors of early breast cancer16. After adjusting for baseline CVD risk, it was found that women with breast cancer had a higher risk of CVD mortality than those without14. Cardiovascular diseases account for nearly 35 per cent of non-breast cancer mortality among breast cancer survivors who were 50 yr of age and older17. The increased risk for CVD-related mortality in breast cancer survivors is reportedly around seven years after its diagnosis17.

Age is a non-modifiable risk factor for CVD. With ageing population and improved survival due to advances in cancer treatment, the overlap of CVD and cancer is likely to increase1819. Ageing cancer survivors may be exposed to potential long-term cardiometabolic side effects of anti-cancer therapy20.

Breast cancer and CVD share a number of modifiable risk factors such as obesity, physical inactivity and smoking21. Hypertension, smoking and family history of ischaemic heart disease (IHD) are strong predictors for the development of breast cancer treatment-related cardiotoxicity222324 despite some studies suggesting that CVD risk factors before or at the time of breast cancer diagnosis may not be elevated relative to those without25. Patients who have pre-existing CVD risk factors or CVD may, however, be more likely to have worse cardiovascular outcomes after a breast cancer diagnosis26. Weight gain, decreased physical activity and decreased exercise tolerance can occur in breast cancer patients and these can further contribute to CVD27.

A comprehensive clinical evaluation should be done before starting cancer treatment to determine the baseline cardiovascular risk as per standard guidelines. This will help in choosing an optimal treatment strategy for cancer. Treatment of cardiac risk factors including hypertension, diabetes and dyslipidaemia may improve overall outcomes in cancer patients on active therapy and also cancer survivors28. In India, we have a small albeit important issue of rheumatic heart disease, and a detailed assessment is required to assess the severity of the disease.

Cardiovascular toxicity due to cancer treatment

Chemotherapy (anthracyclines, taxanes), targeted therapies (trastuzumab, lapatinib), endocrine therapy and radiotherapy are common breast cancer treatments associated with cardiotoxicity (Table). The most frequent cardiotoxicity is asymptomatic or symptomatic left ventricular dysfunction (LVD)29. Other cardiovascular toxic effects include hypertension30, thromboembolic disease31, pericardial disease32, arrhythmia3334 and myocardial ischaemia35. RT to chest can lead to coronary artery disease and fibrotic changes of the valves, pericardium and myocardium when the treatment field involves the heart36.

Table

Common cardiovascular toxicities seen in breast cancer patients

Cardiovascular toxicity	Class of drug	Drug	Incidence per cent
Left ventricular dysfunction	Anthracyclines/analogues	Doxorubicin	3-26
		Epirubicin	0.9-3.3
		Mitoxantrone	5
	Alkylating agents	Cyclophosphamide	7-28
	Anti-microtubule agents	Docetaxel	2.3-8
		Targeted therapy
	HER2 inhibitor	Trastuzumab	2-28
Myocardial ischaemia	Pyrimidine analogue	Capecitabine	3-9
		Fluorouracil	1-68
		Docetaxel	1.7
		Paclitaxel	5-47
	Arrhythmias	Bradycardia
	Anti-microtubule agents	Paclitaxel	<0.1-31
		QT prolongation
	Cyclin dependent kinase inhibitors	Ribociclib
	HER 2 inhibitor	Lapatinib
		Supraventricular tachyarrhythmias
	Anthracyclines	Doxorubicin, epirubicin
	Alkylating agents	Cyclophosphamide
	Pyrimidine analogue	Capecitabine
Venous thromboembolism	Endocrine therapy	Tamoxifen

Source: Refs 2728293031323334,36. HER, human epidermal growth factor receptor 2

Drug-induced cardiotoxicity:

Left ventricular dysfunction (LVD): This is the most common and most feared complication of breast cancer treatment and is largely associated with anthracyclines and trastuzumab.

: Anthracyclines (doxorubicin, epirubicin) are one among the most commonly used and effective drugs in breast cancer treatment. In the past 30 years, these have become an important component of adjunctive and palliative therapy for breast cancer37. Anthracyclines cause irreversible cardiac dysfunction classified as type I cardiotoxicity, and can cause permanent damage at the cellular level, leading to necrosis and apoptosis of myocardial cells followed by fibrosis38. The cellular damage was previously considered due to the formation of toxic reactive oxygen species (ROS) causing oxidative stress with lipid peroxidation of cell membranes and vacuolization of myocardial cells and ultimately cell death39. Recent studies have shown that anthracyclines also inhibit topoisomerase IIb in myocardial cells, which induces DNA double-strand breaks and activation of the apoptotic programme of the heart via mitochondriopathy and increase in ROS40.

For many decades, cancer therapy-induced cardiomyopathy was almost exclusively associated with the use of cumulative doses of anthracyclines and occurred early (within one year) or late38. Rarely, acute cardiotoxicity is also known to occur with anthracyclines which is due to inflammation causing myopericarditis41. The incidence of cardiotoxicity is three, seven and 18 per cent when patients receive a cumulative dose of doxorubicin at 400, 550 and 700 mg/m2, respectively42. However, recent studies have shown that anthracycline-induced cardiotoxicity can occur at lower cumulative doses as well43. Epirubicin, which is a structural analogue of doxorubicin, was suggested to have a lower clinical cardiotoxicity than doxorubicin38; however, a recent Cochrane database review comparing doxorubicin and epirubicin did not find a statistically significant difference in heart failure incidence between the two regimens44. The other risk factors of anthracycline-induced cardiotoxicity include age, underlying CVD, hypertension, concomitant therapy with cardiotoxic agents (cyclophosphamide, paclitaxel and trastuzumab) and mediastinal RT45.

: Trastuzumab, which is a monoclonal antibody against human epidermal growth factor receptor 2 (HER2), has improved survival in HER2-positive breast cancer by more than 30 per cent and is now a standard treatment for both HER2-positive early as well as metastatic breast cancer4647. However, trastuzumab can cause myocardial dysfunction which is not dose dependent. Myocyte dysfunction caused by trastuzumab is most likely secondary to inhibition of cardiomyocyte human ErbB2 signalling, thereby interfering with their normal growth, repair and survival48. Cardiac dysfunction of trastuzumab is typically manifested by an asymptomatic decrease in left ventricular ejection fraction (LVEF) and sometimes by clinical heart failure and is mostly reversible (type 2 cardiotoxicity)49.

The initial trials of trastuzumab were conducted in metastatic breast cancer. The reported incidence of cardiac toxicity for patients who received trastuzumab alone, trastuzumab and paclitaxel, and trastuzumab plus an anthracycline and cyclophosphamide were 3 to 7, 13, and 27 per cent, respectively50. In 2012, Moja et al51 summarized findings from eight major randomized clinical trials of trastuzumab with or without anthracyclines in early breast cancer. The relative risk of developing congestive heart failure and LVEF decline with trastuzumab was 5.11 [90% confidence interval (CI) 3.00 to 8.72] and 1.83 (90% CI 1.36 to 2.47), respectively51. Subsequent studies showed that the risk of cardiotoxicity was less with sequential anthracyclines compared to concurrent anthracyclines without compromising cancer outcomes525354. The current trastuzumab-based regimens use sequential anthracycline, and recently, no anthracycline regimens are being used in selected low-risk groups55.

Pertuzumab is a newer anti-HER2 monoclonal antibody, and addition of pertuzumab to trastuzumab are not associated with increased cardiotoxicity5657. Ado-trastuzumab emtansine which is a conjugate of trastuzumab with a microtubule inhibitor is also not reported to be associated with increased cardiotoxicity58. Lapatinib, a dual kinase inhibitor of HER2 and EGFR, is shown to be associated with low incidence of cardiac complications5933. It can cause LVD and can rarely cause QT prolongation33.

Anthracyclines and trastuzumab have a significant impact on cancer outcomes and are a part of most recommended systemic treatment regimens for breast cancer. The maximum dose of anthracyclines is 200-300 mg/m2. Sequential therapy is preferred as the risk of cardiotoxicity is high with concurrent anthracycline and trastuzumab545556.

Cardiotoxicities other than left ventricular dysfunction (LVD): Myocardial ischaemia, and occasionally myocardial infarction, is caused by 5-fluorouracil60, capecitabine61. Underlying coronary artery disease increases the risk of coronary artery spasm, but patients with normal coronaries may also develop myocardial ischaemia while being treated with these drugs. Pericarditis and pericardial effusion can be caused by anthracyclines and cyclophosphamide32. Malignancy is known to be associated with a prothrombotic milieu, which may be exacerbated by chemotherapy. Conventional chemotherapeutics, signalling inhibitors and endocrine cancer therapies can increase the risk of venous or arterial thromboembolism31. Arrhythmias either supraventricular or ventricular can frequently occur during chemotherapy. Ribociclib and lapatinib are associated with QT prolongation6062 (Table).

Baseline evaluation and risk stratification

Common clinical risk factors for cardiac dysfunction include ‘high-dose anthracycline (cumulative dose of doxorubicin >250 mg/m2), radiotherapy >30 Gy (where heart is in the treatment field), lower-dose anthracycline in combination with lower dose RT, treatment with lower-dose anthracycline or trastuzumab alone and presence of multiple CV risk factors (≥two risk factors, including smoking, hypertension, diabetes, dyslipidaemia, and obesity, during or after completion of therapy), older age (>60 yr) at cancer treatment, compromised cardiac function [e.g., borderline low LVEF (50-55%), history of myocardial infarction and moderate valvular heart disease] at any time before or during treatment’ as stated in the American Society of Clinical Oncology (ASCO) practice guidelines 201763.

As most patients with breast cancer will be receiving combination of anthracycline, trastuzumab, paclitaxel and RT, they would be at a high risk for cardiotoxicity. Currently, there are no evidence-based risk stratification score for predicting the extent of cardiotoxicity. Genetic studies have identified some single-nucleotide polymorphisms which are associated with anthracycline-induced toxicity and trastuzumab cardiotoxicity6465. Further studies are, however, required before they can be used to predict cardiotoxicity in clinical practice

Baseline evaluation and monitoring for left ventricular dysfunction: All patients should undergo a detailed clinical evaluation. A baseline electrocardiography and assessment of LVEF is recommended by all guidelines [ASCO, American Society of Echocardiography (ASE), European Association of Cardiovascular Imaging (EACVI) and European Society of Medical Oncology (ESMO)]636667 before potentially cardiotoxic treatment. Two-dimensional echocardiography (2D echo) is the most common modality for LVEF assessment. 2D echo has limitations such as inter-observer variability and low sensitivity to detect small changes in LVEF, but it is easily available and can be repeated. Some guidelines also suggest LV multigated acquisition scan as an alternative imaging modality6366; however, exposure to radiation is a concern68. LVEF assessment by 3D echo and cardiac magnetic resonance imaging (MRI) is superior to conventional 2D echo LVEF assessment by modified Simpsons method6970. Patients with normal baseline cardiac evaluation are started on the planned breast cancer treatment.

For anthracyclines, routine reassessment of LV function is recommended after a cumulative dose of 250 mg/m2 doxorubicin or its equivalent anthracycline and after approximately each additional 50 mg/m2 and at the end of therapy66. As regards, trastuzumab LVEF assessment is recommended after every three months during treatment66.

There has been a variation in the definition of cardiotoxicity over the last decade. As per the most recent ESMO guidelines 2020, ‘reduction in LVEF by ≥10 per cent from baseline to LVEF <50 per cent or institution lower limit of normal in asymptomatic patients is considered potential evidence of toxicity’67.

In case of a significant drop in LVEF, a reassessment is done after 2-3 wk. If confirmed, further anthracyclines are stopped. Patients who are symptomatic with significant decrease in LVEF should be treated with standard heart failure-specific medications as per clinical guidelines6667. In asymptomatic patients with significant decrease in LVEF, guidelines suggest to consider initiation of cardioprotective treatment [angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockade or beta-blocker]66. In case of trastuzumab, if repeat LVEF done within 3-6 wk is normal (>50%), then trastuzumab can be restarted67. The SAFE-HEART Study71 has shown that, in selected cases with asymptomatic LVD, trastuzumab can be safely continued with appropriate cardioprotective treatment.

Early detection of left ventricular dysfunction: The current universal monitoring guidelines involve change in LVEF as described above636567. A drop in LVEF indicates that myocardial dysfunction has already occurred72. A better tool is required for early detection of cardiotoxicity before LVEF decreases. The current focus of research in cardio-oncology is on early detection of LVD. Global longitudinal strain (GLS)73 and some cardiac biomarkers [troponin I, B-type natriuretic peptide (BNP), N-terminal Pro-BNP and myeloperoxidase]7475 have been studied for identifying patients at risk of cardiotoxicity.

GLS is an index of myocardial deformation and is measured by echo using 2D speckle tracking imaging76. Studies have shown that a significant decrease in GLS can predict the development of reduced LVEF in patients treated with anthracyclines and/or trastuzumab73777879. GLS is performed by a trained sonologist using advanced echo equipment and is preferable to be followed up at the same centre on the same machine. The ASE EACVI 2014 does recommend the estimation of GLS as a part of cardiac monitoring in patients receiving cardiotoxic treatment and a decrease in GLS >15 per cent compared with baseline GLS or an absolute decrease of >8 per cent is considered significant66. A meta-analysis of 21 studies, of which 13 were of breast cancer concluded that an absolute or relative decrease in GLS was predictive of chemotherapy-related cardiac dysfunction; however, due to publication bias, the cut-off could not be assessed80.

Cardinale et al74 first documented that the rise in cardiac troponins during high-dose chemotherapy can predict LVD in the future. A number of later studies, however, confirmed that an increase in plasma concentrations of cardiac troponin, especially persistent elevation, can predict the development of cardiotoxicity in patients treated with anthracyclines and trastuzumab738182. A combination of GLS and cardiac troponin estimation during treatment have been found to be better predictor of LVEF decline in the future in some studies82. Some authors have also suggested that cardioprotective treatment and frequent cardiac monitoring may be considered in high-risk patients with a decrease in GLS or increase in cardiac troponin levels6783. It is yet to be proven that a decrease in LVEF predicted by these early markers will predict major cardiac events in the future84.

Prevention of left ventricular dysfunction: Cardiotoxicity, even asymptomatic, can not only negatively impact patients’ cancer and cardiac outcome but may also limit their therapeutic options in future in case of a relapse. Other than limiting the cumulative dose of anthracyclines, currently, dexrazoxane is recommended to limit cardiotoxic effects of anthracycline chemotherapy in selected patients6385. Liposomal doxorubicin and infusion instead of boluses is also recommended in some high-risk cases6386.

To mitigate cancer therapy-induced cardiotoxicity, a number of primary preventive strategies using standard anti-heart failure medications have been and are being studied. A number of ACE inhibitors (lisinopril87, perindopril88, enalapril87), angiotensin receptor blocker (candesartan89), aldosterone antagonist (spironolactone87, eplerenone87) and beta-blockers (metoprolol89, carvedilol90, bisoprolol88, nebivolol87) have been studied. There are also ongoing studies for primary prevention (preventing cardiac damage at the time of cancer therapy) in patients with breast cancer. Only some of these drugs singly or in combination show modest clinical benefits, probably due to patient selection bias and low event rate8791. The routine use of neurohormonal antagonists for cardioprotection is not currently justified, given the marginal benefits and associated adverse events, particularly with long-term use87. Role of statins due to their pleotropic effects in the prevention of LVD is also being studied87.

There is limited evidence for use of neurohormonal drugs for prevention of cardiotoxicity in cancer patients with subclinical cardiotoxicity (decreased GLS, increased troponin I) but is recommended by some guidelines67 and should be considered on a case-to-case basis. Results of the SUCCOUR (study of role of GLS guidance of cardioprotective therapy (CPT) in improvement of cardiac function of at-risk patients undergoing potentially cardiotoxic chemotherapy) trial92 may provide some guidance regarding use of GLS in clinical practice. This study included cancer patients receiving anthracycline-based chemotherapy with at least one additional risk factor for cardiotoxicity. It compared LVEF vs. GLS-guided approach to start cardioprotective therapy during chemotherapy; the primary end point was change in 3D LVEF92. The study did not achieve the primary end point. In subgroup analysis GLS-guided CPT significantly reduced a meaningful fall of LVEF to the abnormal range. The authors concluded that the results support the use of GLS in monitoring for cancer therapy related cardiac dysfunction92.

Endocrine therapy

Endocrine therapy contributes to cardiotoxicity indirectly by influencing some risk factors for CVD. Endocrine therapy is given in ER/PR-positive patients for long duration of five years and in some cases up to 10 years, so it is important to select appropriately as per patients’ risk profile93. In comparison with tamoxifen, longer duration of aromatase inhibitors (anastrozole, letrozole) use is associated with increased risk for CVD9495. The increased risk of cardiovascular events with aromatase inhibitors relative to tamoxifen is likely the result of cardioprotective effects of the latter96. Tamoxifen use is associated with increased risk of venous thromboembolism31.

Radiotherapy-induced heart disease (RIHD)

Radiotherapy has an important role in the treatment of breast cancer in the adjuvant setting; however, there is potential for cardiac and pulmonary toxicity97. In view of proximity to the heart, those with left-sided breast cancers may be at a higher risk of developing cardiac effects98; however, some studies did not observe a significant difference in cardiac events between women receiving RT for left- vs. right-sided cancers9799100. This may probably be due to modern radiotherapy techniques that are more targeted and less cardiotoxic than older techniques101.

Various mechanisms of damage due to radiation include endothelial injury, oxidative stress and inflammation, endoplasmic reticulum and mitochondrial damage. These cause diffuse myocardial interstitial fibrosis, microcirculatory damage, leading to ischemia and fibrosis, pericardial fibrosis, valvular fibrosis and atherosclerosis102103. Clinical manifestations include coronary artery disease, cardiomyopathy, pericarditis, valvular heart disease, perfusion defects and conduction abnormalities. The time for the development of the above manifestations after radiotherapy varies from a few weeks in case of pericarditis to more than 10 yr for cardiomyopathy103.

Risk factors: The risk of developing cardiac morbidity mainly IHD in breast cancer patients treated with adjuvant radiotherapy was evaluated by Darby et al103. An important observation in this study was that there was no threshold for the development of cardiac toxicities. The authors suggested that it is important to reduce the cardiac dose during irradiation as much as possible and complete shielding of the heart should be considered wherever feasible. The risk of radiation-induced heart disease increases with higher radiotherapy dose, younger age at irradiation and the presence of conventional cardiovascular risk factors (smoking and hypertension)103104 and adjuvant treatment (anthracylines, taxanes, trastuzumab)105.

Diagnosis: There are no specific tests to diagnose radiotherapy-induced heart disease (RIHD). LVEF monitoring and structural evaluation of the heart is done by 2D echo106. In patients with suspected coronary artery disease, stress myocardial perfusion scan, and in selected cases, coronary angiogram can be done106. Cardiac MRI or computerized tomography (CT) scan can help in better cardiac structural evaluation106. The role of cardiac biomarkers and myocardial strain imaging in the early detection of radiation-induced myocardial dysfunction is still under evaluation107.

Prevention and treatment: Deep inspiration breath holding, respiratory gating, lateral decubitus position, use of modern 3D conformal radiotherapy and now proton beam therapy limit the total radiation dose, the dose per fraction and the volume of heart exposed to radiation108109110. Role of statins, colchicine and ACE inhibitors in the prevention of RIHD is also being studied111112. The treatment for RIHD is symptom based, as per standard guidelines and is not specific for it. The results of the ongoing pragmatic Randomized Trial of Proton versus Photon Therapy for Patients with Non-Metastatic Breast Cancer: A Radiotherapy Comparative Effectiveness Consortium Trial which is aimed at studying the cardiovascular morbidity and mortality will add to the current knowledge in this field113.

Cardiac monitoring in breast cancer survivors

Clinicians should focus on optimal management of CVD risks, management of known or treatment- induced CVD and risk and symptom-based cardiac monitoring. There is a variation in recommendations for monitoring of cardiac function in high-risk asymptomatic cancer survivors by different organizations. For instance, ASCO (2017) recommends cardiac imaging between 6 and 12 months, with no recommendations after this period if LVEF is normal63, and recent ESMO 202067 guidelines suggest additional screening at two-year post-treatment and possibly periodically later.

Conclusion

Overall, assessing for CVD risk pre-treatment, minimizing complications from cancer therapy and appropriate cardiac monitoring plans for early detection of potential treatment-induced cardiovascular toxicity are important for better outcomes in patients with breast cancer. Early detection of cardiac injury will facilitate early therapeutic measures, avoiding treatment delays and allows for completion of planned treatment. Cardiac morbidity is an important quality of life issue among breast cancer survivors, and it is important for clinicians to focus on the long-term cardiovascular effects of cancer treatment.

Cardio-oncology is a growing field which involves collaboration between the oncologist, cardiologist, internist and other healthcare professionals in multidisciplinary cardiovascular care of cancer patients. Involvement of cardio-oncologists is advisable from the initial assessment, monitoring, and management of cardiovascular complications of cancer therapy to survivorship, termed as cardio-oncology114. There is a need for developing the cardio-oncology programme which will allow for development of strategies for pre-treatment risk stratification, monitoring on active treatment, cardiac surveillance in cancer survivors which will be specific for Indian population, taking into consideration the cost and benefit ratio.

There is a need for development of a simple to use risk stratification tool so that the primary prevention, monitoring and surveillance are restricted to the highest risk patients, leading to optimal use of available resources. Given that there is no long-term cardiac monitoring protocol for breast cancer patients in India, a collaboration of multiple centres to document the cardiac morbidity and mortality in Indian breast cancer population receiving curative treatment will be useful. This will help in developing cost-effective monitoring protocols for Indian patients with breast cancer.