Cardioprotective strategies to prevent breast cancer therapy-induced cardiotoxicity,☆☆

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Abstract

Breast cancer is the most common malignancy affecting females, with over 260,000 new cases annually and over 3.1 million survivors in the United States alone. Exposure to potentially cardiotoxic therapies, including anthracyclines, trastuzumab, and radiation therapy, coupled with host factors, place patients at increased risk for the development of cardiovascular disease (CVD) compared to non-cancer controls. Overall survival outcomes are significantly worse in patients who develop CVD, and in certain breast cancer populations, cardiovascular death exceeds the risk of cancer death in the long-term. In order to mitigate the risk of CVD, there is a growing interest in the use of cardioprotective strategies at the time of cancer therapy initiation. In this review, we present a detailed evaluation of the evidence from recently completed as well as ongoing cardio-oncology clinical trials in pharmacologic cardioprotection in breast cancer patients. We focus primarily on the potential role of dexrazoxane, alterations in anthracycline dosing or formulation, neurohormonal antagonists, beta-blockers, and combination therapy. We also discuss ongoing studies in statin cardioprotection, radiation delivery strategies, use of risk-guided strategies and the study of specific cancer populations. We close with a discussion of the ongoing needs in the field of cardio-oncology in order to advance the clinical care of patients with rigorous, evidence-based medicine.

Introduction

Currently, there are over 3.1 million breast cancer survivors in the United States with over 260,000 new cases projected annually. Increases in breast cancer incidence, coupled with earlier detection rates and advances in cancer therapies, have resulted in a growing survivor population that is at increased risk for other comorbidities, and specifically, cardiovascular disease (CVD) [1]. Breast cancer patients have an increased incidence of CVD compared to non-cancer controls, and after development of CVD, overall survival outcomes are significantly worse [2], [3]. In large administrative database studies, the cumulative incidence of major cardiac events is reported to be 4.1% at 5 years [4]. Older age and the presence of traditional cardiovascular risk factors have also been associated with a higher rate of cardiac events, on the order of 8.9% at 5 years [4]. CVD accounts for 16.3% of deaths in breast cancer patients, exceeding the mortality due to breast cancer in those with pre-existing cardiovascular risk factors at 10 year follow-up [3]. Broadly speaking, all-cause mortality is increased 3.8-fold in cancer survivors who develop CVD compared to those who do not [2].

Moreover, during or soon after the completion of cancer therapy, the incidence of cancer therapeutics related cardiac dysfunction (CTRCD) ranges from 9 to 26% after treatment with doxorubicin, 13–17% with trastuzumab, and 27–34% with combination therapies [5], [6], [7], [8], [9]. Detailed longitudinal phenotyping in a prospective cohort study of 277 breast cancer patients treated with doxorubicin and/or trastuzumab suggest that the median left ventricular ejection fraction (LVEF) decline with these therapies is to 43% with a median time to development of significant LVEF decline of 7 months (interquartile range 4–12), requiring treatment cessation or interruption in at least 33% of these patients [5]. In a large study of 2625 patients treated with anthracyclines and followed for a median of 5.2 years, including 51% with breast cancer, 98% of the cases of cardiotoxicity were detected within 1 year after completion of chemotherapy [6].

Although there are a number of knowledge gaps in cardio-oncology, one key question is as follows: What is the role of pharmacologic cardioprotection in mitigating the risk of subsequent cardiac events in breast cancer patients treated with potentially cardiotoxic therapies, including anthracyclines, trastuzumab, and radiation therapy [2], [10]? In this review, we perform a detailed evaluation of the evidence from ongoing and recently completed cardio-oncology clinical trials in cardioprotective strategies initiated at the time of cancer therapy. We present below the various Phase I and II clinical trials that evaluate the efficacy of prophylactic therapy with neurohormonal antagonists, beta blockers, or combination therapies in breast cancer patients receiving doxorubicin and/or trastuzumab therapy; trials that use risk-guided strategies to identify subgroups who may derive the most benefit from cardioprotection; and studies that are focused on specific populations within breast cancer (Table 1).

Section snippets

Cardioprotection trials evaluating modifications in cancer therapy in breast cancer patients receiving anthracyclines

Anthracycline chemotherapy is hypothesized to cause cardiomyocyte injury through an increase in oxidative stress, potentially via the inhibition of topoisomerase-2 beta. Specifically, the quinone moiety of doxorubicin undergoes redox cycling resulting in reactive oxygen species, and additionally anthracycline-iron complexes form which create toxic hydroxyl radicals that are cytotoxic to cardiomyocytes, disrupt mitochondrial biogenesis, and damage the cell membrane [11]. Earlier studies have

Cardioprotection trials evaluating neurohormonal antagonists in breast cancer patients receiving anthracyclines

There are a number of studies ongoing evaluating the efficacy of prophylactic neurohormonal blockade with angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), or aldosterone antagonists. These medications, as well as beta-blockers, detailed below, have well-established roles in the treatment of heart failure with reduced LVEF and have been shown to promote ventricular recovery through inhibition of adverse remodeling that is mediated via adrenergic and

Cardioprotection trials evaluating beta-blockers in breast cancer patients receiving anthracyclines

In addition to neurohormonal antagonists, beta-blockers, used widely in heart failure with reduced ejection fraction, have also been studied as a potential cardioprotectant in breast cancer patients treated with anthracyclines. Beta-blockers, such as carvedilol, have been shown to possess anti-oxidant properties, providing a potential mechanistic basis for their efficacy. This may counteract the cardiotoxic reactive oxygen species generated by various breast cancer therapies (e.g.

Cardioprotection trials evaluating ACEI/ARBs and beta-blockers singly or in combination in breast cancer patients receiving anthracyclines and/or trastuzumab

Similar to attempts in patients treated with anthracyclines alone, primary prevention efforts with early beta-blocker or ACEI/ARB therapy have also shown mixed results in breast cancer patients treated with trastuzumab with or without anthracyclines. Trastuzumab is a humanized monoclonal antibody to the Her2-Neu receptor, present within approximately 25% of invasive ductal carcinomas. The Her-2 receptor is found on the cell surface of cardiomyocytes and vascular endothelial cells and is

Cardioprotection trials evaluating statins in breast cancer patients receiving anthracyclines and/or trastuzumab

Statins are widely used for their lipid-lowering effects but have also been proposed to have anti-inflammatory or pleiotropic effects that may prevent chemotherapy cardiotoxicity as well. A current Phase II randomized controlled trial is evaluating the use of statins for cardioprotection in breast cancer and lymphoma patients. The Preventing Anthracycline Cardiovascular Toxicity with Statins (NCT01988571: PREVENT) trial randomized 279 patients with early stage breast cancer or lymphoma treated

Cardioprotection trials evaluating beta-blockers in metastatic her2-positive breast cancer patients

Few trials have included patients with metastatic disease. However, these patients are often at higher risk for development of CTRCD given a higher lifetime cumulative exposure of several cardiotoxic treatments. There is an ongoing trial of prophylactic carvedilol use in the metastatic Her2-positive population receiving trastuzumab by the Southwest Oncology Group (NCT03418961: SWOG S1501). Enrolled patients must have Her2-positive metastatic disease currently receiving trastuzumab without

Cardioprotection trials evaluating radiation therapy in breast cancer patients

Radiation therapy results in various cardiotoxic effects, including valvular disease, coronary disease, heart failure, pericardial disease, and arrhythmias. Valvular heart disease develops secondary to radiation therapy induced increases in osteogenic factors; coronary artery disease results from both macrovascular lipid-rich plaque development and microvascular inflammation and endothelial cell dysfunction; and various phenotypes of cardiomyopathy, including systolic dysfunction or restrictive

Cardioprotection trials evaluating risk-guided strategies using imaging or biomarkers in breast cancer patients

While several studies have investigated the use of prophylactic cardioprotection based upon chemotherapy exposure alone (i.e., anthracyclines or trastuzumab), others have proposed risk-guided strategies targeting patients at higher risk for development of CTRCD. This has the potential to identify the subgroup of patients who will manifest the greatest magnitude of benefit from primary prevention. Several methods of risk stratification have been proposed including a troponin-guided and a

Conclusions and future directions

Breast cancer patients are at increased risk of the development of CVD compared to non-cancer controls. Age, traditional cardiovascular risk factors, and treatment-specific exposures contribute to this increased risk. Once patients develop CVD, overall survival outcomes are significantly worse, and in certain breast cancer populations, cardiovascular death exceeds cancer death rates. It is therefore imperative to identify strategies of effective cardioprotection. Data from the trials summarized

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    Funding sources: This work was supported by R01 HL 118018 (Ky).

    ☆☆

    Conflict of Interest: None

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