SAFE-HEaRt: Rationale and Design of a Pilot Study Investigating Cardiac Safety of HER2 Targeted Therapy in Patients with HER2-Positive Breast Cancer and Reduced Left Ventricular Function

Abstract

Background: Human epidermal growth receptor 2 (HER2) targeted therapies have survival benefit in adjuvant and metastatic HER2 positive breast cancer but are associated with cardiac dysfunction. Current U.S. Food and Drug Administration recommendations limit the use of HER2 targeted agents to patients with normal left ventricular (LV) systolic function.

Methods: The objective of the SAFE-HEaRt study is to evaluate the cardiac safety of HER2 targeted therapy in patients with HER2 positive breast cancer and mildly reduced left ventricular ejection fraction (LVEF) with optimized cardiac therapy. Thirty patients with histologically confirmed HER2 positive breast cancer (stage I-IV) and reduced LVEF (40% to 49%) who plan to receive HER2 targeted therapy for ≥3 months will be enrolled. Prior to initiation on study, optimization of heart function with beta-blockers and angiotensin converting enzyme inhibitors will be initiated. Patients will be followed by serial echocardiograms and cardiac visits during and 6 months after completion of HER2 targeted therapy. Myocardial strain and blood biomarkers, including cardiac troponin I and high-sensitivity cardiac troponin T, will be examined at baseline and during the study.

Discussion: LV dysfunction in patients with breast cancer poses cardiac and oncological challenges and limits the use of HER2 targeted therapies and its oncological benefits. Strategies to prevent cardiac dysfunction associated with HER2 targeted therapy have been limited to patients with normal LVEF, thus excluding patients who may receive the highest benefit from those strategies. SAFE-HEaRt is the first prospective pilot study of HER2 targeted therapies in patients with reduced LV function while on optimized cardiac treatment that can provide the basis for clinical practice changes. The Oncologist 2017;22:518-525 IMPLICATIONS FOR PRACTICE: Human epidermal growth receptor 2 (HER2) targeted therapies have survival benefit in adjuvant and metastatic HER2 positive breast cancer but are associated with cardiac dysfunction. To our knowledge, SAFE-HEaRt is the first clinical trial that prospectively tests the hypothesis that HER2 targeted therapies may be safely administered in patients with mildly reduced cardiac function in the setting of ongoing cardiac treatment and monitoring. The results of this study will provide cardiac safety data and inform consideration of clinical practice changes in patients with HER2 positive breast cancer and reduced cardiac function, as well as provide information regarding cardiovascular monitoring and treatment in this population.

Keywords: Breast cancer; Cardiotoxicity; Clinical trial; Molecular targeted therapy.

Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

© AlphaMed Press 2017.

Figures

Figure 1.

Study phases. Protocol‐specific screening procedures will be performed to exclude coronary ischemia or other treatable causes of cardiomyopathy. The left ventricular ejection fraction used to meet eligibility criteria for each patient will be confirmed by review of the echocardiogram at the MedStar Health Research Institute Echocardiography Core Laboratory. After completion of all screening procedures, eligible patients will proceed with treatment and ineligible patients will be considered screen failures.

Figure 2.

Cardiac monitoring. Echocardiograms will be performed at baseline and after starting HER2 targeted therapy every 6 weeks for 2 assessments and then every 3 months while in the study. All echocardiograms will be analyzed by an independent investigator at the Core Lab blinded to any clinical data and following standard procedures as recommended by the American Society of Echocardiography, and results will be used to determine when HER2 targeted therapy should be held, rechallenged, or stopped. Abbreviations: *, LVEF read by core lab; HER2, human epidermal growth receptor 2; HF, heart failure; LVEF, left ventricular ejection fraction; q3, every 3; q6, every 6.

Figure 3.

Flow diagram of cardiac medication titration. After study enrollment, cardiac treatment with beta blockers and angiotensin‐converting‐enzyme inhibitors will be started in all patients who do not have contraindications. Once a patient reaches the maximum tolerated dose of carvedilol twice daily, ramipril will be added at 1.25 mg daily and increased as tolerated up to the maximum dose of 10 mg. Abbreviations: bid, twice a day; HER2, human epidermal growth receptor 2; qd, once a day.