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    Research Grants Awarded

    Randomized Trial Of Enalapril Vs. Usual Care To Prevent The Development Of Cardiotoxicity In High-Risk Patients Receiving An Anthracycline Or Trastuzumab

    Grant Mechanism:
    Postdoctoral Fellowships

    Scientific Abstract:
    I. BACKGROUND: The use of anthracycline and trastuzumab-based systemic therapy has lead to dramatic decreases in mortality from breast cancer. One limitation of both of these therapies, however, is cardiotoxicity. Since the first widespread recognition in the 1970s of anthracycline-mediated cardiotoxicity, regimens have been modified to maximize anti-neoplastic effects while limiting cardiotoxicity. Despite dose-reductions, the incidence of anthracycline cardiotoxicity remains substantial ? as high as 16.2% at a doxorubicin cumulative dose of 300 mg/m2 and 65.4% at a cumulative dose of 550 mg/m2. Most prior efforts to limit toxicity with structural modifications (e.g. epirubicin) have been disappointing, and the addition of the cardioprotective agent dexrazoxane has been associated with less tumor response. The risk of cardiotoxicity associated with trastuzumab is similarly problematic. In a large North American adjuvant trastuzumab trial, 7.5% of patients were ineligible to receive trastuzumab due to cardiotoxicity that developed during the anthracycline-based portion of the protocol treatment. Among patients who did receive trastuzumab, 3.9% developed severe symptomatic heart failure and overall approximately 20% had to discontinue trastuzumab prematurely due to symptomatic or asymptomatic cardiotoxicity. Recent studies have demonstrated that elevations of cardiac troponin in the serum are extremely predictive of the development of chemotherapy-associated cardiomyopathy. Specifically, in a population of 703 patients receiving high-dose chemotherapy, a rise in troponin at any time during chemotherapy was 100% sensitive for detecting subsequent cardiotoxicity. Furthermore, when troponin-positive patients were randomized to receive the angiotensin-converting enzyme inhibitor enalapril, the incidence of cardiotoxicity was reduced from 43% to 0%. These findings provide the rationale for investigating the ability of the angiotensin-converting enzyme inhibitor enalapril to prevent the development of cardiotoxicity in patients receiving standard-dose cardiotoxic treatment for breast cancer. II. HYPOTHESIS & OBJECTIVES: The hypothesis of this study is that enalapril will prevent the development of cardiotoxicity in high-risk patients receiving standard-dose anthracycline or trastuzumab therapy. A further hypothesis is that elevations in cardiac biomarkers will predict which patients are at high-risk of developing cardiotoxicity in this clinical setting. The primary and secondary objectives of this study, which have been designed to test these hypotheses, are as follows: 1. Primary Objective: To determine the effect of enalapril treatment on the development of left ventricular systolic dysfunction. 2. Secondary Objectives: a. To determine the absolute change in left ventricular ejection fraction, and b. The rate of development of symptomatic (New York Heart Association Class II-IV) heart failure among patients treated with enalapril vs. usual care; c. To determine the incidence of troponin-positivity and rate of development of left ventricular dysfunction among troponin-positive patients receiving standard-dose anthracycline or trastuzumab therapy for breast cancer. d. To determine if an increase in serum B-type natriuretic peptide is associated with the development of left ventricular dysfunction in troponin-positive patients. III. EXPERIMENTAL PLAN: Patients undergoing breast cancer treatment with an anthracycline or trastuzumab will be eligible for this protocol. An echocardiogram, serum troponin I and serum B-type natriuretic peptide will be obtained at baseline. Serial troponin I measurements will be performed with each cycle of chemotherapy or trastuzumab treatment. Subjects will be randomized within 2 weeks of developing a detectable troponin (greater than or equal to 0.1 ng/ml) at any time after beginning chemotherapy or trastuzumab, provided that their left ventricular ejection fraction is within normal limits. Patients will be randomized to treatment with the angiotensin-converting enzyme enalapril or usual care. Troponin I and B-type natriuretic peptide levels will be drawn at the time of randomization and 1, 3, 6 and 12 months after randomization. Patients will have highly sensitive left ventricular ejection fraction assessments at these time points using cardiac magnetic resonance imaging (MRI). The primary endpoint of the study is the development of left ventricular dysfunction, defined as a decline in ejection fraction from baseline of greater than 10 percentage points to below normal. A sample size of 276 patients with 69 patients undergoing randomization will have 80% power to detect a difference between the null and alternative hypotheses when a two-sided alpha level is used. IV. ANTICIPATED SIGNIFICANCE: The goal of this study is to prevent the development of cardiotoxicity in patients receiving anthracycline or trastuzumab therapy for breast cancer. If this strategy is effective, it will have a major clinical impact for patients undergoing breast cancer therapy. Prevention of cardiotoxicity will decrease the morbidity and mortality associated with breast cancer therapy and enable more breast cancer patients to receive optimal doses of anthracycline or trastuzumab therapy leading to better patient outcomes.

    Lay Abstract:
    I. BACKGROUND: The use of anthracycline (e.g. Adriamycin or doxorubicin) and trastuzumab (Herceptin)-based therapy has lead to dramatic decreases in death from breast cancer. One limitation of both of these treatments, however, is toxicity to the heart (cardiotoxicity). Since the first widespread recognition in the 1970s of anthracycline cardiotoxicity, regimens have been modified to maximize anti-cancer effects while limiting toxicity to the heart. Despite dose-reductions, the incidence of anthracycline cardiotoxicity remains substantial and this continues to be one of the greatest long-term risks to women undergoing breast cancer treatment. Most prior efforts to limit toxicity by altering the structure of the compound have been disappointing, and the addition of a medication to protect the heart, dexrazoxane, has been associated with less tumor response. The risk of cardiotoxicity associated with trastuzumab is similarly problematic. In a large North American trastuzumab trial for women with early stage HER2-positive breast cancer, 7.5% of patients were unable to receive trastuzumab due to cardiotoxicity that developed during the anthracycline portion of the protocol treatment. Among patients who did receive trastuzumab, 3.9% developed severe symptomatic heart failure and overall approximately 20% had to discontinue trastuzumab prematurely due to some form of cardiotoxicity. Recent studies have demonstrated that elevations of blood levels of cardiac markers released from dying or injured heart cells, such as troponin, can predict which patients are at risk of developing chemotherapy-associated heart damage. Specifically, in a population of 703 patients receiving high-dose chemotherapy, a rise in troponin at any time during chemotherapy identified all women who subsequently developed cardiotoxicity, with no patients developing this complication when the troponin level remained undetectable. Furthermore, when troponin-positive patients were randomly assigned to treatment with the medication enalapril, cardiotoxicity was prevented in 100% of patients who received the drug, whereas those troponin-positive patients who were assigned to placebo treatment developed cardiotoxicity 43% of the time. These findings provide the rationale for investigating the ability of enalapril to prevent cardiotoxicity in women receiving standard-dose treatment for breast cancer. II. HYPOTHESIS & OBJECTIVES: The hypothesis of this study is that enalapril will prevent the development of cardiotoxicity in high-risk patients receiving breast cancer treatment with an anthracycline or trastuzumab. A further hypothesis is that elevations in heart-specific markers in the blood will be useful in identifying which patients are at high-risk of developing heart damage. The primary and secondary objectives of this study, which have been designed to test these hypotheses, are as follows: 1. Primary Objective: To determine the effect of enalapril treatment on the development of cardiotoxicity. 2. Secondary Objectives: a. To determine the absolute change in heart?s contractility (ejection fraction) from baseline, and b. The rate of development of symptomatic heart failure among patients treated with enalapril vs. usual care; c. To determine how many patients receiving an anthracycline or trastuzumab will develop an elevation in the blood marker troponin and how many in that group actually develop abnormal heart function; d. To determine if an increase in the blood marker B-type natriuretic peptide is associated with the development of cardiotoxicity in patients with detectable blood levels of troponin. III. EXPERIMENTAL PLAN: Patients undergoing breast cancer treatment with an anthracycline or trastuzumab will be eligible for this protocol. An echocardiogram (test to assess the heart?s contractility) and blood tests to measure troponin and B-type natriuretic peptide will be obtained at study entry. Troponin measurements will be performed with each cycle of chemotherapy or trastuzumab treatment. Participants will be randomized within 2 weeks of developing a detectable troponin level at any time after beginning chemotherapy or trastuzumab. Only patients with normal heart contractility at this time will be randomized. Those patients with abnormal contractility will be referred to a cardiologist for appropriate management. Patients will be randomized to treatment with the enalapril or usual care. Troponin and B-type natriuretic peptide levels will be drawn at randomization and 1, 3, 6 and 12 months after randomization. Patients will have highly accurate measurements of heart contractility at these time points using cardiac magnetic resonance imaging (MRI). The primary endpoint of this study is the development of cardiotoxicity among those patients treated with enalapril versus usual care. IV. ANTICIPATED SIGNIFICANCE: Cardiotoxicity can compromise the effectiveness of breast cancer treatment and may seriously limit the treatment options for women with relapsed disease. The goal of this study is to prevent this toxicity in patients receiving anthracycline or trastuzumab therapy for breast cancer. If this strategy is effective, it will have a major impact for patients undergoing breast cancer therapy. Prevention of cardiotoxicity will decrease the risk of serious complications and death from breast cancer therapy and enable more breast cancer patients to receive optimal doses of anthracycline or trastuzumab therapy leading to better patient outcomes and increased cure rates.