This application addresses a neglected major problem: no effective primary prevention for anthracycline- based chemotherapeutic (Anth-bC) myocardial injury experienced during and after treatment for triple negative (estrogen, progesterone, HER-2 receptor negative) breast cancer. Today, cardiovascular (CV) events including heart failure due to myocardial injury and left ventricular (LV) dysfunction are the second leading cause of mortality in women receiving adjuvant therapy for breast cancer. We provide preliminary data indicating that myocardial injury and LV dysfunction occur early upon receipt of Anth-bC (1 to 6 months), and additional data suggesting that treatment with 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors (or statins) prevents cardiac dysfunction during receipt of Anth-bC. Accordingly, we propose to conduct a double blind, randomized, placebo controlled trial of 40 mg per day of atorvastatin in women receiving Anth-bC for triple negative breast cancer. Our primary outcomes are acquired with an innovative form of magnetic resonance imaging (MRI) that identifies LV dysfunction after initiation of Anth-bC. We will collect these MRI measures along with other questionnaire derived and serum measures that will provide understanding of the mechanisms by which statin therapy influences LV function. We will also monitor for the potential occurrence of side effects related to the administration of statins including diabetes, cognitive decline, myalgias and creatine kinase elevations. The study will be conducted at 6 referral sites within North Carolina, South Carolina, and Florida using a permuted block enrollment design with emphasis on recruiting minority subjects. We have assembled an accomplished group of investigators with experience in the conduct of trials of patients with cancer, the administration of statins and assessing CV-related outcomes, and the utilization of innovative MRI and serum biomarkers to identify CV abnormalities in heart failure patients. Uniquely, this NHLBI proposed multi-center study will combine with efforts from the National Cancer Institute supported Wake Forest Research Base Clinical Community Oncology Program. This collaboration is attractive as it combines the investigative strengths of the NHLBI to ascertain CV disease with the existing funding from the NCI to conduct randomized clinical trials in women with breast cancer. Throughout the document, color is used to enhance the readability of Figures and Tables, and many of the additional details regarding conduct of a clinical trial are indexed within the proposal in Table 2 of the scientific plan. This study represents the first clinical trial of primary prevention to avod CV injury in women treated for breast cancer using a low-cost, widely available generic therapy. If successful, this trial will suggest a new paradigm in the management of breast cancer patients using primary prevention to attenuate the cardiotoxic effects from Anth-bC for the purpose of improving the overall long-term survival of women with breast cancer.
Cardiovascular (CV) events including heart failure with impaired left ventricular (LV) function are the second leading cause of morbidity and mortality in breast cancer survivors treated with anthracycline-based chemotherapy (Anth-bC). We provide results from observational pilot studies indicating that primary prevention with HMG-CoA reductase inhibitors or statins (medications typically used to treat hypercholesterolemia, but which also reduce Anth-bC related myocellular oxidative and nitrosative stress) preserves LV function in women receiving adjuvant chemotherapy. Accordingly, we propose to conduct a double-blind, randomized, placebo controlled trial to determine if primary prevention with atorvastatin (a generic statin) preserves LV function that contributes to and serves as a marker for future CV events after Anth-bC.
|Jordan, Jennifer H; D'Agostino Jr, Ralph B; Hamilton, Craig A et al. (2014) Longitudinal assessment of concurrent changes in left ventricular ejection fraction and left ventricular myocardial tissue characteristics after administration of cardiotoxic chemotherapies using T1-weighted and T2-weighted cardiovascular magnetic resonan Circ Cardiovasc Imaging 7:872-9|
|Kongbundansuk, Suwat; Hundley, W Gregory (2014) Noninvasive imaging of cardiovascular injury related to the treatment of cancer. JACC Cardiovasc Imaging 7:824-38|