Preventing Anthracycline Cardiovascular Toxicity with Statins

描述（由申请人提供）：本申请解决了一个被忽视的主要问题：在三阴性（雌激素、孕激素、HER-2受体阴性）乳腺癌治疗期间和之后，蒽环类化疗（Anth-bC）心肌损伤没有有效的一级预防。今天，心血管（CV）事件，包括心肌损伤引起的心力衰竭和左心室（LV）功能障碍，是接受乳腺癌辅助治疗的妇女死亡的第二大原因。我们提供的初步数据表明，心肌损伤和左室功能障碍发生在接受Anth-bC的早期（1至6个月），另外的数据表明，使用3-羟基-3-甲基戊二酰辅酶- a还原酶抑制剂（或他汀类药物）治疗可以预防接受Anth-bC期间的心功能障碍。因此，我们建议对接受Anth-bC治疗三阴性乳腺癌的妇女进行双盲、随机、安慰剂对照试验，每天40mg阿托伐他汀。我们的主要结果是通过一种创新形式的磁共振成像（MRI）获得的，该成像可以识别Anth-bC启动后的左室功能障碍。我们将收集这些MRI测量结果以及其他问卷和血清测量结果，以了解他汀类药物治疗影响左室功能的机制。我们还将监测与他汀类药物管理相关的潜在副作用的发生，包括糖尿病、认知能力下降、肌痛和肌酸激酶升高。该研究将在北卡罗莱纳州、南卡罗来纳州和佛罗里达州的6个推荐站点进行，采用分组招生设计，重点招募少数民族受试者。我们汇集了一组有经验的研究人员，他们在癌症患者的试验、他汀类药物的使用和评估心血管相关结果，以及利用创新的MRI和血清生物标志物来识别心力衰竭患者的心血管异常方面具有丰富的经验。独特的是，这项NHLBI提议的多中心研究将与国家癌症研究所支持的维克森林研究基地临床社区肿瘤项目相结合。这项合作很有吸引力，因为它结合了NHLBI确定CV疾病的调查优势和NCI的现有资金，在乳腺癌女性中进行随机临床试验。在整个文档中，使用了颜色来增强图和表的可读性，并且在表2的建议中索引了许多关于临床试验进行的附加细节

DESCRIPTION (provided by applicant): 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.