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：在治疗三阴性（雌激素、孕酮、HER-2受体阴性）乳腺癌期间和之后，对基于蒽环类药物的化疗（Anth-bC）心肌损伤没有有效的一级预防。如今，心血管（CV）事件（包括心肌损伤和左心室（LV）功能障碍引起的心力衰竭）是接受乳腺癌辅助治疗的女性死亡的第二大原因。我们提供的初步数据表明，心肌损伤和LV功能障碍发生后，早期接收Anth-bC（1至6个月），和额外的数据表明，3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（或他汀类药物）治疗预防心功能障碍期间接收Anth-bC。因此，我们建议在接受Anth-bC治疗三阴性乳腺癌的女性中进行一项每天40 mg阿托伐他汀的双盲、随机、安慰剂对照试验。我们的主要结局是通过一种创新形式的磁共振成像（MRI）来识别Anth-bC启动后的LV功能障碍。我们将收集这些MRI测量值沿着以及其他问卷和血清测量值，以了解他汀类药物治疗影响LV功能的机制。我们还将监测与他汀类药物给药相关的副作用的潜在发生情况，包括糖尿病、认知能力下降、肌痛和肌酸激酶升高。本研究将在北卡罗来纳州、南卡罗来纳州和佛罗里达的6家转诊研究中心进行，采用置换区组入组设计，重点是招募少数族裔受试者。我们已经组建了一个有经验的研究者小组，他们在癌症患者试验、他汀类药物给药和评估CV相关结局以及利用创新的MRI和血清生物标志物识别心力衰竭患者的CV异常方面具有丰富的经验。独特的是，这项NHLBI提出的多中心研究将联合收割机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学计划的努力相结合。这种合作是有吸引力的，因为它结合了NHLBI的调查优势，以确定CV疾病与NCI的现有资金，在乳腺癌妇女中进行随机临床试验。在整个文件中，使用颜色来增强图和表的可读性，并且在表2中的提议中索引了关于临床试验实施的许多附加细节 的科学计划。这项研究代表了第一个一级预防的临床试验，以避免CV损伤的妇女治疗乳腺癌使用低成本，广泛使用的通用疗法。如果成功，这项试验将提出一种新的模式，在乳腺癌患者的管理中使用一级预防，以减轻Anth-bC的心脏毒性作用，以提高乳腺癌女性的总体长期生存率。

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.