Preventing Anthracycline Cardiovascular Toxicity with Statins

描述(申请人提供)：这项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)乳腺癌的治疗过程中和治疗后，没有有效的一级预防基于蒽环类药物的化疗(Anth-BC)心肌损伤。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女性死亡的第二大原因。我们提供的初步数据表明，在接受Anth-BC的早期(1-6个月)就会发生心肌损伤和左心功能障碍，另外的数据表明，在接受Anth-BC期间使用3-羟基-3-甲基戊二酰辅酶-A还原酶抑制剂(或他汀类药物)可以预防心功能障碍。因此，我们建议对接受Anth-BC治疗三阴性乳腺癌的女性进行一项双盲、随机、安慰剂对照试验，每天服用40毫克阿托伐他汀。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，该成像可以在Anth-BC开始后识别左室功能障碍。我们将收集这些MRI指标，以及其他问卷和血清指标，以了解他汀类药物治疗影响左心功能的机制。我们还将监测与服用他汀类药物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。这项研究将在北卡罗来纳州、南卡罗来纳州和佛罗里达州的6个转诊站点进行，采用置换的整体招生设计，重点是招募少数族裔受试者。我们已经组建了一支经验丰富的研究团队，他们在癌症患者的试验、他汀类药物的应用和心血管相关结果的评估方面都有经验，并利用创新的磁共振成像和血清生物标记物来识别心力衰竭患者的心血管异常。独特的是，NHLBI提出的这项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学计划的努力相结合。这项合作很有吸引力，因为它结合了NHLBI确定心血管疾病的研究实力，以及NCI为乳腺癌女性患者进行随机临床试验的现有资金。在整个文档中，颜色被用来增强图和表的可读性，许多关于进行临床试验的附加细节在表2中的提案中被索引 科学计划的一部分。这项研究是使用低成本、可广泛获得的仿制药对接受乳腺癌治疗的女性进行AVOD CV损伤一级预防的第一次临床试验。如果成功，这项试验将提出一种新的治疗乳腺癌患者的范例，使用一级预防来减轻Anth-BC的心脏毒性效应，目的是提高乳腺癌女性患者的总体长期存活率。

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.