Multimarker Risk Prediction in Cancer Therapy Cardiotoxicity

癌症治疗心脏毒性中的多标志物风险预测

• 批准号: 8815198
• 负责人: Bonnie Ky
• 金额: $ 74.77万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8815198
• 关键词: Academic Medical Centers; Adverse effects; Algorithms; Antineoplastic Agents; Biological Markers; Blood Vessels; Blood specimen; Breast Cancer Patient; Cancer Patient; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Cardiovascular system; Cell Death; Cessation of life; Clinical; Clinical Data; Clinical Markers; Cohort Studies; Coupling; Data; Development; Disease; Doxorubicin; Early identification; Echocardiography; Ensure; Functional disorder; General Hospitals; Health; Heart; Heart Transplantation; Heart failure; Image; Incidence; Individual; Inflammation; Injury; Institution; Interruption; Knowledge; Left Ventricular Ejection Fraction; Life; Malignant Neoplasms; Massachusetts; Measures; Mechanics; Methods; Morbidity - disease rate; Myocardial; Myocardial dysfunction; Neuregulins; Outcome; Oxidative Stress; Participant; Pathway interactions; Patients; Pattern; Phase; Phenotype; Physiological; Population; Probability; Research Infrastructure; Risk; Roche brand of trastuzumab; Sensitivity and Specificity; Signal Transduction; Stratification; Stress; Structure; Testing; Time; Trastuzumab; Treatment Protocols; Ventricular; Work; cancer therapy; cardiovascular risk factor; cell injury; chemotherapy; cohort; dosage; experience; high risk; imaging biomarker; improved; insight; mortality; multidisciplinary; outcome forecast; pre-clinical; prevent; prospective; tool

DESCRIPTION (provided by applicant): Highly effective cancer drugs, such as doxorubicin and trastuzumab (Herceptin(R)) are used widely in the treatment of many cancers and have led to important survival gains. However, these agents carry a significant risk of cardiovascular (CV) morbidity and mortality in a growing cancer population of over 12.7 million individuals worldwide. Doxorubicin-induced cardiotoxicity occurs in 9% of treated patients at dosages of 250mg/m2, and carries a particularly poor prognosis once it ensues. The combination of doxorubicin and trastuzumab result in an increased incidence of cardiotoxicity of 18-34% and severe heart failure in 2-4%. The objective of this proposal is to develop multimarker risk prediction algorithms which comprehensively integrate key biologic, imaging, and clinical data to identify patients at increased risk for doxorubicin- and doxorubicin + trastuzumab-induced cardiotoxicity. In Aim 1, we will determine if the level of or interval change in multiple biomarkers is associated with the risk of cardiotoxicity in participants from the Penn Cardiotoxicity of Cancer Therapy (CCT) cohort, an established longitudinal prospective cohort study of breast cancer patients undergoing treatment with doxorubicin or doxorubicin + trastuzumab. In Aim 2, we will determine if baseline or early changes in sensitive echocardiographic measures of cardiac function and myocardial mechanics are associated with the risk of cardiotoxicity in this cohort. We will leverage this new knowledge and integrate these findings in Aim 3, and develop risk prediction algorithms to identify individual patients at increased risk for doxorubicin and doxorubicin + trastuzumab-induced cardiotoxicity. We will derive these scores in the Penn CCT cohort, and externally validate our findings in the Vanderbilt (VUMC) Doxorubicin cohort and Massachusetts General Hospital (MGH) Herceptin cohorts. All analyses, including our risk scores, will be stratified by treatment regimen (doxorubicin alone and doxorubicin + trastuzumab). Through this comprehensive proposal, we will define the utility of an integrated multimarker approach in predicting cancer therapy cardiotoxicity. By improving the CV risk stratification of individual patients, we will help ensure the safe delivery of highly effective an necessary cancer therapies; enable the early institution of cardioprotective strategies; prevent the interruption or discontinuation of cancer therapy; and reduce early and late CV and oncologic morbidity and mortality. This work will advance our biologic and physiologic understanding of this disease and accelerate the discovery of strategies to help prevent and treat cancer therapy cardiotoxicity.

描述（由申请人提供）：高效的癌症药物，例如阿霉素和曲妥珠单抗（Herceptin（r））被广泛用于许多癌症的治疗，并带来了重要的生存率。但是，这些药物在全球不断增长的癌症人群中，有大量的心血管（CV）发病率和死亡率的风险很高。阿霉素诱导的心脏毒性发生在9％的治疗患者中，剂量为250mg/m2，一旦随之而来，预后也特别较差。阿霉素和曲妥珠单抗的结合导致心脏毒性的发病率增加了18-34％，心力衰竭的发生率增加了2-4％。该提案的目的是开发多标记风险预测算法，该算法全面整合了关键的生物学，成像和临床数据，以识别有阿霉素 - 阿霉素和阿霉素 + trastuzumab诱导的心脏毒素风险增加的患者。在AIM 1中，我们将确定多个生物标志物的间隔变化水平或间隔是相关的 癌症治疗（CCT）队列的参与者有心脏毒性的风险，这是一项已建立的纵向前瞻性队列研究，对接受阿霉素或阿霉素 + trastuzumab治疗的乳腺癌患者。在AIM 2中，我们将确定心脏功能和心肌力学敏感超声心动图测量的基线或早期变化是否与该队列中心脏毒性的风险有关。我们将利用这一新知识并将这些发现整合到AIM 3中，并开发风险预测算法，以鉴定有阿霉素和阿霉素 +曲妥珠单抗诱导的心脏毒性风险增加的个别患者。我们将在Penn CCT队列中得出这些分数，并在外部验证我们在Vanderbilt（VUMC）阿霉素队列和马萨诸塞州综合医院（MGH）赫斯蒂汀队列中的发现。所有分析，包括我们的风险评分，都将通过治疗方案（单独的阿霉素和阿霉素 +曲妥珠单抗）进行分层。通过这项全面的建议，我们将定义一种综合多标记方法在预测癌症治疗心脏毒性方面的实用性。通过改善各个患者的简历风险分层，我们将帮助确保安全提供高效的癌症疗法；启用早期的心脏保护策略机构；防止癌症治疗的中断或中断；并降低早期和晚期的简历以及肿瘤学的发病率和死亡率。这项工作将提高我们对这种疾病的生物学和生理学理解，并加速发现有助于预防和治疗癌症治疗心脏毒性的策略。