Multimarker Risk Prediction in Cancer Therapy Cardiotoxicity

描述（由申请人提供）：高效的癌症药物，如多柔比星和曲妥珠单抗（赫赛汀（R））广泛用于治疗许多癌症，并导致重要的生存收益。然而，这些药物在全球超过1270万人的不断增长的癌症人群中具有显著的心血管（CV）发病率和死亡率风险。在250 mg/m2剂量下，9%的患者发生多柔比星诱导的心脏毒性，一旦发作，预后特别差。多柔比星和曲妥珠单抗的组合导致心脏毒性的发生率增加18-34%，严重心力衰竭的发生率增加2- 4%。本提案的目的是开发多标志物风险预测算法，全面整合关键生物学、成像和临床数据，以识别多柔比星和多柔比星+曲妥珠单抗诱导的心脏毒性风险增加的患者。在目标1中，我们将确定多种生物标志物的水平或间隔变化是否与 与来自Penn癌症治疗毒性（CCT）队列的参与者的心脏毒性风险相关，CCT队列是一项对接受多柔比星或多柔比星+曲妥珠单抗治疗的乳腺癌患者进行的已建立的纵向前瞻性队列研究。在目标2中，我们将确定敏感的心脏功能和心肌力学超声心动图指标的基线或早期变化是否与该队列的心脏毒性风险相关。我们将利用这些新知识，并将这些发现整合到目标3中，并开发风险预测算法，以识别多柔比星和多柔比星+曲妥珠单抗诱导的心脏毒性风险增加的个体患者。我们将在Penn CCT队列中得出这些评分，并在范德比尔特（VUMC）多柔比星队列和马萨诸塞州综合医院（MGH）赫赛汀队列中外部验证我们的发现。所有分析，包括我们的风险评分，将按治疗方案（多柔比星单药和多柔比星+曲妥珠单抗）分层。通过这一全面的建议，我们将确定一个综合的多标记方法在预测癌症治疗心脏毒性的效用。通过改善个体患者的CV风险分层，我们将有助于确保安全提供高效和必要的癌症治疗;使心脏保护策略的早期机构;防止癌症治疗的中断或停止;并降低早期和晚期CV和肿瘤的发病率和死亡率。这项工作将推进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。

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.