Multimarker Risk Prediction in Cancer Therapy Cardiotoxicity

描述(申请人提供)：阿霉素和曲妥珠单抗(Herceptin(R))等高效抗癌药物被广泛用于多种癌症的治疗，并带来了重要的存活率提高。然而，这些药物在全球超过1270万人的不断增长的癌症人口中存在心血管(CV)发病率和死亡率的显著风险。阿霉素引起的心脏毒性发生在9%的治疗患者中，剂量为250 mg/m2，一旦发生，预后特别差。阿霉素和曲妥珠单抗联合使用会导致心脏毒性增加18-34%，严重心力衰竭的发生率增加2-4%。这项建议的目的是开发多标记物风险预测算法，综合整合关键的生物学、影像和临床数据，以识别阿霉素和阿霉素+曲妥珠单抗诱导的心脏毒性风险增加的患者。在目标1中，我们将确定多个生物标志物的水平或间隔变化是否相关 在宾夕法尼亚大学癌症治疗心脏毒性(CCT)队列参与者中存在心脏毒性风险的情况下，对接受阿霉素或阿霉素+曲妥珠单抗治疗的乳腺癌患者进行了一项已建立的纵向前瞻性队列研究。在目标2中，我们将确定心脏功能和心肌力学的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相关。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来识别阿霉素和阿霉素+曲妥珠单抗导致心脏毒性风险增加的个别患者。我们将在宾夕法尼亚大学CCT队列中得出这些分数，并在Vanderbilt(VUMC)阿霉素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，将根据治疗方案(单独使用阿霉素和阿霉素+曲妥珠单抗)进行分层。通过这项全面的提案，我们将确定综合多标记物方法在预测癌症治疗心脏毒性方面的效用。通过改进单个患者的心血管风险分层，我们将有助于确保高效和必要的癌症治疗的安全提供；使心脏保护策略得以及早制定；防止癌症治疗的中断或中断；以及降低早期和晚期心血管疾病以及肿瘤的发病率和死亡率。这项工作将促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.