Long Term Effects of Breast Cancer Therapy on Cardiac Remodeling and Function

项目摘要 高效的乳腺癌治疗方法，包括蒽环类药物和HER2+靶向治疗被广泛使用 并导致了重要的肿瘤学生存收益。然而，这些药物-阿霉素，曲妥珠单抗 (Herceptin®)和pertuzumab(Perjeta®)-存在短期心脏毒性(CTX)风险， 癌症治疗开始2年后。阿霉素诱导的CTX，主要由左心室射血来定义 心脏射血分数(LVEF)下降，心肌病和心力衰竭(HF)，在10%-15%的患者中发生 240 mg/m2。HER2+靶向治疗，如曲妥珠单抗和培妥珠单抗可导致左心室射血分数下降9-18% 接受治疗的病人的数量。阿霉素和HER2+联合靶向治疗与左心室射血分数下降相关 高达33%的个体，以及2-4%的严重症状性心衰患者。环磷酰胺的短期发展 结果导致剂量中断、治疗延误和更糟糕的肿瘤学结果。然而，从长远来看， 这些疗法的后果人们知之甚少，因为之前的研究报告了不一致的发现，并 受外部有效性的限制。我们的应用程序直接响应NIH PA 19-111，全面定义了 与癌症治疗相关的CTX的长期发病率和严重程度，重点放在远期效应上。 在此R21中，我们利用宾夕法尼亚州立大学CCT队列队列研究中的现有基础设施 (R01 HL 118018,2014年-2020年)，共纳入611例乳腺癌患者。我们将定义 蒽环类药物和/或HER2+的长期靶向癌症治疗，最长随访时间为10 多年来，通过详细和全面地评估心脏重塑和功能的轨迹。 我们特别关注晚期心功能不全，定义为318年≥5年随访的发生率。 随机对照研究的受试者接受≥5年随访。我们还关注心脏恢复，定义为：1)部分(LVEF 增加&gt；5%绝对点和&gt；50%)或2)Full(LVEF增加到&gt；55%)。在目标1中，我们将全面 测定乳腺癌患者心脏重塑和功能的晚期变化 蒽环类药物和/或HER2+靶向治疗。在目标2中，我们将确定晚期LVEF的临床预测因素 衰退和复苏。在目标3中，我们将确定超声心动图预测晚期LVEF下降和 恢复。通过解决这些具体目标，我们将深入了解有效的 心力衰竭高危人群的心功能监测和治疗策略。乳腺癌治疗：环磷酰胺 是一个重大问题，减少这种公共卫生负担是心脏病学和 肿瘤学。在R21中，我们将在R01 HL118018的早期洞察和独特资源的基础上获得新的 将知识转化为后期的CV效果。

Project Summary Highly effective breast cancer therapies, including anthracyclines and HER2+ targeted therapies are used widely and have led to important oncologic survival gains. However, these agents --- doxorubicin, trastuzumab (Herceptin®), and pertuzumab (Perjeta®) --- carry an established short-term cardiotoxicity (CTX) risk, within 1- 2 years after initiation of cancer therapy. Doxorubicin-induced CTX, defined primarily by left ventricular ejection fraction (LVEF) declines, cardiomyopathy, and heart failure (HF), occurs in 10-15% of patients at dosages of 240mg/m2. HER2+ targeted therapies such as trastuzumab and pertuzumab result in LVEF declines in 9-18% of treated patients. Doxorubicin and HER2+ targeted therapies in combination are associated with LVEF declines in up to 33% of individuals, and severe, symptomatic HF in 2-4%. The development of CTX in the short term results in dose interruptions, treatment delays, and worse oncologic outcomes. However, the long-term consequences of these therapies are poorly understood, as prior studies report inconsistent findings and are limited by external validity. Our application, directly responsive to NIH PA 19-111, comprehensively defines the incidence and severity of cancer-treatment related CTX in the long-term, with a focus on late effects. In this R21, we leverage the existent infrastructure within the prospective, longitudinal Penn CCT cohort study (R01 HL 118018, 2014-2020), which enrolled 611 breast cancer patients. We will define the effects of anthracyclines and/or HER2+ targeted cancer therapies in the long-term, over a maximum follow-up time of 10 years, through a detailed and comprehensive evaluation of the trajectories of cardiac remodeling and function. We focus specifically on late cardiac dysfunction, defined as the incidence at ≥5 years’ of followup in the 318 CCT participants with ≥5 years’ of followup. We also focus on cardiac recovery, defined as: 1) partial (LVEF increase >5% absolute points and >50%) or 2) full (LVEF increase to >55%). In Aim 1, we will comprehensively determine the late changes in cardiac remodeling and function in women with breast cancer receiving anthracyclines and/or HER2+ targeted therapy. In Aim 2, we will determine the clinical predictors of late LVEF declines and recovery. In Aim 3, we will determine the echocardiographic predictors of late LVEF declines and recovery. By addressing each of these Specific Aims, we will provide insight into the development of effective cardiac function monitoring and treatment strategies in this high CV risk population. Breast cancer therapy CTX is a significant problem, and decreasing this public health burden is a high priority in both cardiology and oncology. In this R21, we will build upon the early insights and unique resources of R01 HL118018 to gain new knowledge into late CV effects.