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

项目摘要 包括蒽环类药物和HER 2+靶向治疗在内的高效乳腺癌治疗方法被广泛使用 并导致了重要的肿瘤生存率的提高。然而，这些药物-阿霉素，曲妥珠单抗， （赫赛汀®）和帕妥珠单抗（Perjeta®）-具有已确定的短期心脏毒性（CTX）风险，在1- 10天内， 开始癌症治疗后2年。多柔比星诱导的CTX，主要定义为左心室射血 在10-15%的患者中，在200 mg/kg的剂量下，发生LVEF下降、心肌病和心力衰竭（HF）。 240mg/m2。HER 2+靶向治疗（如曲妥珠单抗和帕妥珠单抗）导致LVEF下降9-18% 治疗的病人。多柔比星和HER 2+靶向治疗联合与LVEF下降相关 在高达33%的个体中，2- 4%为严重的症状性HF。CTX的近期发展 导致剂量中断、治疗延迟和更差的肿瘤学结果。但长期 这些疗法的后果知之甚少，因为先前的研究报告不一致的结果， 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 癌症治疗相关CTX的长期发生率和严重程度，重点关注晚期效应。 在这项R21研究中，我们利用了前瞻性、纵向Penn CCT队列研究中的现有基础设施 (R01 HL 118018，2014-2020），入组了611例乳腺癌患者。我们将定义 长期接受蒽环类和/或HER 2+靶向癌症治疗，最长随访时间为10年 年，通过详细和全面的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例患者中随访≥5年的发生率。 随访≥5年的CCT受试者。我们还关注心脏恢复，定义为：1）部分（LVEF 增加>5%绝对点和>50%）或2）完全（LVEF增加至>55%）。目标1：全面 确定接受乳腺癌治疗的女性心脏重塑和功能的晚期变化， 蒽环类和/或HER 2+靶向治疗。在目标2中，我们将确定晚期LVEF的临床预测因素 下降和复苏。在目标3中，我们将确定超声心动图预测晚期LVEF下降的指标， 复苏通过解决这些具体目标中的每一个，我们将提供有效的发展洞察力， 心功能监测和治疗策略。乳腺癌治疗CTX 是一个严重的问题，减少这种公共卫生负担是心脏病学和 肿瘤学在本次R21中，我们将以R 01 HL 118018的早期见解和独特资源为基础， 知识转化为后期CV效应。

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.