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

乳腺癌治疗对心脏重塑和功能的长期影响

基本信息

批准号：
10475641
负责人：
Bonnie Ky
金额：
$ 20.31万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475641
关键词：
3-Dimensional Address Adjuvant Adverse effects Anthracycline Biological Biological Markers Black race Breast Cancer Patient Breast Cancer therapy Cardiac Cardiology Cardiomyopathies Cardiotoxicity Clinical Clinical Data Cohort Studies Coupled Cyclophosphamide Data Development Diabetes Mellitus Disease Dose Doxorubicin ERBB2 gene Enrollment Evaluation Funding Heart Heart failure Hypertension Incidence Individual Infrastructure Interruption Knowledge Late Effects Left Left Ventricular Ejection Fraction Long-Term Effects Malignant Neoplasms Manuscripts Measures Monitor Myocardial dysfunction Oncology Outcome Participant Patients Pertuzumab Phase Population Public Health Radiation therapy Randomized Clinical Trials Recovery Registries Reporting Resources Risk Severities Side Time Trastuzumab Treatment-Related Cancer United States National Institutes of Health Ventricular Woman cancer initiation cancer therapy clinical predictors combination cancer therapy dosage follow-up heart function insight malignant breast neoplasm mortality risk prospective risk prediction model targeted cancer therapy targeted treatment treatment strategy

项目摘要

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.

项目概要包括蒽环类药物和 HER2+ 靶向治疗在内的高效乳腺癌疗法得到广泛应用然而，这些药物——阿霉素、曲妥珠单抗，显着提高了肿瘤生存率。（赫赛汀®）和帕妥珠单抗（Perjeta®）——具有确定的短期心脏毒性（CTX）风险，在 1- 癌症治疗开始后 2 年，阿霉素诱导的 CTX，主要由左心室射血定义。剂量为 10-15% 的患者会出现左心室射血分数 (LVEF) 下降、心肌病和心力衰竭 (HF) 240mg/m2 HER2+靶向治疗（例如曲妥珠单抗和帕妥珠单抗）导致 LVEF 下降 9-18%。接受治疗的患者中阿霉素和 HER2+ 靶向治疗的联合治疗与 LVEF 下降有关。高达 33% 的个体发生这种情况，而 2-4% 的个体发生严重、有症状的心力衰竭。短期内发生 CTX。导致剂量中断、治疗延迟和更差的肿瘤学结果。人们对这些疗法的后果知之甚少，因为之前的研究报告的结果不一致，并且受外部有效性的限制，我们的应用程序直接响应 NIH PA 19-111，全面定义了长期癌症治疗相关 CTX 的发生率和严重程度，重点关注后期影响。在此 R21 中，我们利用前瞻性宾夕法尼亚大学纵向 CCT 队列研究中的存在基础设施（R01 HL 118018，2014-2020），招募了 611 名乳腺癌患者，我们将定义其影响。长期蒽环类药物和/或 HER2+ 靶向癌症治疗，最长随访时间超过 10 年多年来，通过对心脏重塑和功能的轨迹进行详细而全面的评估。我们特别关注晚期心功能障碍，定义为 318 项研究中≥5 年随访时的发生率随访时间≥5 年的 CCT 参与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增加到> 55％）在目标1中，我们将全面。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。在目标 3 中，我们将确定晚期 LVEF 下降和恢复的超声心动图预测因子。通过解决每个具体目标，我们将深入了解有效性的发展。高心血管风险人群的心脏功能监测和治疗策略乳腺癌治疗 CTX。是一个重大问题，减轻这一公共卫生负担是心脏病学和医学界的首要任务在 R21 中，我们将基于 R01 HL118018 的早期见解和独特资源来获得新的知识。了解晚期 CV 效应。