Biomarkers of oxidative stress, inflammation, and cardiac damage as markers of long-term radiation-induced cardiovascular outcomes in breast cancer

氧化应激、炎症和心脏损伤的生物标志物作为乳腺癌长期辐射诱发心血管结局的标志物

• 批准号: 10217251
• 负责人: Kerryn W Reding
• 金额: $ 15.8万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217251
• 关键词: 8-hydroxy-2' -deoxyguanosine; Acute; Address; Adjuvant Therapy; Adverse effects; Aftercare; Ancillary Study; Attention; Biological Markers; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer survivor; C-reactive protein; Cancer Survivor; Cancer Survivorship; Cardiac; Cardiotoxicity; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Characteristics; Chronic; Collection; Control Groups; Coronary; Coronary heart disease; Data; Data Set; Detection; Development; Disease; Disease Outcome; Enzyme-Linked Immunosorbent Assay; Event; Exposure to; Fibrosis; Future; GDF15 gene; Handedness; Heart; Heart Valve Diseases; Heart failure; Individual; Inflammation; Interleukin-6; Intervention; Lead; Left; Life; Literature; Logistic Regressions; Longevity; Malignant Neoplasms; Methods; Monitor; Morbidity - disease rate; Myocardial Infarction; Myocardial Ischemia; Myocarditis; National Heart, Lung, and Blood Institute; Nested Case-Control Study; Oncology; Outcome; Oxidative Stress; Participant; Pathway interactions; Patients; Pericardial body location; Peroxidases; Pharmaceutical Preparations; Play; Prospective cohort study; Radiation; Radiation therapy; Research; Risk; Role; Sampling; Serum; Side; Specimen; Survival Rate; Testing; Time; Transforming Growth Factor beta; Translating; Troponin I; United States; Woman; Women' s Health; Work; acute coronary syndrome; adjudicate; adjudication; base; breast cancer diagnosis; cardioprotection; cardiovascular disorder risk; case control; chemotherapy; clinical practice; cohort; design; experience; follow-up; heart damage; high risk; improved; inclusion criteria; malignant breast neoplasm; mortality; neglect; post gamma-globulins; programs; prospective; radiation risk; research study; risk prediction model; risk stratification; targeted biomarker

Background: Survival rates from breast cancer have improved; however, many breast cancer survivors experience treatment-induced adverse effects including late-onset cardiovascular disease due to radiation therapy. Radiation-induced cardiovascular disease (RICVD), which can appear 5 – 10 or more years after radiation, is a substantial cause of increased morbidity and mortality among breast cancer survivors. Currently, it is not known how to best identify individuals who will develop RICVD, as RICVD often occurs years after treatment and is often neglected in research due to the expense of following participants long-term. As a result, the primary body of literature in cardio-oncology examines short-term cardiac outcomes, mainly related to chemotherapy. Based on these studies, biomarkers of cardiac damage and inflammation have been identified as acute contributors of cardiotoxicity. While RICVD likely shares some pathways of chemotherapy-induced CVD, this has not been definitively tested in research studies. Pathways, such as oxidative stress and fibrosis, are thought to play a large role in the development of RICVD. Purpose: The purpose of this study is to examine post-treatment serum biomarkers of oxidative stress (8-OH-dG, MPO), fibrosis (TGF-B), cardiac damage (TnI-I, cystatin-C), and inflammation (IL-6, GDF-15, CRP) in the development of long-term RICVD in breast cancer survivors treated with radiation and to stratify by right- vs. left-sided radiation. Specifically, we aim to 1) to examine the risk of RICVD and CVD death in breast cancer survivors treated with radiation (vs. controls) associated with biomarkers (post-treatment), 2) to examine the risk of RICVD and CVD death (vs. controls) comparing breast cancer survivors treated with right-sided radiation vs. left-sided radiation, and 3) to examine the association of post-treatment biomarkers in the risk of RICVD and CVD death (vs. controls) among breast cancer survivors, stratified by right- vs. left-sided radiation. Methods: We propose a nested, case-control design within the Women's Health Initiative Life and Longevity After Cancer (WHI LILAC), a national, prospective, cohort study. Inclusion criteria are: 1) serum sample available at WHI baseline and year 3 and 2) a breast cancer diagnosis and radiation treatment between the two serum collection time points. All biomarkers will be assessed at both timepoints using ELISA. Women with an adjudicated heart failure, myocardial infarction, coronary coronary heart disease, or other cardiovascular death outcome occurring post-breast cancer will constitute the case group (n = 56) while women without a RICVD outcome will constitute the control group (n = 128). Logistic regression will be used. Summary: This study leverages the WHI dataset, which is an excellent cohort to address the identified research gaps, given the availability of biospecimens previously collected from participants with nearly 20 years of outcome follow-up. This study is significant as it will investigate biomarkers targeting multiple, relevant pathways potentially associated with RICVD, which could be used in future studies to improve the identification and prediction of RICVD in cancer survivors.

背景：乳腺癌的存活率有所提高；然而，许多乳腺癌幸存者 经历治疗引起的不良反应，包括由于辐射引起的迟发性心血管疾病 治疗。辐射诱发的心血管疾病 (RICVD)，可能在 5 – 10 或更长时间后出现 辐射是乳腺癌幸存者发病率和死亡率增加的一个重要原因。现在， 目前尚不清楚如何最好地识别将患 RICVD 的个体，因为 RICVD 常常在数年后发生 由于长期跟踪参与者的费用，治疗中经常被忽视。因此， 心脏肿瘤学的主要文献检查短期心脏结果，主要与 化疗。基于这些研究，已经确定了心脏损伤和炎症的生物标志物 作为心脏毒性的急性贡献者。虽然 RICVD 可能与化疗诱导的某些途径有共同之处 CVD，这尚未在研究中得到明确测试。途径，例如氧化应激和纤维化， 被认为在 RICVD 的发展中发挥着重要作用。目的：本研究的目的是检验 治疗后氧化应激（8-OH-dG、MPO）、纤维化（TGF-B）、心脏损伤（TnI-I、 胱抑素-C）和炎症（IL-6、GDF-15、CRP）在乳腺癌长期 RICVD 发展中的作用 幸存者接受放射治疗，并通过右侧与左侧放射进行分层。具体来说，我们的目标是 1) 检查接受放射治疗的乳腺癌幸存者的 RICVD 和 CVD 死亡风险（与对照相比） 与生物标志物（治疗后）相关，2) 检查 RICVD 和 CVD 死亡风险（与对照相比） 比较接受右侧放疗与左侧放疗的乳腺癌幸存者，以及 3) 检查 乳腺治疗后生物标志物与 RICVD 和 CVD 死亡风险（与对照相比）的关联 癌症幸存者，按右侧与左侧放射进行分层。方法：我们提出了一种嵌套的病例对照设计 妇女健康倡议“癌症后的生命和长寿”(WHI LILAC)，这是一个全国性、前瞻性的队列 学习。纳入标准为：1) 在 WHI 基线和第 3 年可获得血清样本，2) 乳腺癌 诊断和放射治疗在两个血清采集时间点之间。将评估所有生物标志物 在两个时间点使用 ELISA。患有心力衰竭、心肌梗塞、冠状动脉疾病的女性 冠心病或乳腺癌后发生的其他心血管死亡结果将构成 病例组 (n = 56)，而没有 RICVD 结果的女性将构成对照组 (n = 128)。物流 将使用回归。摘要：本研究利用了 WHI 数据集，这是一个很好的解决问题的队列 考虑到先前从参与者那里收集的生物样本的可用性，已确定的研究差距 近20年的结果随访。这项研究意义重大，因为它将研究针对多种、 可能与 RICVD 相关的相关途径，可用于未来的研究以改善 癌症幸存者 RICVD 的识别和预测。