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：乳腺癌的生存率有所提高;然而，许多乳腺癌幸存者， 经历治疗引起的不良反应，包括辐射引起的迟发性心血管疾病 疗法辐射诱发的心血管疾病（RICVD），可在辐射后5 - 10年或更长时间出现。 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。目前， 目前还不知道如何最好地识别将发展为RICVD的个体，因为RICVD经常在几年后发生， 由于长期跟踪参与者的费用，在研究中经常被忽视。因此，在本发明中， 心脏肿瘤学的主要文献研究了短期心脏结局，主要涉及 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相同， CVD，这还没有在研究中得到明确的测试。途径，如氧化应激和纤维化， 被认为在RICVD的发展中发挥了重要作用。目的：本研究的目的是检查 治疗后的氧化应激（8-OH-dG，MPO）、纤维化（TGF-β）、心脏损伤（TnI-I， 半胱氨酸蛋白酶抑制剂-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，并按右侧和左侧放射进行分层。具体而言，我们的目标是：1） 检查接受放射治疗的乳腺癌幸存者（与对照组相比）的RICVD和CVD死亡风险 与生物标志物相关（治疗后），2）检查RICVD和CVD死亡的风险（与对照组相比） 比较右侧放射与左侧放射治疗的乳腺癌幸存者，以及3）检查 乳腺癌患者治疗后生物标志物与RICVD和CVD死亡风险（与对照组相比）的相关性 癌症幸存者，按右侧与左侧放射分层。方法：我们提出了一个嵌套的病例对照设计 在妇女健康倡议癌症后的生命和长寿（WHI LILAC）中， study.入选标准为：1）WHI基线和第3年时可获得血清样本，2）乳腺癌 两个血清采集时间点之间的诊断和放射治疗。将评估所有生物标志物 在两个时间点使用ELISA。判定为心力衰竭、心肌梗死、冠状动脉 乳腺癌后发生的冠心病或其他心血管死亡结局将构成 病例组56例，对照组128例。Logistic 将使用回归。总结：这项研究利用了WHI数据集，这是一个很好的队列，以解决 确定的研究差距，考虑到以前从参与者那里收集的生物标本的可用性， 近20年的随访结果。这项研究意义重大，因为它将研究靶向多种生物标志物， 可能与RICVD相关的相关途径，可用于未来的研究，以改善 癌症幸存者中RICVD识别和预测。