Immune and Inflammatory Biomarkers in Radiotherapy-Induced Skin Toxicities

放射治疗引起的皮肤毒性中的免疫和炎症生物标志物

• 批准号: 8895684
• 负责人: Jennifer J Hu
• 金额: $ 7.68万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8895684
• 关键词: Adjuvant Radiotherapy; Adverse effects; Adverse reactions; African American; Age; American; Anti-Inflammatory Agents; Biological Assay; Biological Markers; Body mass index; Breast; Breast Cancer Patient; C-reactive protein; Cancer Etiology; Cessation of life; Clinical; Clinical Data; Data; Development; Diagnostic; Diagnostic Neoplasm Staging; Dose; Ensure; Environment; Epidemiologist; Epidemiology; Ethnic Origin; Ethnic group; Fibrosis; Funding; Future; Goals; Hispanics; Immune; Immune response; Immunosuppressive Agents; Immunotherapy; Individual; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Laboratories; Late Effects; Learning; Malignant Neoplasms; Medial; Medical; Minority; Modeling; Molecular; Molecular Genetics; Normal tissue morphology; Not Hispanic or Latino; Obesity; Outcome; Outcomes Research; Patients; Plasma; Population; Positioning Attribute; Postoperative Period; Predictive Value; Quality of life; Race; Radiation Tolerance; Radiation therapy; Reaction; Recurrence; Research; Research Project Grants; Resources; Sampling; Second Primary Cancers; Skin; Smoking Status; Target Populations; Testing; Toxic effect; Transforming Growth Factor beta; Tumor stage; Underrepresented Minority; Validation; Variant; Woman; Work; anticancer research; base; cancer diagnosis; cancer health disparity; cost effective; cytokine; design; experience; health disparity; high risk; improved; inhibitor/antagonist; innovation; innovative technologies; malignant breast neoplasm; mortality; patient population; personalized intervention; personalized medicine; personalized therapeutic; precision medicine; prevent; public health relevance; racial and ethnic; racial/ethnic difference; response; tool; treatment response

 DESCRIPTION (provided by applicant): Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in American women. Postoperative adjuvant radiotherapy (RT) significantly reduces local-regional recurrence and breast cancer death. However, some patients experience moist desquamation as early adverse skin reactions (EASRs) and fibrosis as late effect. Underserved minorities are less likely than Whites to receive the recommended adjuvant RT and if treated, have a higher risk for developing RT-related EASRs and worse clinical outcomes. Therefore, to achieve our long-term goals in improving quality of life and reducing breast cancer mortality, the primary objective of the proposed research is to develop and validate two immune and inflammatory biomarkers in predicting RT-induced EASRs and quality of life. We will test the overall working hypothesis that worse clinical outcomes, such as RT-induced EASRs, late effects, and recurrence occur more frequently in women with: (i) modulated immune response and (ii) stimulated inflammation and hyper-radio-sensitivity. We will test a new paradigm that combined immune and inflammatory responses contribute to individual variations in radio-sensitivity that may predict RT-induced adverse reactions and clinical outcomes. Investigating this new paradigm will develop powerful tools in identifying high-risk populations and targets for personalized intervention and therapeutic strategies, such as immunotherapies and anti-inflammatory agents. Capitalizing on existing plasma samples and extensive clinical data from 1,200 breast cancer patients (400 black or African Americans, 400 Hispanic Whites, and 400 non-Hispanic Whites), this extremely cost-effective proposed research will be the first and the largest tri-racial/ethnic study evaluating th association between RT- induced EASRs and: (i) a pleiotropic immunosuppressive cytokine, transforming growth factor-beta (TGF-ß), (ii) an inflammatory biomarker, C-reactive protein (CRP), and (iii) the combined effects of TGF-ß and CRP after adjustment for potential confounders or effect modifiers, such as age, race/ethnicity, body mass index, tumor stage, smoking status, other medical conditions, RT dose, and breast volume. Capitalizing on the existing samples and clinical data from a large breast cancer patient population, promising pilot data, strong institutional support, and established laboratory assays, we are in an exceptional position to carry out the proposed research. Overall Impact: Using a hypothesis-driven strategy to rationally design the proposed research, the anticipated outcome will significantly impact the desperately needed innovative biomarker development and validation for basic, preventative, diagnostic, translational, epidemiological, health disparities, and clinical cancer research. As we learn more about underlined molecular mechanisms of RT-induced EASRs and clinical outcomes, the knowledge gained will significantly impact precision medicine and ensure that every breast cancer patient gets the most optimal treatment(s) with maximal efficacy and minimal side effects, particularly in underserved minorities with worse treatment response, side effects, and survival.

 描述（由申请人提供）：乳腺癌是最常诊断出的癌症，也是美国女性癌症死亡的第二大原因。术后辅助放疗（RT）显着减少局部区域复发和乳腺癌死亡。然而，一些患者会出现早期皮肤不良反应 (EASR) 出现潮湿脱屑，以及晚期出现纤维化的情况。与白人相比，服务不足的少数族裔接受推荐的辅助放疗的可能性较小，如果接受治疗，发生与放疗相关的 EASR 的风险更高，临床结果更差。因此，为了实现改善生活质量和降低乳腺癌死亡率的长期目标，本研究的主要目标是开发和验证两种免疫和炎症生物标志物来预测放疗诱导的 EASR 和生活质量。我们将测试总体工作假设，即更糟糕的临床结果，例如放疗引起的 EASR、迟发效应和复发，在具有以下特征的女性中更常见：(i) 免疫反应调节和 (ii) 刺激炎症和放射敏感性过高。我们将测试一种新的范例，该范例结合免疫和炎症反应导致放射敏感性的个体差异，这可以预测放疗引起的不良反应和临床结果。研究这一新范式将开发强大的工具来识别高危人群和个性化干预和治疗策略的目标，例如免疫疗法和抗炎药物。利用现有血浆样本和来自 1,200 名乳腺癌患者（400 名黑人或非裔美国人、400 名西班牙裔白人和 400 名非西班牙裔白人）的广泛临床数据，这项极具成本效益的拟议研究将是第一个也是最大的三种族/族裔研究，评估 RT 诱导的 EASR 与以下因素之间的关联：(i) 多效性免疫抑制细胞因子， 转化生长因子-β (TGF-ß)，(ii) 炎症生物标志物 C 反应蛋白 (CRP)，以及 (iii) 调整潜在混杂因素或效应修饰因素（例如年龄、种族/民族、体重指数、肿瘤分期、吸烟状况、其他医疗状况、放疗剂量和乳房体积）后 TGF-ß 和 CRP 的综合影响。利用来自大量乳腺癌患者群体的现有样本和临床数据、有希望的试点数据、强大的机构支持和已建立的实验室检测，我们处于开展拟议研究的特殊地位。总体影响：使用假设驱动的策略合理设计拟议的研究，预期结果将显着影响基础、预防、诊断、转化、流行病学、健康差异和临床癌症研究急需的创新生物标志物的开发和验证。正如我们 了解更多关于放疗诱导的 EASR 的分子机制和临床结果，所获得的知识将显着影响精准医疗，并确保每位乳腺癌患者得到最佳治疗，具有最大疗效和最小副作用，特别是在治疗反应、副作用和生存率较差的服务不足的少数群体中。