Immune and Inflammatory Biomarkers in Radiotherapy-Induced Skin Toxicities

 描述（由申请人提供）：乳腺癌是最常见的癌症，也是美国女性癌症死亡的第二大原因。术后辅助放疗（RT）显著降低局部区域复发和乳腺癌死亡。然而，一些患者经历潮湿脱皮作为早期皮肤不良反应（EASR）和纤维化作为晚期效应。服务不足的少数民族比白人更不可能接受推荐的辅助RT，如果接受治疗，发生RT相关EASR的风险更高，临床结局更差。因此，为了实现我们改善生活质量和降低乳腺癌死亡率的长期目标，拟议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，以预测RT诱导的EASR和生活质量。我们将检验总体工作假设，即更差的临床结果，如RT诱导的EASR，迟发效应和复发更频繁地发生在女性中：（i）调节免疫应答和（ii）刺激炎症和超放射敏感性。我们将测试一种新的范式，即联合免疫和炎症反应有助于放射敏感性的个体差异，可以预测RT诱导的不良反应和临床结果。研究这一新的范式将开发强有力的工具，用于识别高风险人群和个性化干预和治疗策略的目标，如免疫疗法和抗炎药。利用现有的血浆样本和1,200名乳腺癌患者的广泛临床数据（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），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/民族研究，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-β），（ii）炎性生物标志物，C-反应蛋白（CRP），和（iii）在调整潜在混杂因素或效应调节因子（如年龄）后，TGF-β和CRP的联合效应，人种/种族、体重指数、肿瘤分期、吸烟状况、其他医学状况、RT剂量和乳房体积。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，强大的机构支持和建立的实验室检测，我们处于特殊的位置来开展拟议的研究。总体影响：使用假设驱动的策略来合理设计拟议的研究，预期的结果将显著影响基础，预防，诊断，转化，流行病学，健康差异和临床癌症研究迫切需要的创新生物标志物开发和验证。正如我们 了解更多关于RT诱导EASR和临床结果的分子机制，所获得的知识将显著影响精准医学，并确保每一位乳腺癌患者获得最佳治疗，具有最大疗效和最小副作用，特别是在治疗反应较差，副作用和生存率较低的少数群体中。

 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.