Immune and Inflammatory Biomarkers in Radiotherapy-Induced Skin Toxicities

 描述(申请人提供)：乳腺癌是美国女性最常被诊断的癌症，也是导致癌症死亡的第二大原因。术后辅助性放射治疗可显著降低乳腺癌局部复发和死亡率。然而，一些患者经历了湿性脱皮作为早期不良皮肤反应(EASR)和纤维化作为晚期影响。与白人相比，服务不足的少数族裔接受推荐的辅助RT的可能性较小，如果接受治疗，发生RT相关EASR的风险更高，临床结果更差。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，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，以预测RT诱导的EASR和生活质量。我们将测试总体工作假设，即较差的临床结果，如RT诱导的EASR、晚期效应和复发更频繁地发生在具有(I)调节的免疫反应和(Ii)刺激的炎症和超放射敏感性的女性中。我们将测试一种新的范式，即结合免疫和炎症反应有助于个体放射敏感性的变化，这可能预测RT诱导的不良反应和临床结果。对这一新范式的研究将开发出强大的工具来确定高危人群以及个性化干预和治疗策略的目标，如免疫疗法和抗炎剂。利用现有的血浆样本和1200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，这项极其经济高效的拟议研究将是第一项也是最大规模的三种族/民族研究，评估RT诱导的EASR与以下因素之间的相关性：(I)多效性免疫抑制细胞因子转化生长因子-β(转化生长因子-β)，(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物，如年龄、种族/民族，体重指数、肿瘤分期、吸烟状况、其他医疗条件、放射治疗剂量和乳房体积。利用现有的样本和大量乳腺癌患者的临床数据，有前景的试点数据，强大的机构支持和成熟的实验室分析，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，预期结果将对基础、预防、诊断、转换、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记物的开发和验证产生重大影响。因为我们 为了进一步了解RT诱导EASR的分子机制和临床结果，所获得的知识将对精密医学产生重大影响，并确保每个乳腺癌患者得到最优治疗(S)，同时最大限度地提高疗效，将副作用降至最低，尤其是在服务不足、治疗反应、副作用和生存率较差的少数群体中。

 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.