Impact of the Breast Cancer Immune Microenvironment on Racial Disparities and Survivorship

乳腺癌免疫微环境对种族差异和生存的影响

• 批准号: 10371767
• 负责人: Alina Marie Hamilton
• 金额: $ 0.25万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371767
• 关键词: Address; Age; Aggressive behavior; Biological; Breast Cancer Prevention; Cancer Etiology; Cancer Prevention Intervention; Cells; Cessation of life; Clinical; Clinical Data; Clinical Trials; Conflict (Psychology); DNA sequencing; Data; Development; Diagnosis; ERBB2 gene; Expression Profiling; Female; Frequencies; Functional disorder; Gene Expression; Genetic Transcription; Genomics; Heterogeneity; Histologic; Human; Immune; Immune response; Immunohistochemistry; Immunologic Markers; Immunotherapy; Incidence; Individual; Intervention; Knowledge; Literature; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mediator of activation protein; Mentors; Methods; Molecular; Mutation; Outcome; Outcome Study; Participant; Pathway interactions; Patients; Pattern; Phenotype; Population; Population Study; Process; Prognosis; Public Health; RNA; Race; Recurrence; Regulatory T-Lymphocyte; Reproductive Health; Research; Research Design; Research Personnel; Resources; Retrospective Studies; Role; Sampling; Stains; TP53 gene; Testing; The Cancer Genome Atlas; Tumor Subtype; Tumor-Infiltrating Lymphocytes; Woman; Work; adaptive immune response; base; black women; breast cancer genomics; breast pathology; cancer subtypes; cell type; cohort; epidemiologic data; functional status; health disparity; immunogenicity; immunoregulation; immunosuppressive macrophages; insight; malignant breast neoplasm; mortality; nano-string; neoplastic cell; novel; novel strategies; prognostic value; racial difference; racial disparity; recruit; response; specific biomarkers; study population; survival prediction; survivorship; training opportunity; tumor; tumor initiation; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenic

PROJECT SUMMARY Breast cancer (BC) is the most commonly diagnosed malignancy and second leading cause of cancer-related deaths among women in the US. Among all BC cases, black women suffer higher incidence of poor-prognosis BC subtypes and worse stage-specific mortality. Growing evidence supports the importance of the immune component of the BC microenvironment (BCME) in clinical outcomes. However, despite an abundance of clinical trials and retrospective studies investigating the immune microenvironment in BC, biomarkers of immune response are lacking and there is limited research regarding differences by race. By studying immune cells and immune-related gene expression alone, the positive prognostic utility of tumor infiltrating lymphocytes in BC thus far has been limited to triple negative and HER2-positive subtypes. The identification of a tumor-cell specific biomarkers associated with BC immunogenicity could help identify additional candidates for immunotherapy. In this regard, TP53 mutations are the most frequently occurring mutation in BC, vary in frequency by race, and are associated with immune response in several tumor types. However, literature addressing the association between TP53 dysfunction and BC immunogenicity is conflicting, and has never been studied in the context of racial disparities. Thus, whether and how immune response differs by race, p53 functional status and survival represents a critical knowledge gap in BC. To address this gap, I will leverage two major BC cohorts rich in molecular, histological, clinical and epidemiological data: 1) the Carolina Breast Cancer Study (CBCS), a large population-based study designed to investigate racial disparities in BC, and 2) The Cancer Genome Atlas (TCGA) BC cohort, a well-known study with multiple data platforms for each sample. Using these resources, I have obtained preliminary data suggesting that gene expression related to adaptive immune response is enriched in breast tumors from black women vs non-black women, and that dysfunction in the p53 pathway is associated with this response. Based on these findings, I hypothesize that differences in the immune BCME contribute to racial disparities and survivorship outcomes, and that p53 function is a tumor-intrinsic mediator of this process. I will test my hypothesis with two specific aims. In aim 1, I will characterize immune BCME phenotypes using RNA expression profiling and immunohistochemistry and will evaluate associations with race, age, tumor intrinsic subtypes and survival. In aim 2, I will investigate the relationship between TP53 functional status and immune phenotypes in association with race and tumor intrinsic subtype. Given the low representation of black women in clinical trials and gene expression studies, this will be the largest study of its kind to investigate the immune BCME in black and non-black women. The results of this work will collectively elucidate how the immune BCME contributes to tumor progression leading to racial disparities in survival, and inform the development of novel strategies for BC prevention and intervention.

项目摘要 乳腺癌（BC）是最常诊断的恶性肿瘤，也是癌症相关疾病的第二大病因 美国女性的死亡率。在所有BC病例中，黑人女性预后不良的发生率较高 BC亚型和更差的阶段特异性死亡率。越来越多的证据支持免疫的重要性 BC微环境（BCME）在临床结果中的作用。然而，尽管有大量的临床 研究BC中免疫微环境的试验和回顾性研究， 缺乏回应，关于种族差异的研究有限。通过研究免疫细胞， 单独的免疫相关基因表达，肿瘤浸润淋巴细胞在BC中的积极预后效用， 目前仅限于三阴性和HER2阳性亚型。一种肿瘤细胞特异性 与BC免疫原性相关的生物标志物可以帮助识别用于免疫疗法的其他候选者。在 在这方面，TP53突变是BC中最常发生的突变，频率因种族而异， 与几种肿瘤类型的免疫反应有关。然而，涉及该协会的文献 TP53功能障碍和BC免疫原性之间的关系是矛盾的，并且从未在 种族差异因此，免疫反应是否以及如何因种族、p53功能状态和生存而有所不同 这是BC的一个重要知识缺口。为了解决这一差距，我将利用两个主要的BC群体， 分子、组织学、临床和流行病学数据：1）卡罗莱纳乳腺癌研究（CBCS），一个大型的 以人口为基础的研究，旨在调查BC的种族差异，以及2）癌症基因组图谱 （TCGA）BC队列，这是一项众所周知的研究，每个样本都有多个数据平台。利用这些资源，我 已经获得的初步数据表明，与适应性免疫反应相关的基因表达是 在黑人女性和非黑人女性的乳腺肿瘤中，p53通路的功能障碍是 与这个答案有关。基于这些发现，我假设免疫BCME的差异 有助于种族差异和生存结果，p53功能是肿瘤内在的介导因子， 这个过程我将用两个具体目标来检验我的假设。在目标1中，我将描述免疫BCME 使用RNA表达谱和免疫组织化学分析表型，并将评估与种族的关联， 年龄、肿瘤内在亚型和存活率。在目的2中，我将研究TP53功能与 与种族和肿瘤内在亚型相关的状态和免疫表型。鉴于代表性低 黑人妇女的临床试验和基因表达研究，这将是同类研究中最大的研究 黑人和非黑人女性的免疫BCME。这项工作的结果将共同阐明如何 免疫BCME有助于肿瘤进展，导致生存期的种族差异，并告知 制定BC预防和干预的新战略。

项目成果

Prognostic significance of RNA-based TP53 pathway function among estrogen receptor positive and negative breast cancer cases.

• DOI: 10.1038/s41523-022-00437-7
• 发表时间: 2022-06-14
• 期刊: NPJ BREAST CANCER
• 影响因子: 5.9
• 作者: Hurson, Amber N.;Abubakar, Mustapha;Hamilton, Alina M.;Conway, Kathleen;Hoadley, Katherine A.;Love, Michael I.;Olshan, Andrew F.;Perou, Charles M.;Garcia-Closas, Montserrat;Troester, Melissa A.
• 通讯作者: Troester, Melissa A.

Reproducibility and intratumoral heterogeneity of the PAM50 breast cancer assay.

• DOI: 10.1007/s10549-023-06888-1
• 发表时间: 2023-05
• 期刊: BREAST CANCER RESEARCH AND TREATMENT
• 影响因子: 3.8
• 作者: Hurson, Amber N. N.;Hamilton, Alina M. M.;Olsson, Linnea T. T.;Kirk, Erin L. L.;Sherman, Mark E. E.;Calhoun, Benjamin C. C.;Geradts, Joseph;Troester, Melissa A. A.
• 通讯作者: Troester, Melissa A. A.