Leveraging high-risk populations for precision prevention: A novel approach for improving risk prediction for outcomes after a breast cancer diagnosis

利用高危人群进行精准预防：一种改善乳腺癌诊断后结果风险预测的新方法

• 批准号: 10300319
• 负责人: Nur Zeinomar
• 金额: $ 19.99万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10300319
• 关键词: Accounting; Address; Advisory Committees; Affect; African ancestry; Australia; Biological Assay; Black race; Breast; Breast Cancer Risk Factor; Breast Cancer survivor; Breast Cancer survivorship; Canada; Cancer Prognosis; Characteristics; Clinical; Clinical Markers; Contralateral Breast; Data; Development; Development Plans; Diagnosis; Educational workshop; Enrollment; Epidemiology; Estrogen receptor negative; Ethnic group; European; Event; Family; Family history of; Follow-Up Studies; Future; Gene Expression Profiling; Genetic; Genetic Variation; Genomics; Genotype; Goals; Health; Heritability; Hormone Receptor; Inherited; International; Intervention; Interview; K22 Award; Knowledge; Learning Skill; Linkage Disequilibrium; Longitudinal Studies; Lymph Node Involvement; Modeling; Molecular; New Jersey; Outcome; Performance; Persons; Prognosis; Public Health; RNA; Race; Recommendation; Research; Research Personnel; Resources; Risk; Risk Assessment; Socioeconomic Status; Subgroup; Time; Training; Training Support; Translating; Translations; United States; Variant; Woman; base; black women; breast cancer diagnosis; breast cancer family registry; breast cancer survival; cancer diagnosis; cancer recurrence; cancer subtypes; cancer therapy; career development; clinical care; clinical implementation; clinical translation; cohort; experience; follow-up; genetic association; genetic pedigree; genome-wide; health disparity; high risk; high risk population; improved; improved outcome; individualized prevention; knowledge translation; lymph nodes; malignant breast neoplasm; meetings; mortality; mortality risk; neoplasm registry; novel; novel strategies; oncotype; outcome prediction; polygenic risk score; population based; precision medicine; predictive modeling; prognostic index; prognostic tool; racial and ethnic; recruit; risk prediction; risk stratification; screening guidelines; skills; survival prediction; symposium; tertiary prevention; tumor

PROJECT SUMMARY Despite dramatic improvements in Breast Cancer (BC) prognosis over the past two decades, major survival differences after diagnosis persist based on a number of clinical factors and tumor characteristics. However, even within similar molecular BC subtypes there are differences in survival, supporting that additional factors should be considered to better predict outcomes after diagnosis. Surprisingly, unlike risk models for first incident BC, current models for prediction of survival after a BC diagnosis and treatment do not incorporate host germline genetic variation. In addition, Black women experience a 40% higher mortality rate due to BC compared to their White counterparts. Further, they have been greatly underrepresented in genomic studies; so future clinical implementations of new precision medicine solutions based on germline genetic variation may exacerbate existing health disparities. This proposal aims to produce empirical evidence that will be an essential first step to improve BC prognosis based on appropriate clinical recommendations targeted to those with the highest risk of poor outcomes. In Aim 1a, I will investigate if a polygenic risk score (PRS) improves risk prediction of BC prognosis, over and beyond standard clinical markers and tumor characteristics in the Breast Cancer Family Registry (BCFR). Aim 1b will utilize the BCFR to examine the impact of adding a PRS to existing BC prognostic tools such as the Nottingham Prognostic Index (NPI), which incorporates information on tumor size, tumor grade, and lymph node involvement. In Aim 2a, I will examine if the PRS improves risk prediction for BC prognosis in the Women’s Circle of Health Follow-Up Study (WCHFS), a longitudinal study of Black BC survivors. Aim 2b will examine the impact of adding PRS to NPI using data from the WCHFS. My long-term goal is to translate epidemiologic findings into clinical care through more accurate risk assessment and risk-reducing strategies for outcomes after a cancer diagnosis. This K22 award will provide me with the necessary training and support to accomplish the following short-term goals: (1) obtain advanced skills in statistical genetics; (2) training in the translation of scientific research findings in the clinical context; and (3) professional development including learning the skills necessary to be a successful independent investigator. To achieve these goals, I have proposed a detailed career development plan, including taking short courses and workshops, attending national conferences, meetings with my advisory committee, and obtaining research experience by completing the proposed research aims. This K22 research will address critical knowledge and clinical translation gaps in identifying women who are the highest risk for poor BC prognosis. Given the increasing number of BC survivors and persisting BC survival differences for certain subgroups, this is a timely and important proposal.

项目摘要 尽管过去二十年来乳腺癌（BC）预后有了显着改善，但主要生存 根据许多临床因素和肿瘤特征，诊断后的差异持续存在。然而， 即使在类似的分子BC亚型中，生存也存在差异，这支持了其他因素 应考虑在诊断后更好地预测结果。令人惊讶的是，与第一次事件的风险模型不同 卑诗省，当前预测BC诊断和治疗后生存的模型不纳入宿主种系 遗传变异。此外，黑人妇女的死亡率高40％。 白色对准。此外，在基因组研究中，它们的人数大大不足。因此未来的临床 基于种系遗传变异的新精密药物解决方案的实施可能会加剧 现有的健康差异。该提议旨在提供经验证据，这将是至关重要的第一步 根据针对具有最高风险的临床建议，改善BC预后 结果不佳。在AIM 1A中，我将调查多基因风险评分（PRS）是否改善了BC的风险预测 预后，超出标准临床标记和乳腺癌家族的肿瘤特征 注册表（BCFR）。 AIM 1B将利用BCFR检查在现有BC Probestic中添加PR的影响 诺丁汉预后指数（NPI）等工具，该指数输入了有关肿瘤大小，肿瘤等级的信息 和淋巴结受累。在AIM 2A中，我将检查PRS是否改善了BC预后的风险预测 妇女卫生后续研究（WCHFS），一项对黑色卑诗省奔放者的纵向研究。 AIM 2B会 使用来自WCHF的数据检查将PR添加到NPI的影响。我的长期目标是翻译 通过更准确的风险评估和降低风险的策略，流行病学发现进入临床护理 癌症诊断后的结果。该K22奖将为我提供必要的培训和支持 实现以下短期目标：（1）获得统计遗传学的高级技能； （2）培训 在临床背景下的科学研究发现的翻译； （3）专业发展，包括 学习成为成功的独立研究者所需的技能。为了实现这些目标，我有 提出了一项详细的职业发展计划，包括参加简短的课程和研讨会，参加了国家 会议，与我的咨询委员会会议，并通过完成研究经验 拟议的研究目的。这项K22研究将解决关键的知识和临床翻译差距 确定妇女是BC预后不良的最高风险。鉴于BC幸存者数量增加 并持续某些亚组的卑诗省生存差异，这是一个及时且重要的建议。