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 尽管在过去的二十年里，乳腺癌（BC）的预后有了显着的改善，但主要的生存率仍然很低。 诊断后的差异基于许多临床因素和肿瘤特征而持续存在。然而，在这方面， 即使在相似的分子BC亚型中，存活率也存在差异，这支持了其他因素 应该考虑更好地预测诊断后的结果。令人惊讶的是，与第一次事件的风险模型不同， BC，目前用于预测BC诊断和治疗后存活率的模型不包括宿主生殖系 遗传变异此外，黑人妇女因BC的死亡率比黑人妇女高40%。 白色对应物。此外，它们在基因组研究中的代表性大大不足;因此未来的临床 基于生殖系遗传变异的新精准医学解决方案的实施可能会加剧 现有的健康差距。这项建议旨在提供经验证据，这将是至关重要的第一步， 根据针对最高风险患者的适当临床建议改善BC预后 可怜的结果。在目标1a中，我将研究多基因风险评分（PRS）是否能改善BC的风险预测 乳腺癌家族的预后、超标准临床标志物和肿瘤特征 登记研究（BCFR）。目标1b将利用BCFR检查在现有BC预后中添加PRS的影响 诸如诺丁汉预后指数（NPI）的工具，其结合了关于肿瘤大小，肿瘤等级， 和淋巴结受累。在目标2a中，我将检查PRS是否改善了BC预后的风险预测， 妇女健康随访研究圈（WCHFS），一项对BC省黑人幸存者的纵向研究。目标2b将 使用WCHFS的数据检查将PRS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风险降低策略， 癌症诊断后的结果。这个K22奖项将为我提供必要的培训和支持， 完成以下短期目标：（1）获得统计遗传学方面的高级技能;（2） 临床科研成果的翻译;及（3）专业发展，包括 学习成为一名成功的独立调查员所需的技能。为了实现这些目标，我 提出了详细的职业发展计划，包括参加短期课程和讲习班，参加国家 会议，与我的咨询委员会会议，并通过完成 提出研究目标。这项K22研究将解决关键知识和临床翻译差距， 确定谁是最高风险的妇女BC预后不良。鉴于不列颠哥伦比亚省幸存者的数量不断增加 以及某些亚组持续存在的BC生存差异，这是一个及时而重要的建议。