Optimal Colorectal Cancer Surveillance Strategy for Lynch Syndrome by Genotype

按基因型分类的林奇综合征最佳结直肠癌监测策略

• 批准号: 10298217
• 负责人: Chin Hur
• 金额: $ 38.47万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10298217
• 关键词: Address; Adherence; Affect; Age; Area; Attitude; Award; Cancer Control; Cancer Model; Clinical; Collaborations; Colonoscopy; Colorectal Adenocarcinoma; Colorectal Adenoma; Colorectal Cancer; Cost Savings; DNA; DNA Repair; Deimplementation; Development; Effectiveness; Feces; Focus Groups; Foundations; Gender; Genes; Genotype; Goals; Guidelines; Health; Health Personnel; Hereditary Breast and Ovarian Cancer Syndrome; Hereditary Nonpolyposis Colorectal Neoplasms; Hybrids; Incidence; Individual; Inherited; Interdisciplinary Study; MLH1 gene; MSH2 gene; MSH6 gene; Malignant Neoplasms; Methodology; Mismatch Repair; Modality; Modeling; Oncogenes; Outcome; PMS2 gene; Pathogenicity; Patient risk; Patients; Polyps; Precision Medicine Initiative; Provider; Quality of life; Recommendation; Regimen; Research; Resources; Risk; Risk Estimate; Risk Factors; Surveys; Syndrome; Testing; base; cancer care; cancer prevention; cohort; colorectal cancer risk; colorectal cancer screening; comorbidity; cost effectiveness; gene repair; genetic variant; genomic data; high risk; improved; improved outcome; insight; lifetime risk; models and simulation; mortality; mutation carrier; novel; overtreatment; prevent; risk stratification; screening; surveillance strategy; syndromic surveillance

The overall goal of the proposed research is to optimize colorectal cancer (CRC) screening strategies for individuals at the highest risk for CRC development attributable to Lynch Syndrome (LS). Germline alterations in one of four DNA mismatch repair (MMR) genes causes LS, an autosomal dominant condition associated with multiple malignancies and the most common inherited CRC syndrome. LS affects nearly 1/300 individuals and ~1 million individuals in the US, similar to BRCA-related hereditary breast and ovarian cancer syndrome. Current CRC surveillance recommendations for LS involve colonoscopy every 1-2 years starting at age 25 years; in their lifetime, individuals with LS will have completed ~50 colonoscopies (vs. 3 for average-risk screening). This intensive strategy is based on inflated lifetime CRC risk estimates and do not account for variable risk based on genotype. As a result, the current “one-size-fits-all” approach to CRC surveillance in LS individuals with the less aggressive genotypes subjects them to over-testing and overtreatment, with a negative impact on quality of life and significant resource utilization. The overarching hypothesis of our proposal is that CRC surveillance in LS should be tailored to the risk of CRC incidence and mortality associated with each genotype to improve individual health outcomes, resource utilization, and acceptability to providers and patients alike. The hypothesis will be tested with three aims: Aim 1: Determine the optimal gene-specific colonoscopy regimen in LS and estimate the improved resource utilization (colonoscopy demand) with a personalized LS surveillance approach. Using simulation modeling, we will refine the LS-CRC model to project the long-term outcomes for numerous strategies for each of the four MMR genes (MLH1, MSH2, MSH6, and PMS2) with varying (a) surveillance intervals. This will allow us to estimate the number of colonoscopies with current and various regimens evaluated. Aim 2: Evaluate the impact of incorporating non-invasive CRC screening modalities, such as stool studies (fecal immunohistochemical testing (FIT) and FIT-fecal DNA) to colonoscopy surveillance for LS carriers. We will use our model to evaluate a novel, hybrid approach to CRC surveillance that will incorporate non-invasive approaches to colonoscopy to minimize overutilization of colonoscopy, potentially improving outcomes by increasing adherence and saving costs. Aim 3: Assess barriers, facilitators, and attitudes towards current and new, personalized, gene-specific CRC surveillance strategies. We will assess attitudes towards colonoscopy with or without non-invasive CRC screening tests among healthcare providers and patients. Impact: By award period end, we will have produced personalized risk-tailored CRC surveillance regimens with LS that optimize effectiveness and cost-effectiveness. Results of this proposal will provide evidence to support the de-implementation of colonoscopy overuse in LS.

拟议研究的总体目标是优化结直肠癌（CRC）筛查策略 林奇综合征 (LS) 导致结直肠癌发生风险最高的个体。种系改变 四种 DNA 错配修复 (MMR) 基因之一中的 LS 会导致 LS，这是一种与以下疾病相关的常染色体显性病症： 多种恶性肿瘤和最常见的遗传性结直肠癌综合征。 LS 影响近 1/300 的个体 美国约有 100 万人，类似于 BRCA 相关的遗传性乳腺癌和卵巢癌综合征。 目前 CRC 对 LS 的监测建议包括从 25 岁开始每 1-2 年进行一次结肠镜检查； LS 患者一生中将完成约 50 次结肠镜检查（平均风险筛查为 3 次）。 这种强化策略基于夸大的终生 CRC 风险估计，并未考虑基于可变风险的情况。 关于基因型。因此，目前对 LS 个体进行 CRC 监测的“一刀切”方法 攻击性较小的基因型使他们遭受过度测试和过度治疗，结果呈阴性 对生活质量和大量资源利用的影响。我们提案的总体假设是 LS 的 CRC 监测应根据与每个相关的 CRC 发病率和死亡率风险进行调整 基因分型可改善个人健康结果、资源利用率以及提供者和患者的可接受性 一样。该假设将通过三个目标进行检验： 目标 1：确定 LS 的最佳基因特异性结肠镜检查方案并估计改进效果 通过个性化 LS 监测方法利用资源（结肠镜检查需求）。使用 仿真建模，我们将完善 LS-CRC 模型来预测众多策略的长期结果 对于四个 MMR 基因（MLH1、MSH2、MSH6 和 PMS2）中的每一个，具有不同的 (a) 监测间隔。这 将使我们能够估计当前和评估的各种治疗方案的结肠镜检查数量。 目标 2：评估纳入非侵入性 CRC 筛查方式（例如粪便）的影响 研究（粪便免疫组织化学检测 (FIT) 和 FIT-粪便 DNA）到结肠镜检查监测 LS 载体。我们将使用我们的模型来评估一种新颖的混合 CRC 监测方法，该方法将结合 结肠镜检查的非侵入性方法可最大限度地减少结肠镜检查的过度使用，从而可能改善 通过提高依从性和节省成本来取得成果。 目标 3：评估对当前和新的、个性化的、基因特异性的障碍、促进因素和态度 CRC 监测策略。我们将评估对有或没有无创结直肠癌结肠镜检查的态度 医疗保健提供者和患者之间的筛查测试。 影响：到奖励期结束时，我们将制定个性化的风险定制 CRC 监测方案 LS 优化有效性和成本效益。该提案的结果将提供证据支持 LS 中过度使用结肠镜检查的取消。