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

基本信息

批准号：
10674701
负责人：
Chin Hur
金额：
$ 36.48万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/10674701
关键词：
Acceleration 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 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 autosome 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

项目摘要

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.

支撑研究的总体目标是优化结直肠癌（CRC）筛查策略 CRC的CRC发育风险最高的个体可归因于Lynch综合征（LS）。在四个DNA不匹配中的一个中，引起LS，与之相关的常染色体DOMINT部分。多种恶性肿瘤和最常见的CRC综合征。在美国，约有100万人类似于与BRCA相关的遗传性乳房和卵巢癌综合症。当前对LS的CRC监视建议涉及每1-2年级的结肠镜检查，从25岁开始。在他们的一生中，患有LS的人完成了约50个结肠镜检查（平均风险筛查3）。这种密集的策略是基于通货膨胀寿命CRC风险估算的，并且不考虑基于风险的可变风险在基因型上。由于侵略性较低的基因型受到过度测试和过度处理对生活质量和大量资源利用的影响。 LS中的CRC监视应根据CRC的侵入和死亡率的风险进行量身定制个人健康成果，资源利用和可破解性的基因型和专有性同样，有三个目标的假设： AIM 1：确定LS中最佳基因特异性结肠镜检查方案，并估计改进采用个性化LS监视方法的资源利用（结肠镜检查需求）。仿真建模，我们将完善LS-CRC模型以投影长期遥远的策略对于四个MMR基因（MLH1，MSH2，MSH6和PMS2）中的每一个，都具有不同的监视间隔将允许我们估计具有各种方案的当前各种方案的结肠镜检查数量。 AIM 2：评估合并非侵入性CRC筛查方式的影响，例如粪便研究（粪便免疫组织化学测试（拟合）和FECAL DNA）对LS的结肠镜检查监测运营商。非侵入性结肠镜检查方法以最大程度地减少结肠镜检查的过度耐药性，有可能改善通过增加依从性和节省成本来取得成果。目标3：评估对当前和新的，个性化的基因特定的障碍，促进者和态度 CRC监视策略。医疗保健提供者和患者的筛查测试。影响：到奖励期结束时，我们将与优化有效性和成本效益的LS。在LS中，色素镜检查过度刷掉。