Optimal Colorectal Cancer Surveillance Strategy for Lynch Syndrome by Genotype

拟议研究的总体目标是优化结直肠癌(CRC)筛查策略 可归因于林奇综合征(LS)的CRC发展风险最高的个人。生殖系改变 在四个DNA错配修复(MMR)基因之一导致LS，一种常染色体显性疾病与 多发性恶性肿瘤和最常见的遗传性CRC综合征。LS影响了近1/300人， 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。 目前对LS的CRC监测建议包括从25岁开始每1-2年进行一次结肠镜检查； 在他们的一生中，LS患者将完成约50次结肠镜检查(平均风险筛查为3次)。 这一密集策略基于夸大的终生CRC风险估计，没有考虑基于可变风险的因素 关于基因分型。因此，目前对LS患者进行CRC监测的“一刀切”方法 攻击性较弱的基因使他们遭受过度检测和过度治疗，结果为阴性 对生活质量和显著的资源利用率的影响。我们提案的首要假设是 LS的结直肠癌监测应针对与每个结直肠癌相关的结直肠癌发病率和死亡率风险而量身定做 改善个体健康结果、资源利用和提供者和患者接受程度的基因分型 一模一样。这一假设将通过三个目标进行检验： 目的1：确定LS的最佳基因特异性结肠镜检查方案，并评估改进后的方案 个性化LS监视方法的资源利用(结肠镜检查需求)。vbl.使用 模拟建模，我们将改进LS-CRC模型，以预测各种策略的长期结果 对于四个MMR基因(MLH1、MSH2、MSH6和PMS2)中的每一个，具有不同的(A)监视间隔。这 将使我们能够通过评估当前和各种方案来估计结肠镜检查的数量。 目的2：评估纳入非侵入性结直肠癌筛查方式的影响，如粪便 粪便免疫组织化学检测(FIT)和FIT-粪便DNA用于结肠镜检查LS的研究 承运人。我们将使用我们的模型来评估一种新的、混合的CRC监测方法，该方法将包括 非侵入性的结肠镜检查方法，以最大限度地减少过度使用结肠镜检查，潜在地改善 通过提高遵从性和节省成本来实现成果。 目标3：评估对当前和新的、个性化的、特定于基因的障碍、促进者和态度 儿童权利公约监督战略。我们将评估使用或不使用非侵入性结直肠癌进行结肠镜检查的态度 在医疗保健提供者和患者中进行筛查测试。 影响：到获奖期结束时，我们将生产出个性化的风险定制的CRC监测方案， LS可优化效果和成本效益。这项提案的结果将提供证据支持 结肠镜过度使用在LS中的取消实施。

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.