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， 处于可归因于Lynch综合征（LS）的CRC发展的最高风险的个体。生殖系改变 四个DNA错配修复（MMR）基因之一导致LS，这是一种常染色体显性疾病， 多发性恶性肿瘤和最常见的遗传性CRC综合征。LS影响近1/300的个体， 在美国约有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，患有LS的个体将完成约50次结肠镜检查（相对于平均风险筛查的3次）。 这种强化策略基于夸大的终生CRC风险估计，并且不考虑基于风险的可变风险。 基因型因此，目前LS个体中CRC监测的“一刀切”方法 与侵略性较低的基因型，使他们受到过度测试和过度治疗，与阴性 对生活质量和重大资源利用的影响。我们建议的首要假设是 LS中的CRC监测应针对与每种疾病相关的CRC发病率和死亡率风险进行调整， 基因型，以改善个人的健康结果，资源利用，并接受供应商和患者 一模一样。该假设将通过三个目标进行检验： 目的1：确定LS中最佳的基因特异性结肠镜检查方案，并估计改良的 资源利用（结肠镜检查需求）与个性化LS监测方法。使用 通过模拟建模，我们将改进LS-CRC模型，以预测多种策略的长期结果 对于四种MMR基因（MLH 1、MSH 2、MSH 6和PMS 2）中的每一种，具有不同的（a）监测间隔。这 将使我们能够估计结肠镜检查的数量与当前和各种方案的评价。 目的2：评估纳入非侵入性CRC筛查方式的影响，如粪便检查 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 载波我们将使用我们的模型来评估一种新的，混合的方法来监测CRC， 结肠镜检查的非侵入性方法，以尽量减少结肠镜检查的过度使用， 通过提高依从性和节省成本来实现成果。 目标3：评估障碍，促进者和对当前和新的，个性化的，基因特异性的态度 CRC监测战略。我们将评估对结肠镜检查有或没有非侵入性CRC的态度 在医疗服务提供者和患者中进行筛查测试。 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， 优化效率和成本效益的一次总付。本提案的结果将提供证据支持 停止在LS中过度使用结肠镜检查。

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.