Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York; Division of Digestive and Liver Diseases, Columbia University Irving Medical Cancer and Vagelos College of Physicians and Surgeons, New York, New York.
Division of General Medicine, Columbia University Irving Medical Cancer and Vagelos College of Physicians and Surgeons, New York, New York.
Gastroenterology. 2021 Aug;161(2):453-462.e15. doi: 10.1053/j.gastro.2021.04.010. Epub 2021 Apr 9.
Lynch syndrome is associated with pathogenic variants in 4 mismatch repair (MMR) genes that increase lifetime risk of colorectal cancer. Guidelines recommend intensive colorectal cancer surveillance with colonoscopy every 1-2 years starting at age 25 years for all carriers of Lynch syndrome-associated variants, regardless of gene product. We constructed a simulation model to analyze the effects of different ages of colonoscopy initiation and surveillance intervals for each MMR gene (MLH1, MSH2, MSH6, and PMS2) on colorectal cancer incidence and mortality, quality-adjusted life-years, and cost.
Using published literature, we developed a Markov simulation model of Lynch syndrome progression for patients with each MMR variant. The model simulated clinical trials of Lynch syndrome carriers, varying age of colonoscopy initiation (5-year increments from 25-40 years), and surveillance intervals (1-5 years). We assessed the optimal strategy for each gene, defined as the strategy with the highest quality-adjusted life-years and incremental cost-effectiveness ratio below a $100,000 willingness-to-pay threshold.
Optimal surveillance for patients with pathogenic variants in the MLH1 and MSH2 genes was colonoscopy starting at age 25 years, with 1- to 2-year surveillance intervals. Initiating colonoscopy at age 35 and 40 years, with 3-year intervals, was cost-effective for patients with pathogenic variants in MSH6 or PMS2, respectively.
We developed a simulation model to select optimal surveillance starting ages and intervals for patients with Lynch syndrome based on MMR variant. The model supports recommendations for intensive surveillance of patients with Lynch syndrome-associated variants in MLH1 or MSH2. However, for patients with Lynch syndrome-associated variants of MSH6 or PMS2, later initiation of surveillance at 35 and 40 years, respectively, and at 3-year intervals, can be considered.
林奇综合征与 4 个错配修复（MMR）基因中的致病性变异有关，这些变异会增加终生结直肠癌的风险。指南建议所有携带林奇综合征相关变异的患者从 25 岁开始，无论基因产物如何，都应进行密集的结直肠癌监测，每 1-2 年进行一次结肠镜检查。我们构建了一个模拟模型，以分析不同年龄开始结肠镜检查和每个 MMR 基因（MLH1、MSH2、MSH6 和 PMS2）的监测间隔对结直肠癌发病率和死亡率、质量调整生命年和成本的影响。
我们使用已发表的文献为每个 MMR 变异的患者开发了林奇综合征进展的马尔可夫模拟模型。该模型模拟了林奇综合征携带者的临床试验，结肠镜检查的起始年龄（从 25 岁到 40 岁每 5 岁增加一次）和监测间隔（1-5 年）。我们评估了每个基因的最佳策略，定义为质量调整生命年最高且增量成本效益比低于 100,000 美元的意愿支付阈值的策略。
MLH1 和 MSH2 基因致病性变异患者的最佳监测方案是 25 岁开始结肠镜检查，监测间隔为 1-2 年。对于 MSH6 或 PMS2 致病性变异患者，分别在 35 岁和 40 岁开始结肠镜检查，间隔 3 年是具有成本效益的。
我们开发了一个模拟模型，根据 MMR 变异为林奇综合征患者选择最佳的监测起始年龄和间隔。该模型支持对 MLH1 或 MSH2 中携带林奇综合征相关变异的患者进行密集监测的建议。然而，对于携带 MSH6 或 PMS2 林奇综合征相关变异的患者，可以考虑分别在 35 岁和 40 岁开始，间隔 3 年进行监测。
