Molecular testing for Lynch syndrome in people with colorectal cancer: systematic reviews and economic evaluation
Molecular testing for Lynch syndrome in people with colorectal cancer: systematic reviews and economic evaluation
复制标题
DOI：
10.3310/hta21510
复制
发表时间：
2017-09-01
影响因子：
3.6
通讯作者：
Hyde, Chris
中科院分区：
文献类型：
--
作者：
Snowsill, Tristan;Coelho, Helen;Hyde, Chris
背景：脱氧核糖核酸 (DNA) 错配修复 (MMR) 基因的遗传性突变会导致结直肠癌 (CRC)、妇科癌症和其他癌症（称为林奇综合征 (LS)）的风险增加。可以向具有已知 LS 致病突变的个体提供降低风险的干预措施。这些突变可以通过对 MMR 基因进行全面测试来识别，但这对于普通人群来说成本高昂。基于肿瘤的检测——微卫星不稳定性 (MSI) 和 MMR 免疫组织化学 (IHC)——用于 CRC 患者，以识别 LS 高风险个体进行基因检测。可以对肿瘤材料进行 MLH1（MutL 同源物 1）启动子甲基化和 BRAF V600E 检测，以排除某些散发性癌症。 目的：调查使用 MSI 或 IHC（有或没有 MLH1 启动子甲基化检测和 BRAF V600E 检测）对 CRC 患者进行 LS 检测是否具有临床效果（在识别 Lynch 综合征和改善预后方面） 审查方法：对已发表的关于 LS 的 MSI 和/或 IHC 测试的诊断测试准确性研究、CRC 患者 LS 筛查的端到端研究以及 CRC 患者 LS 筛查的经济评估的已发表文献进行了系统审查。进行了基于模型的经济评估，以根据诊断测试准确性审查的结果推断长期结果。该模型是作者之前开发的模型的扩展。结果：确定了 10 项研究，评估了 MSI 和/或 IHC 测试在 CRC 患者中识别 LS 的诊断测试准确性。对于MSI测试，敏感性范围为66.7%至100.0%，特异性范围为61.1%至92.5%。对于 IHC，敏感性范围为 80.8% 至 100.0%，特异性范围为 80.5% 至 91.9%。当显示低水平 MSI 的肿瘤被视为阳性结果时，MSI 检测的敏感性增加，但特异性下降。尚未发现对 CRC 患者进行 LS 筛查的端到端研究。确定了 CRC 筛查 LS 的九项经济评估。纳入的研究均不完全符合决策问题，因此需要进行新的经济评估。经济评估的基本案例结果表明，在每质量调整生命年 (QALY) 20,000 磅的阈值下，使用 IHC、BRAF V600E 和 MLH1 启动子甲基化测试对 CRC 患者进行 LS 筛查将具有成本效益。与不进行筛查相比，该策略的增量成本效益比为每 QALY 11,008 磅。预计不进行肿瘤测试的筛查具有成本效益。 局限性：大多数确定的诊断测试准确性研究被认为存在偏倚风险，或者是在不具有代表性的样本中进行的。没有直接证据表明筛查可以改善长期结果。未进行概率敏感性分析。 结论：系统评价证据表明，基于 MSI 和 IHC 的检测可用于识别 CRC 患者的 LS，尽管所确定的研究中使用的方法和研究结果存在异质性。没有高质量的经验证据表明筛查可以改善长期结果，因此需要使用建模的证据关联方法。筛查是否具有成本效益的关键决定因素是基于肿瘤的检测的准确性、未经监测的结直肠癌风险、确定进行级联检测的亲属数量、结肠镜监测的有效性以及基因检测的接受程度。未来的工作应该调查遗传性 CRC 的更多病因筛查以及子宫内膜癌患者的 LS 筛查。
Background: Inherited mutations in deoxyribonucleic acid (DNA) mismatch repair (MMR) genes lead to an increased risk of colorectal cancer (CRC), gynaecological cancers and other cancers, known as Lynch syndrome (LS). Risk-reducing interventions can be offered to individuals with known LS-causing mutations. The mutations can be identified by comprehensive testing of the MMR genes, but this would be prohibitively expensive in the general population. Tumour-based tests-microsatellite instability (MSI) and MMR immunohistochemistry (IHC) - are used in CRC patients to identify individuals at high risk of LS for genetic testing. MLH1 (MutL homologue 1) promoter methylation and BRAF V600E testing can be conducted on tumour material to rule out certain sporadic cancers.Objectives: To investigate whether testing for LS in CRC patients using MSI or IHC (with or without MLH1 promoter methylation testing and BRAF V600E testing) is clinically effective (in terms of identifying Lynch syndrome and improving outcomes for patients) and represents a cost-effective use of NHS resources.Review methods: Systematic reviews were conducted of the published literature on diagnostic test accuracy studies of MSI and/or IHC testing for LS, end-to-end studies of screening for LS in CRC patients and economic evaluations of screening for LS in CRC patients. A model-based economic evaluation was conducted to extrapolate long-term outcomes from the results of the diagnostic test accuracy review. The model was extended from a model previously developed by the authors.Results: Ten studies were identified that evaluated the diagnostic test accuracy of MSI and/or IHC testing for identifying LS in CRC patients. For MSI testing, sensitivity ranged from 66.7% to 100.0% and specificity ranged from 61.1% to 92.5%. For IHC, sensitivity ranged from 80.8% to 100.0% and specificity ranged from 80.5% to 91.9%. When tumours showing low levels of MSI were treated as a positive result, the sensitivity of MSI testing increased but specificity fell. No end-to-end studies of screening for LS in CRC patients were identified. Nine economic evaluations of screening for LS in CRC were identified. None of the included studies fully matched the decision problem and hence a new economic evaluation was required. The base-case results in the economic evaluation suggest that screening for LS in CRC patients using IHC, BRAF V600E and MLH1 promoter methylation testing would be cost-effective at a threshold of 20,000 pound per quality-adjusted life-year (QALY). The incremental cost-effectiveness ratio for this strategy was 11,008 pound per QALY compared with no screening. Screening without tumour tests is not predicted to be cost-effective.Limitations: Most of the diagnostic test accuracy studies identified were rated as having a risk of bias or were conducted in unrepresentative samples. There was no direct evidence that screening improves long-term outcomes. No probabilistic sensitivity analysis was conducted.Conclusions: Systematic review evidence suggests that MSI- and IHC-based testing can be used to identify LS in CRC patients, although there was heterogeneity in the methods used in the studies identified and the results of the studies. There was no high-quality empirical evidence that screening improves long-term outcomes and so an evidence linkage approach using modelling was necessary. Key determinants of whether or not screening is cost-effective are the accuracy of tumour-based tests, CRC risk without surveillance, the number of relatives identified for cascade testing, colonoscopic surveillance effectiveness and the acceptance of genetic testing. Future work should investigate screening for more causes of hereditary CRC and screening for LS in endometrial cancer patients.