{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T03:48:20Z","timestamp":1780544900983,"version":"3.54.1"},"reference-count":126,"publisher":"National Institute for Health and Care Research","issue":"42","license":[{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/www.nationalarchives.gov.uk\/doc\/non-commercial-government-licence\/non-commercial-government-licence.htm"}],"funder":[{"DOI":"10.13039\/501100000664","name":"Health Technology Assessment programme","doi-asserted-by":"publisher","award":["NIHR129546"],"award-info":[{"award-number":["NIHR129546"]}],"id":[{"id":"10.13039\/501100000664","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journalslibrary.nihr.ac.uk"],"crossmark-restriction":false},"short-container-title":["Health Technol Assess"],"abstract":"<jats:sec id=\"abs1-1\"><jats:title>Background<\/jats:title><jats:p>Lynch syndrome is an inherited genetic condition that is associated with an increased risk of certain cancers. The National Institute for Health and Care Excellence has recommended that people with colorectal cancer are tested for Lynch syndrome. Routine testing for Lynch syndrome among people with endometrial cancer is not currently conducted.<\/jats:p><\/jats:sec><jats:sec id=\"abs1-2\"><jats:title>Objectives<\/jats:title><jats:p>To systematically review the evidence on the test accuracy of immunohistochemistry- and microsatellite instability-based strategies to detect Lynch syndrome among people who have endometrial cancer, and the clinical effectiveness and the cost-effectiveness of testing for Lynch syndrome among people who have been diagnosed with endometrial cancer.<\/jats:p><\/jats:sec><jats:sec id=\"abs1-3\"><jats:title>Data sources<\/jats:title><jats:p>Searches were conducted in the following databases, from inception to August 2019 \u2013 MEDLINE ALL, EMBASE (both via Ovid), Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (both via Wiley Online Library), Database of Abstracts of Reviews of Effects, Health Technology Assessment Database (both via the Centre for Reviews and Dissemination), Science Citation Index, Conference Proceedings Citation Index \u2013 Science (both via Web of Science), PROSPERO international prospective register of systematic reviews (via the Centre for Reviews and Dissemination), NHS Economic Evaluation Database, Cost-Effectiveness Analysis Registry, EconPapers (Research Papers in Economics) and School of Health and Related Research Health Utilities Database. The references of included studies and relevant systematic reviews were also checked and experts on the team were consulted.<\/jats:p><\/jats:sec><jats:sec id=\"abs1-4\"><jats:title>Review methods<\/jats:title><jats:p>Eligible studies included people with endometrial cancer who were tested for Lynch syndrome using immunohistochemistry- and\/or microsatellite instability-based testing [with or without mutL homologue 1 (<jats:italic>MLH1<\/jats:italic>) promoter hypermethylation testing], with Lynch syndrome diagnosis being established though germline testing of normal (non-tumour) tissue for constitutional mutations in mismatch repair. The risk of bias in studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool, the Consolidated Health Economic Reporting Standards and the Philips\u2019 checklist. Two reviewers independently conducted each stage of the review. A meta-analysis of test accuracy was not possible because of the number and heterogeneity of studies. A narrative summary of test accuracy results was provided, reporting test accuracy estimates and presenting forest plots. The economic model constituted a decision tree followed by Markov models for the impact of colorectal and endometrial surveillance, and aspirin prophylaxis with a lifetime time horizon.<\/jats:p><\/jats:sec><jats:sec id=\"abs1-5\"><jats:title>Results<\/jats:title><jats:p>The clinical effectiveness search identified 3308 studies; 38 studies of test accuracy were included. (No studies of clinical effectiveness of endometrial cancer surveillance met the inclusion criteria.) Four test accuracy studies compared microsatellite instability with immunohistochemistry. No clear difference in accuracy between immunohistochemistry and microsatellite instability was observed. There was some evidence that specificity of immunohistochemistry could be improved with the addition of methylation testing. There was high concordance between immunohistochemistry and microsatellite instability. The economic model indicated that all testing strategies, compared with no testing, were cost-effective at a willingness-to-pay threshold of \u00a320,000 per quality-adjusted life-year. Immunohistochemistry with<jats:italic>MLH1<\/jats:italic>promoter hypermethylation testing was the most cost-effective strategy, with an incremental cost-effectiveness ratio of \u00a39420 per quality-adjusted life-year. The second most cost-effective strategy was immunohistochemistry testing alone, but incremental analysis produced an incremental cost-effectiveness ratio exceeding \u00a3130,000. Results were robust across all scenario analyses. Incremental cost-effectiveness ratios ranged from \u00a35690 to \u00a320,740; only removing the benefits of colorectal cancer surveillance produced an incremental cost-effectiveness ratio in excess of the \u00a320,000 willingness-to-pay threshold. A sensitivity analysis identified the main cost drivers of the incremental cost-effectiveness ratio as percentage of relatives accepting counselling and prevalence of Lynch syndrome in the population. A probabilistic sensitivity analysis showed, at a willingness-to-pay threshold of \u00a320,000 per quality-adjusted life-year, a 0.93 probability that immunohistochemistry with<jats:italic>MLH1<\/jats:italic>promoter hypermethylation testing is cost-effective, compared with no testing.<\/jats:p><\/jats:sec><jats:sec id=\"abs1-6\"><jats:title>Limitations<\/jats:title><jats:p>The systematic review excluded grey literature, studies written in non-English languages and studies for which the reference standard could not be established. Studies were included when Lynch syndrome was diagnosed by genetic confirmation of constitutional variants in the four mismatch repair genes (i.e.<jats:italic>MLH1<\/jats:italic>, mutS homologue 2, mutS homologue 6 and postmeiotic segregation increased 2). Variants of uncertain significance were reported as per the studies. There were limitations in the economic model around uncertainty in the model parameters and a lack of modelling of the potential harms of gynaecological surveillance and specific pathway modelling of genetic testing for somatic mismatch repair mutations.<\/jats:p><\/jats:sec><jats:sec id=\"abs1-7\"><jats:title>Conclusion<\/jats:title><jats:p>The economic model suggests that testing women with endometrial cancer for Lynch syndrome is cost-effective, but that results should be treated with caution because of uncertain model inputs.<\/jats:p><\/jats:sec><jats:sec id=\"abs1-8\"><jats:title>Future work<\/jats:title><jats:p>Randomised controlled trials could provide evidence on the effect of earlier intervention on outcomes and the balance of benefits and harms of gynaecological cancer surveillance. Follow-up of negative cases through disease registers could be used to determine false negative cases.<\/jats:p><\/jats:sec><jats:sec id=\"abs1-9\"><jats:title>Study registration<\/jats:title><jats:p>This study is registered as PROSPERO CRD42019147185.<\/jats:p><\/jats:sec><jats:sec id=\"abs1-10\"><jats:title>Funding<\/jats:title><jats:p>This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in<jats:italic>Health Technology Assessment<\/jats:italic>; Vol. 25, No. 42. See the NIHR Journals Library website for further project information.<\/jats:p><\/jats:sec>","DOI":"10.3310\/hta25420","type":"journal-article","created":{"date-parts":[[2021,6,25]],"date-time":"2021-06-25T10:01:50Z","timestamp":1624615310000},"page":"1-216","update-policy":"https:\/\/doi.org\/10.3310\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Testing strategies for Lynch syndrome in people with endometrial cancer: systematic reviews and economic evaluation"],"prefix":"10.3310","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9054-1940","authenticated-orcid":true,"given":"Chris","family":"Stinton","sequence":"first","affiliation":[{"name":"Warwick Medical School, University of Warwick, Coventry, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0497-8634","authenticated-orcid":true,"given":"Mary","family":"Jordan","sequence":"additional","affiliation":[{"name":"Warwick Medical School, 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