Molecular testing for Lynch syndrome in people with colorectal cancer: systematic reviews and economic evaluation

Abstract

BackgroundInherited 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 andBRAFV600E testing can be conducted on tumour material to rule out certain sporadic cancers.ObjectivesTo investigate whether testing for LS in CRC patients using MSI or IHC (with or withoutMLH1promoter methylation testing andBRAFV600E 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 methodsSystematic 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.ResultsTen 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,BRAFV600E andMLH1promoter methylation testing would be cost-effective at a threshold of £20,000 per quality-adjusted life-year (QALY). The incremental cost-effectiveness ratio for this strategy was £11,008 per QALY compared with no screening. Screening without tumour tests is not predicted to be cost-effective.LimitationsMost 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.ConclusionsSystematic 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.Study registrationThis study is registered as PROSPERO CRD42016033879.FundingThe National Institute for Health Research Health Technology Assessment programme.

Mismatch repair protein loss in breast cancer: clinicopathological associations in a large British Columbia cohort

“…Currently, universal testing in colorectal cancer is recommended by the National Comprehensive Cancer Network and the Evaluation of Genomic Applications in Practice and Prevention Working Group [7] as neither Amsterdam criteria nor Bethesda guidelines [8] can entirely identify all mutation carriers [9]. Likewise, supporting evidence is growing for systematic screening of MMR in endometrial cancers, reflecting the similar rates of Lynch Syndrome in patients presenting with endometrial carcinoma and colorectal carcinoma [11][12].…”

The predicted impact and cost‐effectiveness of systematic testing of people with incident colorectal cancer for Lynch syndrome

“…We adopted a similar approach to that applied by the UK Health Technology Assessment report, using published parameters for developing our natural history model . Briefly, CRC development in LS carriers was modelled as cumulative CRC risk, with and without colonoscopic surveillance, for incident CRC and for second CRC in treated individuals .…”

“…In Stage 1 and 2 analyses, we assumed that colonoscopic surveillance (with polypectomy if required) reduces the incidence of CRC and also downstages a proportion of the cancers not prevented. The estimated hazard ratio (HR) for first CRC in LS carriers undergoing 2‐ or 3‐yearly colonoscopic surveillance ( v no surveillance) was 0.387, for those undergoing annual surveillance it was assumed to be 0.3. We analysed stage‐specific CRC 5‐year survival for people with CRC .…”

“…Pooled estimates of sensitivity and specificity for MMR immunohistochemistry and microsatellite instability testing were used . The sensitivity and specificity of gene panel testing were each assumed to be 100% .…”

“…We assumed that each LS proband has a mean of six relatives eligible for cascade testing (equal numbers of children, siblings, and siblings' children), of whom 1.42 are found to be LS carriers after predictive genetic testing. This number was estimated by multiplying the number of eligible relatives (six) by the proband's referral rate for relatives (0.90) and the relatives' adherence rates to genetic counselling (0.78) and predictive genetic testing (0.77), and by the expected proportion of relatives with LS (44%) (, section 7) …”