3 Evidence

The diagnostics advisory committee (section 7) considered evidence on testing strategies using immunohistochemistry (IHC) and microsatellite instability (MSI) testing for Lynch syndrome from several sources. Full details of all the evidence are in the committee papers.

3.1 The external assessment group (EAG) did a systematic review to identify evidence on the clinical effectiveness and diagnostic accuracy of IHC- and MSI-based testing strategies for detecting Lynch syndrome in people with endometrial cancer.

Test performance

3.2 The EAG identified 41 studies (reported in 44 papers) with data on the test accuracy of IHC- and MSI-based strategies for detecting Lynch syndrome in people with endometrial cancer, prevalence of Lynch syndrome in this population, and concordance of IHC and MSI testing done on endometrial tumour samples. One unpublished study (PETALS) was also available as academic in confidence.

3.3 Two studies were done in the UK (Anagnostopoulos et al. 2017 and PETALS). Nine studies (Backes et al. 2009, Bruegl et al. 2017, Buchanan et al. 2014, Dillon et al. 2017, Dudley et al. 2015, Egoavil et al. 2013, Hampel et al. 2006, PETALS, Svampane et al. 2014) were in unselected populations. That is, all patients diagnosed with endometrial cancer during the study's recruitment period were included.

3.4 Seven complete test accuracy studies were identified. These were studies in which people who had IHC or MSI testing, with or without MLH1promoter hypermethylation testing, went on to have reference standard testing whatever the results of the index tests were. The EAG only included studies in which at least 95% of people who had index tests also had a reference standard test.

3.5 Data on the prevalence of Lynch syndrome from 33 studies and concordance between IHC and MSI-based testing in 23 studies were also extracted.

Prevalence of Lynch syndrome in people with endometrial cancer

3.6 Prevalence of Lynch syndrome was lower in studies that recruited unselected samples of people (which matches the population for this assessment). The median value was 3.2%. In the studies with unselected samples, variants in the MSH6 mismatch repair (MMR) gene were the most common, then MSH2.

Accuracy of index tests

3.7 The EAG did not do a meta-analysis of test accuracy because the few studies identified were heterogeneous. Individual patient data from Lu et al. (2007) were used to inform strategy accuracy estimates in the economic model base case.

3.8 Accuracy of the index tests, that is, IHC- and MSI-based testing strategies used alone, in combination, and with or without subsequent MLH1 promoter hypermethylation testing, were compared against a reference standard used to determine if a person did have Lynch syndrome. The reference standard used was germline testing (testing of non-tumour tissue) for Lynch syndrome-associated mutations in MMR genes.

IHC testing alone

3.9 Data on the accuracy of IHC alone (that is, without MLH1 promoter hypermethylation testing) were available from 5 studies (Berends et al. 2003, Chao et al. 2019, Lu et al. 2007, Rubio et al. 2016, Tian et al. 2019). Sensitivity values ranged from 66.7% to 100%. Specificity values ranged from 6.5% to 83.3%.

MSI testing alone

3.10 Data on the accuracy of MSI testing alone (that is, without MLH1 promoter hypermethylation testing) were available from 4 studies (Berends et al. 2003, Chao et al. 2019, Lu et al. 2007, Rubio et al. 2016). Sensitivity values ranged from 41.7% to 100%. Specificity values ranged from 69.2% to 88.9%.

MLH1 promoter hypermethylation testing after IHC or MSI testing

3.11 There were data from 4 studies on the accuracy of IHC- or MSI-based testing strategies when these tests were done before MLH1promoter hypermethylation testing. The studies varied in when promoter hypermethylation testing was done:

In 2 studies (Lu et al. 2007, Salvador et al. 2019) MLH1 promoter hypermethylation testing was done for tumours that were categorised as MSI-H or had IHC loss (MLH1 or MLH1/PMS2). In Lu et al. (2007), 92.3% of tumours tested were hypermethylated.
In Chao et al. (2019) MLH1 promoter hypermethylation testing was done only if MLH1 loss was seen on IHC; 80% of tumours tested were hypermethylated.
In Ring et al. (2016) the circumstances for MLH1 promoter hypermethylation testing were not reported.

Sensitivity values ranged from 90.5% to 100%. Specificity values ranged from 6.6% to 92.3%.

IHC and MSI testing done on the same population

3.12 Four of the complete test accuracy studies assessed both IHC and MSI testing on the same population (Lu et al. 2007, Berends et al. 2003, Chao et al. 2019, Rubio et al. 2016). Point estimates for sensitivity ranged from 66.7% to 100% for IHC and from 41.7% to 100% for MSI. For specificity, point estimates for IHC ranged from 60.9% to 83.3%. For MSI the range was 69.2% to 89.9%. The EAG commented that there was no statistically significant difference between the tests.

Concordance between IHC and MSI testing

3.13 Complete concordance between IHC and MSI testing was reported in 20 studies. That is, in these studies IHC and MSI testing were both done on samples whatever the results of 1 of the tests. There was a median agreement of 91.8% with a range of 68.2% to 100%.

Clinical effectiveness

3.14 The EAG did a systematic review to identify evidence on the benefits and harms of testing for Lynch syndrome for people with endometrial cancer and their relatives, with a focus on the benefits and harms of colorectal and endometrial cancer surveillance. No studies met the inclusion criteria.

Cost effectiveness

Systematic review of cost-effectiveness evidence

3.15 The EAG did a systematic review to find studies assessing the cost effectiveness of testing for Lynch syndrome in people with endometrial cancer using IHC- and MSI-based strategies, compared with no testing for Lynch syndrome. Five studies were identified (Resnick et al. 2009, Kwon et al. 2011, Bruegl et al. 2014, Goverde et al. 2016, Snowsill et al. 2019). Snowsill et al. (2019) was the only study that took a UK perspective. The EAG thought that Snowsill et al. (2019) provided a comprehensive reference model. It used this study and previous reviews of testing for Lynch syndrome for people with colorectal cancer (Snowsill et al. 2014; Snowsill et al. 2017) to inform its modelling approach.

Economic model

3.16 The EAG developed a de novo economic model to estimate the costs and benefits of offering testing to identify Lynch syndrome (using different testing strategies) for people with a new diagnosis of endometrial cancer. The EAG's model had 2 parts. A decision tree (in Excel) modelled the accuracy and costs of the different testing strategies to identify people with Lynch syndrome after being diagnosed with endometrial cancer (known as probands; the first family member to have medical testing for a genetic condition). This also included testing for the relatives of people diagnosed with Lynch syndrome (cascade testing). A second model (in R) then modelled the longer-term effects of this diagnosis (and adopting surveillance and risk-reducing interventions) on colorectal and endometrial cancer incidence across the rest of people's lives. This was for both the first family member to have Lynch syndrome identified after endometrial cancer and their relatives.

Population

3.17 The cohort of people entering the model with recently diagnosed endometrial cancer was 48 years old. Relatives diagnosed with Lynch syndrome could be any age between 25 and 74 years old. The prevalence of Lynch syndrome in this population (3.2%) was taken from the PETALS study. The proportion of each MMR gene mutation in people with Lynch syndrome diagnosed after endometrial cancer was pooled from 4 studies (Hampel et al. 2006, Bruegl et al. 2017, Egoavil et al. 2013, unpublished PETALS study).

Model inputs

Diagnostic accuracy

3.18 The EAG used data from 1 study (Lu et al. 2007) to inform estimates of sensitivity and specificity for the different test strategies for the model. One study was used for consistency (that is, accuracy estimates produced from the same population) and to avoid illogical results, which may have happened if different studies were used for different strategies. The EAG did not consider that pooling results across studies was appropriate because the few studies identified were heterogeneous. Data from a recent meta-analysis (Snowsill et al. 2019), Chao et al. (2019) and the unpublished PETALS study were used in scenario analyses.

Colorectal cancer incidence and effect of surveillance

3.19 Age-related incidence of colorectal cancer for people with Lynch syndrome was taken from Snowsill et al. (2019). This was assumed to differ by which MMR gene was mutated and was estimated using gene specific data from the Prospective Lynch Syndrome Database. A log-normal distribution was fitted to the data to estimate the incidence of colorectal cancer over time. A hazard ratio of 0.387 (Jarvinnen et al. 2000) was applied to estimate the effect of colonoscopic surveillance on reducing the incidence of colorectal cancer. If a person was having colonoscopic surveillance because Lynch syndrome had been diagnosed, this was assumed to identify colorectal cancer at an earlier stage (as well as reducing incidence).

Endometrial cancer incidence, surgical prophylaxis and gynaecological surveillance

3.20 Incidence data for endometrial cancer were taken from the Prospective Lynch Syndrome Database (Dominguez-Valentin et al. 2020). The incidence differed by which MMR gene was mutated. A fitted piecewise linear model was used to estimate annual incidence at different ages. Data from Cancer Research UK on uterine cancer survival statistics were used for the incidence of death from endometrial cancer, assuming no difference for people with and without Lynch syndrome.

3.21 Female relatives with Lynch syndrome could choose to have hysterectomy with removal of both ovaries and fallopian tubes (bilateral salpingo-oophorectomy), which eliminated all future risk of endometrial cancer. The uptake of this surgery increased with age, from 20% at 35 years old to 80% at 75 years old. The EAG highlighted considerable uncertainty about the benefit of gynaecological surveillance, and variation in practice across the UK. In its base case, the EAG assumed all female relatives with Lynch syndrome who were 25 years or older (who had not had a hysterectomy) would have annual non-invasive gynaecological surveillance done by a GP. Of these, 10% would be referred for invasive surveillance (gynaecological examination, pelvic ultrasound, cancer antigen‑125 analysis and aspiration biopsy). Gynaecological surveillance was assumed to reduce mortality by 10.2% (Snowsill et al. 2017).

Costs

3.22 Most costs were taken from work done for previous NICE guidance on testing for Lynch syndrome after colorectal cancer (Snowsill et al. 2017). Hospital-related costs were from the most current NHS reference tables. The EAG used test costs from the UK Genetic Testing Network (confirmed by clinical experts) in the base case.

Health-related quality of life

3.23 Baseline health-related quality of life for people in the model was calculated based on age and sex. Testing, the results of a diagnosis of Lynch syndrome, surveillance and risk-reducing interventions were assumed to have no effect on health-related quality of life.

3.24 In the base case, a decrease in health-related quality of life for people with colorectal cancer was only assumed to occur at stage 4 (a multiplier of 0.789; Snowsill et al. 2017). Because this may underestimate the effect of colorectal cancer on a person's quality of life, the EAG did a scenario analysis in which people with stage 3 colorectal cancer also had a decrease in health-related quality of life. The health-related quality of life of people with endometrial cancer decreased by 0.036 (Snowsill et al. 2017) for 1 year.

Base-case results

3.25 When compared independently with no testing, all strategies had an incremental cost-effectiveness ratio (ICER) of less than £17,500 per quality-adjusted life year (QALY) gained. The fully incremental analysis (that is, all testing strategies compared against each other as well as no testing) is shown in table 1.

Table 1 Fully incremental base-case cost-effectiveness results (deterministic)

Strategy	Incremental costs	Incremental QALYs	ICER	Net monetary benefit (compared with no testing; using a maximum ICER of £20,000 per QALY gained)
No testing	–	–	–	£0
Strategy 2: MSI then MLH1promoter hypermethylation testing	£520	0.0419	Extendedly dominated	£323
Strategy 4: IHC then MLH1promoter hypermethylation testing	£630	0.0669	£9,460	£705
Strategy 6: MSI then IHC then MLH1promoter hypermethylation testing	£90	-0.0249	Dominated	£124
Strategy 3: IHC alone	£160	0.0012	£133,330	£570
Strategy 1: MSI alone	£50	0.0002	£250,000	£529
Strategy 8: IHC then MSI then MLH1promoter hypermethylation testing	£30	-0.0012	Dominated	£475
Strategy 10: MSI and IHC then MLH1promoter hypermethylation testing	£20	0.0000	Dominated	£451
Strategy 7: IHC then MSI	£185	0.0002	£925,000	£344
Strategy 5: MSI then IHC	£5	0.0000	Dominated	£341
Strategy 9: MSI and IHC	£45	0.0000	Dominated	£302
Strategy 11: No index testing (straight to germline testing)	£135	-0.0019	Dominated	£168

Abbreviations in table: ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year. Extendedly dominated means the ICER for a given strategy is higher than that of the next, more effective, alternative that is not extendedly dominated or dominated (that is, it is dominated by a combination of 2 alternatives and should not be used to calculate appropriate ICERs). Dominated means if a strategy has higher costs and worse outcomes than an alternative strategy.

3.26 The probabilistic ICER for strategy 4 was £11,600 per QALY gained compared with no testing (compared with a deterministic ICER of £9,420 per QALY gained). At a maximum ICER of £20,000 per QALY gained, which is what NICE normally considers a cost-effective use of NHS resources, this strategy had a 93% probability of being cost effective compared with no testing.

Scenario analyses

3.27 The EAG did several scenario analyses in its main report:

Scenario 1: Using alternative test accuracy estimates (for strategies 1, 2, 3 and 4) from the unpublished PETALS study.
Scenario 2: Using alternate test costs from a micro-costing study (Ryan et al. 2019).
Scenario 3: Combining scenarios 1 and 2.
Scenario 4: Including further disutility for colorectal cancer (for stage 3) and people with endometrial cancer have the same utility as people with stage 4 colorectal cancer in their last year of life.
Scenario 5: Excluding gynaecological surveillance (cost and benefits).
Scenario 6: Colonoscopy assumed to be every 3 years (instead of 2).
Scenario 7: Aspirin removed from model.
Scenario 8: Surveillance for colorectal cancer assumed to have no benefit.

3.28 In fully incremental analysis in the base case, MLH1 promoter hypermethylation testing (strategy number 4) was the most cost-effective strategy. In all scenarios except scenario 8, this strategy had an ICER of less than £12,000 per QALY gained in fully incremental analyses. In scenario 8, the ICER was £20,740 per QALY gained. In all scenarios except scenario 4, all other strategies were either extendedly dominated (the ICER was higher than that of the next, more effective, alternative), fully dominated (had higher costs and worse outcomes than an alternative strategy) or had ICERs of over £90,000 per QALY gained (fully incremental analysis). In scenario 4, the ICER for IHC testing alone was £41,180 per QALY gained in the fully incremental analysis.

3.29 The EAG also did more scenario analyses in an addendum to its main report. In additional scenario 1, diagnostic accuracy estimates from a meta-analysis done for recent modelling work (Snowsill et al. 2019) were used instead of estimates from Lu et al. (2007). Accuracy data were only available for strategies using MSI and IHC alone (with or without subsequent MLH1 promoter hypermethylation; strategies 1 to 4 in this assessment). In fully incremental analysis, IHC with MLH1 promoter hypermethylation testing had an ICER of £10,464 per QALY gained and IHC alone had an ICER of about £100,000 per QALY gained. MSI and MSI done beforeMLH1 promoter hypermethylation were either dominated or extendedly dominated.

3.30 In additional scenario 2, accuracy data from Chao et al. (2019) were used. Only accuracy estimates for IHC and MSI alone were available. Here, MSI and no testing extendedly dominated IHC testing and MSI testing had an ICER of £10,455 per QALY gained compared with no testing. In Chao et al. higher estimates of both sensitivity and specificity were seen for MSI testing than IHC testing.

3.30.1 In additional scenario analysis 3, people with variants of uncertain significance and people who were assumed to have Lynch syndrome did not gain any benefit from surveillance and risk-reducing interventions (in the base case, they were assumed to get the same benefit as people with Lynch syndrome). IHC with MLH1 promoter hypermethylation had an ICER of £9,514 per QALY gained and dominated or extendedly dominated all other strategies.

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Testing strategies for Lynch syndrome in people with endometrial cancer