Testing strategies for Lynch syndrome in people with endometrial cancer

IHC testing may give quicker results than MSI testing, which can give patients more chances to join clinical trials

4.3 A patient expert explained that waiting for test results can be a very anxious time. The strategies assessed included IHC and MSI as the first tests used to identify tumours with MMR deficiency. The external assessment group (EAG) commented that it did not find data on the time taken to get test results when using IHC or MSI. However, clinical experts commented that based on their experience in the NHS the time taken to get IHC results (about 1 day) is much shorter than for MSI testing (about 6 weeks). They highlighted that when MSI testing is used, information may not be available for the first multidisciplinary team discussions on a person's cancer where decisions about treatment and further testing are made. They also noted that there is a risk that results arrive weeks later, separate to the histopathology report, may be missed and not acted on. Also, if a person's tumour is quickly identified as having MMR deficiency, they are able to be considered for clinical trials for new treatments such as immunotherapies. Clinical experts highlighted that it is important for all people with cancer to have the opportunity to enter relevant clinical trials, and that this is a way to access new treatments which could benefit them. Clinical experts also commented that an advantage of IHC testing is that it shows which MMR gene is likely to contain a pathogenic mutation. The committee concluded that there may be benefits for clinicians and for patients from using IHC compared with MSI as a first test for potential Lynch syndrome.

The relative accuracy of IHC and MSI testing is uncertain, but IHC may detect more people with Lynch syndrome

4.4 The EAG commented that in studies assessing both MSI and IHC testing on the same sample of patients (4 studies, see section 3.12) there was no statistically significant difference between the accuracy of the tests. But the committee noted that the studies were unlikely to be powered to show any difference. The committee preferred to use comparative estimates of sensitivity and specificity for IHC and MSI from the individual studies, rather than ranges of midpoint estimates from all 4 studies. It noted that sensitivity estimates were generally higher for IHC than for MSI (that is, using IHC as the first test may detect more people with Lynch syndrome). Clinical experts commented that a concern about MSI testing is that it may miss tumours with mutations in MSH6 and highlighted the relatively high prevalence of mutations in this gene in Lynch syndrome-associated endometrial cancer (see section 3.6). The committee further noted that the level of concordance between IHC and MSI studies was in a range of 68% to 100% (see section 3.13). The committee concluded that there is uncertainty about the relative accuracy of IHC and MSI testing for potential Lynch syndrome done on endometrial tumour samples, but that there is some evidence that IHC may detect more people with Lynch syndrome.

The PETALS study is highly relevant for this assessment

4.5 An unpublished manuscript of the PETALS study was given to the committee as academic in confidence. The study authors commented that their results showed that IHC was more sensitive than MSI. The sensitivity of MSI testing was 56.3% compared with 100% for IHC testing. The committee noted that this was in general agreement with the results of the 4 studies directly comparing IHC and MSI in the EAG's systematic review (see section 4.4). The study authors also commented that they did not test everyone who had IHC or MSI testing with a reference standard; people with a negative result for both MSI and IHC testing for Lynch syndrome did not have the reference standard (germline testing) because of the cost. The committee noted that this may be a limitation of the study. The committee concluded that PETALS was likely to be highly relevant for this assessment because it was a recent UK-based study that assessed IHC, MSI and MLH1 promoter hypermethylation testing in a population in the NHS newly diagnosed with endometrial cancer.

There is uncertainty about the effect of colonoscopic surveillance on colorectal cancer incidence

4.6 For the effect of colonoscopic surveillance on colorectal cancer incidence in the model, the EAG used a hazard ratio of 0.387 from Jarvinnen et al. (2000). The committee noted that this was an observational study and that the true effect size is uncertain. The EAG did a scenario analysis in which no benefit of colonoscopy on colorectal cancer incidence was assumed. This was the only scenario in which the incremental cost-effectiveness ratios (ICERs) for all of the testing strategies compared with no testing were above £20,000 per quality-adjusted life year (QALY) gained, although the ICER for strategy 4 (IHC then MLH1promoter methylation testing) was only just higher. Clinical experts commented that it would not be ethical to do a trial in which people with Lynch syndrome were randomised to have colonoscopic surveillance or not. They highlighted that the recent Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG) recommend colonoscopic surveillance for people with Lynch syndrome. The committee concluded that although there is uncertainty about the effect of colonoscopic surveillance on colorectal cancer incidence, the EAG's scenario assuming no benefit was extreme and unlikely to be realistic.

There is uncertainty about the benefit of gynaecological surveillance, but raising awareness of symptoms is likely to improve earlier detection

4.7 Clinical experts commented that the extent of surveillance for gynaecological cancers offered to people with Lynch syndrome varies across the NHS. There was also considerable uncertainty about the effectiveness of this surveillance to reduce the occurrence or severity of gynaecological cancer. The EAG included the cost and impact of gynaecological surveillance in its base-case model but highlighted that removing this from the model in a scenario analysis did not have a large effect on results. Clinical and patient experts (see section 4.1) commented that, even if gynaecological surveillance is not done, raising awareness of the early symptoms of gynaecological cancers to people with Lynch syndrome is likely to improve early diagnosis.

The costs of straight-to-germline testing may have been underestimated

4.8 Strategy 11 assessed the costs and benefits of going straight to germline testing for people diagnosed with endometrial cancer; that is, no first testing of tumour samples to identify people likely to have Lynch syndrome. Clinical experts commented that this would result in more variants of uncertain significance being detected (that is, mutations in MMR genes which may or may not cause Lynch syndrome) because initial tumour tests would not rule out non-pathogenic mutations (with no MMR deficiency in the tumour). This would mean staff time would be needed to analyse and assess if the person should be considered as having Lynch syndrome. Tests on endometrial tumour tissue may be needed in these people to determine if the tumour was MMR-deficient. Costs related to this were not included in the economic model. In addition, clinical experts commented that if everyone with endometrial cancer had germline testing this would drastically increase the workload of genetic services who would need to offer genetic counselling to ensure that informed consent for the tests was obtained. Clinical experts also highlighted that there have been fewer studies done on Lynch syndrome-causing mutations for some ethnic groups, so there were likely to be more variants of uncertain significance identified by a straight-to-germline testing strategy (without the benefit of information from the tumour tests). The committee concluded that the costs of strategy 11 were likely to have been underestimated in the model.

The effect of cancer on health-related quality of life is likely to have been underestimated, which undervalues the benefit of diagnosing Lynch syndrome

4.9 In the economic model, an effect on health-related quality of life for people with colorectal cancer was only assumed to happen at stage 4 of the disease. A relatively small effect on health-related quality of life for people with endometrial cancer was also assumed, which lasted for only 1 year in the model. A scenario analysis in which people with stage 3 colorectal cancer also had reduced health-related quality of life increased the incremental gain in quality-adjusted life years (QALYs) for all strategies compared with no testing (and cost effectiveness compared with no testing). The committee concluded that the effect of cancer on health-related quality of life was likely to have been underestimated in the model, so the cost effectiveness of testing for Lynch syndrome may also have been underestimated.

There is uncertainty about the costs of testing for Lynch syndrome

4.10 The EAG explained that the post-test clinic-related costs and follow-up costs it had used in its model related to time taken to give results of testing to patients. Clinical experts commented that the cost of about £141 used was likely to be an underestimate. The committee also discussed the costs used in the base-case model for the tests. The EAG commented that costs of testing were reducing over time. It had used cost estimates from a micro-costing study (Ryan et al. 2019) in a scenario analysis to investigate this, which were much lower than the base-case values. Using these lower costs improved the cost effectiveness of testing for Lynch syndrome. The committee concluded that there is some uncertainty about the true value of costs associated with testing for Lynch syndrome.

It is appropriate to use a linked-evidence approach to estimate the cost effectiveness of testing for Lynch syndrome after endometrial cancer

4.11 The EAG did not find any evidence on the effect on clinical outcomes of testing for Lynch syndrome when people were diagnosed with endometrial cancer. So, it used a linked-evidence approach to assess:

A clinical expert commented that their hospital has been routinely testing for Lynch syndrome in all people with endometrial cancer for about 5 years. This has led to Lynch syndrome being identified in many families who otherwise would not have known, and for relatives to start cancer surveillance and risk-reducing measures. Clinical experts also highlighted that there is a strong link between Lynch syndrome and an increased risk of cancer. The committee also noted that the strategies all included the gold standard assessment (germline testing) to provide a diagnosis of Lynch syndrome after first testing. The committee concluded that it was appropriate to use a linked-evidence approach to estimate the cost effectiveness of testing for Lynch syndrome after a diagnosis of endometrial cancer.

Testing for Lynch syndrome for people with endometrial cancer is likely to be a cost-effective use of NHS resources

4.12 In the base case all testing strategies had ICERs of under £20,000 per QALY gained compared with no testing. Excluding the scenario in which no benefit was assumed for colonoscopic surveillance on colorectal cancer incidence (which the committee considered was unrealistic, see section 4.6), almost all of the testing strategies had ICERs under £20,000 per QALY gained compared with no testing in scenario analyses. In the scenario in which no benefit for aspirin was assumed, some strategies had ICERs of just over £20,000 per QALY gained. The committee also recalled that the effect of cancer on health-related quality of life was likely to have been underestimated in the model (see section 4.9). If a greater effect of cancer was used this would have improved the cost effectiveness of the testing strategies. The committee concluded that the most likely ICER for testing for Lynch syndrome for people with endometrial cancer is likely to be less than £20,000 per QALY gained and that testing is likely to be a cost-effective use of NHS resources.

IHC then MLH1 promoter hypermethylation testing is likely to be the most cost-effective strategy

4.13 In its base case, the EAG used data from Lu et al. (2007) for the testing strategies' accuracy. This was because this study had individual patient data that could be used to estimate sensitivity and specificity for most of the strategies. But, because of a lack of data, the EAG had to make assumptions to estimate values for MSI testing then MLH1 promoter hypermethylation testing. The EAG explained that its assumption that 66% of MLH1 promoter hypermethylation tests done after MSI testing were correct was based on an estimate used in Snowsill et al. (2019) of the probability ofMLH1 promoter hypermethylation in sporadic tumours with MSI. The committee noted that when test accuracy estimates from Lu et al. (2007), the PETALS study and a recent meta-analysis (Snowsill et al. 2019) were used in the model, IHC then MLH1 promoter hypermethylation testing was consistently the most cost-effective strategy. Accuracy estimates from Chao et al. (2019) had also been used in a scenario analysis (only for IHC alone and MSI alone). Unlike the other studies, sensitivity was higher for MSI than IHC in this study, and MSI testing and no testing extendedly dominated IHC testing. Clinical experts highlighted that the sensitivity estimate from this study was based on 6 people with Lynch syndrome (4 people whose Lynch syndrome was identified by IHC testing and 2 people whose Lynch syndrome was not identified). A clinical expert highlighted that the 2 people whose Lynch syndrome was not identified by IHC had mutations in either the MSH2 or MSH6 gene. They explained that pathogenic mutations in these genes in particular often show some expression on IHC, which can make identifying MMR deficiency more difficult. They highlighted that the sensitivity of IHC to detect such mutations depends on the expertise of the pathologist and will be improved by following guidance on interpreting MMR IHC. The committee concluded that, based on the base case and scenario analyses, IHC then MLH1 promoter hypermethylation testing (then germline testing to confirm a Lynch syndrome diagnosis) was likely to be the most cost-effective strategy.

Laboratories doing IHC testing for MMR proteins should take part in a recognised external quality assurance programme

4.14 Clinical experts emphasised the importance of quality assurance to ensure that IHC testing for MMR proteins is done correctly. They also highlighted the British Association of Gynaecological Pathologists' recommended terminology for reporting mismatch repair protein immunohistochemistry with or without MLH1 promoter methylation results, which will be incorporated in future guidance from the Royal College of Pathologists. The committee concluded that laboratories doing IHC testing for MMR proteins should take part in a recognised external quality assurance programme.

Future developments in testing, interventions and increased testing for Lynch syndrome may affect cost effectiveness

4.15 The committee noted that costs and other parameter estimates used in the economic model can change over time, which may affect the cost effectiveness of testing. For example, if more testing for Lynch syndrome increases the number of people with known Lynch syndrome in the general population, fewer people with the condition will need testing after endometrial cancer, and the prevalence of the condition for those tested will decrease. This could reduce the cost effectiveness of testing. However the committee noted that, in sensitivity analysis, decreasing prevalence of Lynch syndrome to 1.6% only increased the ICER for strategy 4 to about £13,500 per QALY gained. Clinical experts also highlighted ongoing research on further interventions that could be used for people with Lynch syndrome. The committee also noted that the costs of sequencing DNA are decreasing. It concluded that future developments may affect the cost effectiveness of testing strategies, or their relative cost effectiveness compared with each other. The committee concluded that it is important to monitor future developments to identify if any changes to the recommendations are needed.

It is important to monitor the effect of more widespread testing for Lynch syndrome to make sure that the expected benefits are seen in the NHS

4.16 The committee considered it important to monitor the effect of adopting testing for Lynch syndrome for people with endometrial cancer. For example:

Clinical experts commented that there are plans to set up a national registry for Lynch syndrome, but that no funding for this work has yet been identified. The committee concluded that it is important to monitor the outcomes related to implementing more widespread testing for Lynch syndrome after endometrial cancer, to make sure that the expected benefits, as estimated by the model, are seen in the NHS.