Description of the health problem
Purpose of the decision to be made
Lynch syndrome is an inherited genetic condition. It is caused by mutations in genes that are involved in repairing errors that occur in deoxyribonucleic acid (DNA) when cells replicate. When mutations occur in these genes, DNA errors are not repaired. Over time, this can lead to uncontrolled cell growth. Lynch syndrome is associated with an increased risk of cancers, including colorectal, endometrial, gastric, pancreatic and kidney cancers. There is 50 : 50 chance that a person with Lynch syndrome will pass it to their children.
Recently, the National Institute for Health and Care Excellence (NICE) has recommended that people who are diagnosed with colorectal cancer (CRC) are tested for Lynch syndrome.1 Routine testing for Lynch syndrome among people with endometrial cancer is not currently conducted. Detection of Lynch syndrome might lead to reductions in the risk of developing cancer for both the individual and their family members (through surveillance and risk-reducing strategies, such as chemoprevention) and to earlier treatment of cancers.2,3
The external assessment group (EAG) assessed the accuracy of immunohistochemistry (IHC)-based and microsatellite instability (MSI)-based testing strategies to identify people who are at high risk of Lynch syndrome, and assessed the clinical effectiveness and cost-effectiveness of testing for Lynch syndrome among people who have endometrial cancer and their biological relatives. This will inform the NICE Diagnostics Advisory Committee guidance on whether or not testing for Lynch syndrome in people who have endometrial cancer represents a cost-effective use of NHS resources.
Population and target condition
Parts of this section have been reproduced with permission of Stinton et al.4 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) license, which permits others to share and redistribute, for non-commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
Population: people with endometrial cancer
Endometrial cancer (cancer that develops from the lining of the uterus) is the most common gynaecological cancer in the Western world.5 Each year in the UK, there are approximately 9300 new cases of endometrial cancer and 2200 endometrial cancer-related deaths.6,7 The incidence of endometrial cancer generally increases with age, reaching a peak of 97.3 per 100,000 population between the ages of 75 and 79 years.6,7 The most recent estimates suggest that people with endometrial cancers have a 1-year survival rate of 89.6% and a 5-year survival rate of 75.7%.8 Risk factors for the development of endometrial cancer include obesity, nulliparity, early age at menarche, use of hormone-replacement therapy and Lynch syndrome.9–11
Target condition: Lynch syndrome
Lynch syndrome, formally called hereditary non-polyposis colorectal cancer (HNPCC), is a cancer-predisposition syndrome. It is estimated that there are approximately 175,000 people with Lynch syndrome in the UK.12
Lynch syndrome is usually caused by mutations to any one of four DNA mismatch repair (MMR) genes: mutL homologue 1 (MLH1), mutS homologue 2 (MSH2), mutS homologue 6 (MSH6) or postmeiotic segregation increased 2 (PMS2).13 A small proportion of Lynch syndrome cases are caused by deletions to the epithelial cellular adhesion molecule (EPCAM) gene, which leads to epigenetic silencing of MSH2.13 MMR genes encode proteins that are involved in recognising and repairing errors that occur in DNA during cell division. Mutations in MMR genes prevent DNA errors from being corrected. This can lead to uncontrolled cell growth and the development of cancer. A range of cancers have been associated with Lynch syndrome, the most common of which are endometrial and colorectal.14 Lynch syndrome accounts for 2–9% of endometrial cancers.15,16 By the age of 75 years, approximately 57% of people with Lynch syndrome will have endometrial cancer.14 The type and prevalence of cancer appears to vary according to which of the genes are affected.14
Lynch syndrome has an autosomal dominant inheritance pattern, meaning that a person has a 50% chance of passing the mutated gene(s) onto their children.
Copyright © 2021 Stinton et al. This work was produced by Stinton et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. Thisis an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution,reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: http://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.
Parts of this section have been reproduced with permission of Stinton et al.4 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) license, which permits others to share and redistribute, for non-commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
Description of technologies under assessment
Three tests are considered in this assessment (see Testing strategies). There are two primary diagnostic tests (IHC and MSI), and a third test, MLH1 promoter hypermethylation testing, may be added to either or both of these two. Eleven predefined testing strategies are considered, involving varying combinations of the three tests.
Immunohistochemistry
Immunohistochemistry, in this case, uses antibodies to look for the expression of four MMR proteins (MLH1, MSH2, MSH6 and PMS2). An absence of staining for any of the proteins suggests a genetic mutation. IHC testing identifies which MMR gene is potentially affected. If MLH1 has an abnormal expression, an additional test (MLH1 promoter hypermethylation testing) can be conducted (see MLH1 promoter hypermethylation testing). IHC can detect non-functional, but antibody-binding, MLH1 proteins (which would be incorrectly classified as normal);17 therefore, this may lead to a false negative result.
Microsatellite instability testing
Microsatellites are short repeats of DNA sequences. These repeats are prone to acquiring errors. When the MMR genes are not functioning, these errors are not corrected. Mutations in MMR genes lead to variations in the size of these repeats. This is called MSI. MSI testing is used to determine whether or not there are differences in the repeat numbers between tumour and non-tumour regions in a person being tested. Various markers have been described.18 The Bethesda guidelines19 identify five markers (BAT25, BAT26, DS123, D17S250 and D5S346) for MSI for Lynch syndrome. Typically, three classifications are derived from this approach:
MSI-high – two or more markers show instability/> 30% of markers show instability.
MSI-low – one marker shows instability/< 30% of markers show instability.
MSI-stable – zero markers show instability [also known as microsatellite stable (MSS)].
Additional testing can be conducted to help rule out sporadic epigenetic silencing of MLH1, which might present as Lynch syndrome (see MLH1 promoter hypermethylation testing).
MLH1 promoter hypermethylation testing
Hypermethylation is an epigenetic process that stops a protein being produced by a gene. MLH1 promoter hypermethylation testing is initially conducted on tumours. The test is undertaken following IHC or MSI testing, usually on patients with a MSI-high result or IHC loss in the MLH1 protein. A positive result on this test suggests that the tumour is sporadic and not a result of Lynch syndrome. However, there is some evidence that constitutional epimutations of MLH1 in normal tissue may be a cause of Lynch syndrome in a small number of cases.20
Comparators
The comparator currently used in the UK is no diagnostic testing for Lynch syndrome in those with endometrial cancer, and therefore no subsequent cascade testing of family members.
Reference standard
Typically, Lynch syndrome is diagnosed on the basis of constitutional mutations (i.e. mutations that are present in every cell) in MMR genes, which involves sequencing [including next-generation sequencing (NGS)] to detect point mutation, small insertions or deletions in these genes and multiplex ligation-dependent probe amplification (MLPA) or NGS to detect larger structural changes (such as deletions, duplications or rearrangements) to genetic sequences that could be missed by sequencing alone. Sequencing and MLPA may be used in combination to diagnose Lynch syndrome. However, these techniques also detect novel sequence variation in MMR genes that are of unknown significance. Sequencing of tumours can be used to identify sporadic tumours (i.e. those not caused by Lynch syndrome). If a person has deficient MMR (from tumour testing), but no germline mutation is identified and no somatic cause is identified, they can be considered to have Lynch-like syndrome (also known as putative or cryptic Lynch syndrome). Additional testing has been suggested in cases for which tumour testing is positive, but no Lynch syndrome-related pathogenic variants are identified.21,22 This includes testing for other somatic or germline pathogenic variants [e.g. biallelic mutY DNA glycosylase (MUTYH), DNA polymerase epsilon (POLE), double somatic MMR variants].
Testing strategies
The NICE has published guidance on testing for Lynch syndrome among people diagnosed with CRC.1 Currently, there is no NICE guidance for testing for Lynch syndrome in people who have endometrial cancer. The NHS National Genomic Test Directory provides testing criteria for people who have Lynch syndrome-related cancers.23 In brief, testing is recommended in people who have a family history of Lynch syndrome-related cancers or who have been diagnosed with endometrial cancer before the age of 50 years. The 11 proposed testing pathways for the current review are outlined in –. Testing strategies include all possible combinations of index tests, followed by reference standard testing.
Strategy 1: MSI testing alone. LS, Lynch syndrome.
Strategy 11: germline testing only.
Strategy 2: MSI testing with MLH1 promoter hypermethylation testing. a, If a germline sample is tested and is also hypermethylated, diagnose LS. LS, Lynch syndrome.
Strategy 3: IHC-based testing. LS, Lynch syndrome.
Strategy 4: IHC testing with MLH1 promoter hypermethylation testing. a, If a germline sample is tested and is also hypermethylated, diagnose LS. LS, Lynch syndrome.
Strategy 5: MSI testing followed by IHC testing. LS, Lynch syndrome.
Strategy 6: MSI testing followed by IHC testing with MLH1 promoter hypermethylation testing. a, If a germline sample is tested and is also hypermethylated, diagnose LS. LS, Lynch syndrome.
Strategy 7: IHC followed by MSI testing. LS, Lynch syndrome.
Strategy 8: IHC testing followed by MSI testing with MLH1 promoter hypermethylation testing. a, If a germline sample is tested and is also hypermethylated, diagnose LS. LS, Lynch syndrome.
Strategy 9: MSI and IHC testing. LS, Lynch syndrome.
Strategy 10: MSI and IHC testing with MLH1 promoter hypermethylation testing. a, MLH1 promoter hypermethylation testing not conducted after MSI if MLH1 expression on IHC is normal and abnormal expression of other MMR proteins is present; b, If a germline (more...)
Possible diagnostic pathways and approaches to the management of Lynch syndrome have been suggested by a range of societies and expert groups, including the British Gynaecological Cancer Society,24 the European HNPCC Expert group,25 the Royal College of Obstetricians and Gynaecologists,26 and the Manchester International Consensus Group.22
Care pathways
Currently, there is no NICE guidance on the testing and management of Lynch syndrome in people with endometrial cancer. There is NICE guidance available on molecular testing strategies and a care pathway for people with CRC.1 NHS England’s National Genomic Test Directory (Testing Criteria for Rare and Inherited Disease) specifies testing criteria for inherited MMR deficiency (Lynch syndrome).23 Affected individuals with Lynch syndrome-related cancer should meet one of the following criteria:
CRC (any age, as per NICE guidance
1).
Lynch syndrome-related cancer (aged < 50 years).
Two Lynch syndrome-related cancers (any age, one is colorectal or endometrial).
Lynch syndrome-related cancer and one or more first-degree relative has Lynch syndrome-related cancer (both occurred before the age of 60 years, one is colorectal or endometrial).
Lynch syndrome-related cancer and two or more relatives (first-/second-/third-degree relatives) have Lynch syndrome-related cancer (all occurring before the age of 75 years, one is colorectal or endometrial).
Lynch syndrome-related cancer and three or more relatives (first-/second-/third-degree relatives) have Lynch syndrome-related cancer (occurring at any age, one is colorectal or endometrial).
The recommended follow-up care for those with CRC diagnosed with Lynch syndrome is outlined in the guidelines for the management of hereditary CRC from the British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland/UK Cancer Genetics Group,27 NICE diagnostics guidance 271 and the NICE draft guideline on the effectiveness of aspirin in the prevention of CRC.28 The main follow-on care recommended includes biennial colonoscopy surveillance, daily aspirin use for those with CRC and cascade testing for CRC probands. As of August 2018, uptake of the guidance on molecular testing strategies for CRC is around 97.5%.1
Testing for Lynch syndrome in people with endometrial cancer in the UK varies, with some NHS services testing all tumours and others doing no routine testing. The Manchester International Consensus Group,22 American College of Obstetricians and Gynecologists,29 and European Society for Medical Oncology30 clinical practice guidelines recommended a range of surveillance and preventative measures for those with gynaecological cancers, including risk-reducing total hysterectomy and bilateral salpingo-oophorectomy (H-BSO), individualised counselling, colorectal surveillance, lifestyle modifications, use of the combined oral contraceptive and daily aspirin for those with MMR pathogenic variant carriers.
Outcomes
The outcomes from the clinical effectiveness assessment were as follows:
The outcome from the cost-effectiveness analysis is cost per quality-adjusted life-year (QALY) for each of the 11 testing strategies, compared with usual care. Other intermediate outcomes reported include the following:
number of probands with Lynch syndrome receiving Lynch syndrome surveillance (true positive accepting)
number of probands with Lynch syndrome not receiving Lynch syndrome surveillance (Lynch syndrome positive who decline and those assumed to be false negative, although without testing this cannot be confirmed)
number of VUSs and Lynch-assumed diagnoses.
