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Lynch syndrome diagnostic testing pathways in endometrial cancers: a nationwide English registry-based study

Lynch syndrome diagnostic testing pathways in endometrial cancers: a nationwide English... Cancer genetics Original research Lynch syndrome diagnostic testing pathways in endometrial cancers: a nationwide English registry- based study 1,2 1,2 2 2 Lucy Loong, Catherine Huntley, Joanna Pethick, Fiona McRonald, 2,3 2 2 2,3 Francesco Santaniello, Brian Shand, Oliver Tulloch, Shilpi Goel, 2,4 1,2 1 5 Margreet Lüchtenborg, Sophie Allen , Bethany Torr , Katie Snape , 6,7 8 9 10 Angela George, Fiona Lalloo, Gail Norbury, Diana M Eccles , 11 12 13 14 Marc Tischkowitz, Antonis C Antoniou , Paul Pharoah, Adam Shaw , 15 16 17,18 2 1,2 Eva Morris, John Burn, Kevin Monahan, Steven Hardy, Clare Turnbull ► Additional supplemental ABSTRACT WHAT IS ALREADY KNOWN ON THIS TOPIC material is published online Background For female patients with Lynch syndrome only. To view, please visit the ⇒ Existing evidence describes how universal reflex (LS), endometrial cancer (EC) is often their first cancer journal online (https:// doi. org/ mismatch repair tumour testing, compared diagnosis. A testing pathway of somatic tumour testing 10. 1136/ jmg- 2024- 110231). with post hoc order- initiated testing, leads triage followed by germline mismatch repair (MMR) gene For numbered affiliations see to increased proportions of patients with testing is an effective way of identifying the estimated end of article. endometrial cancer receiving testing for Lynch 3% of EC caused by LS. syndrome. Methods A retrospective national population- based Correspondence to observational study was conducted using comprehensive Professor Clare Turnbull; WHAT THIS STUDY ADDS national data collections of functional, somatic and turnbull. lab@ icr. ac. uk ⇒ This study is the first national evaluation of the germline MMR tests available via the English National diagnostic testing pathway for Lynch syndrome LL and CH contributed equally. Cancer Registration Dataset. For all EC diagnosed in in patients with endometrial cancer, and the 2019, the proportion tested, median time to test, yield of Received 11 July 2024 first to examine delays between diagnosis and abnormal results and factors influencing testing pathway Accepted 18 September 2024 test receipt. initiation were examined. Published Online First 21 October 2024 Results There was an immunohistochemistry (IHC) or HOW THIS STUDY MIGHT AFFECT RESEARCH, microsatellite instability (MSI) test recorded for 17.8% PRACTICE OR POLICY (1408/7928) of patients diagnosed with EC in 2019. ⇒ This study highlights regional variation, delays Proportions tested varied by Cancer Alliance and age. and missed opportunities to diagnose Lynch There was an MLH1 promoter hypermethylation test syndrome in England in 2019, which may recorded for 43.1% (149/346) of patients with MLH1 also be reflective of other health systems in protein IHC loss or MSI. Of patients with EC eligible from countries which have not moved to universal tumour- testing, 25% (26/104) had a germline MMR test reflex testing. recorded. Median time from cancer diagnosis to germline MMR test was 315 days (IQR 222–486). Conclusion This analysis highlights the regional variation in recorded testing, patient attrition, delays reduce the chance of lethal cancers through colo- and missed opportunities to diagnose LS, providing an noscopy surveillance, aspirin chemoprophylaxis, informative baseline for measuring the impact of the risk- reducing gynaecological surgeries and cascade 3–6 national guidance from the National Institute for Health testing of relatives. EC is one of the canonical and Care Excellence on universal reflex LS testing in EC, cancers associated with LS and for many females implemented in 2020. is the first LS cancer to be diagnosed. For females with LS, the life-time risk of EC is comparable to that of CRC for MSH2-associated LS, and is double the risk of CRC for MSH6- associated LS. INTRODUCTION Tumours arising due to LS typically exhibit Lynch syndrome (LS) is characterised by an elevated deficient dMMR, which can be detected via genetic risk of gastrointestinal and gynaecological immunohistochemistry (IHC) staining and/or cancers, in particular colorectal cancer (CRC) and microsatellite instability (MSI) testing, hereafter © Author(s) (or their employer(s)) 2024. Re- use endometrial cancer (EC). LS is caused by germ- collectively referred to as functional MMR tumour permitted under CC BY. line inactivation of one of four genes acting in testing. IHC analysis comprises examination for Published by BMJ. DNA mismatch repair (dMMR) pathways (MLH1, loss of staining of one or more MMR proteins. To cite: Loong L, Huntley C, MSH2, MSH6 and PMS2), typically due to inher- MSI is a DNA manifestation of dMMR that can be 1 2 8 Pethick J, et al. J Med Genet ited pathogenic variants (PVs). Early identifi- quantified via a laboratory tissue assay. In series 2024;61:1080–1088. cation of patients with LS offers opportunities to of unselected EC, approximately 26% of tumours 1080 Loong L, et al. J Med Genet 2024;61:1080–1088. doi:10.1136/jmg-2024-110231 Cancer genetics were reported to exhibit dMMR on IHC and 22% showed MSI samples and excluding tumours exhibiting hypermethylation can (either at ≥2/5 tested loci (MSI-high) or 1/5 tested loci (MSI- further refine the subset of EC cases that are enriched for LS. low)). Of these tumours showing dMMR on either IHC or Thus, typically diagnostic pathways for LS testing in EC MSI, approximately 10% were the result of an inherited PV in comprise three sequential steps: (i) functional MMR tumour an MMR gene (ie, LS). This equates to approximately 3% of testing (via IHC or MSI), followed by (ii) somatic MLH1 unselected EC being attributable to LS. Thus, functional MMR promoter hypermethylation analysis of tumours exhibiting tumour testing can identify a subset of EC cases that are enriched MLH1 protein loss on IHC or MSI and then (iii) germline genetic for LS. sequencing of MMR genes to identify PVs (figure 1). In England The majority of dMMR arises as a somatic (non-inherited) in October 2020, the National Institute for Health and Care event. Loss of function of both alleles of an MMR gene is required Excellence (NICE) issued guidance recommending universal to result in dMMR. In sporadic tumours with dMMR, both reflex functional MMR tumour testing in all EC. Subsequently, mutational events have arisen somatically. Somatic hypermeth- National Health Service England (NHSE) published a handbook ylation of the MLH1 promoter region accounts for the majority to support local implementation. These documents recommend of somatic events in sporadic dMMR tumours. In LS, the first that initial tumour testing be performed using IHC as part of mutational event is inherited and the second is somatic, typi- standard pathology, MLH1 promoter hypermethylation should cally deletion of a large region of the second allele. Performing be conducted by genomic laboratories and routine germline assays for MLH1 promoter hypermethylation in dMMR tumour testing should be offered by cancer treating teams, with clinical Figure 1 Consolidated Standards of Reporting Trials diagram showing progression of patients with endometrial cancer through the Lynch syndrome diagnostic pathway. The cohort includes patients diagnosed with endometrial cancer in 2019. The sequential three-step diagnostic pathw ay is depicted within the yellow outline. All patients with loss of MLH1 staining on immunohistochemistry (IHC) are included in the MLH1 def. (deficiency) category regardless of the presence or absence of other mismatch repair (MMR) protein deficits on IHC. The results of germline MMR gene testing for patients following different routes within and outside of the three- step diagnostic pathway are displayed at the bottom separated by result. Where patients have >1 test result for a test, the result is selected according to the hierarchies described in ‘Methods’ section. Attrition and yield for each of the sequential three testing steps within the diagnostic pathway are displayed on the left. Attrition: (patients with no test recorded)/(patients eligible for a test). Yield: (abnormal results)/(patients tested). Not all possible combinations of tests are shown. BV/None, benign variant or no variant identified; MSI, microsatellite instability, pMLH1 Meth. Test, MLH1 promoter hypermethylation test; PV, pathogenic variant; VUS, variant of uncertain significance. Loong L, et al. J Med Genet 2024;61:1080–1088. doi:10.1136/jmg-2024-110231 1081 Cancer genetics genetics managing families with PVs and conducting testing for IHC tumour analyses were considered abnormal if an 13 14 those with more complex family histories. For example, abnormal or equivocal/borderline result was obtained. MSI patients with EC with a family history of cancer fulfilling revised tumour analyses were considered abnormal if an MSI-high or Amsterdam clinical diagnostic criteria for LS may also progress MSI- low result was obtained. Somatic MLH1 promoter hyper- to germline MMR gene testing as a first- line test. Additionally, methylation analyses were considered unmethylated (suggestive functional MMR tumour testing may be initiated post hoc on of LS), if an unmethylated or equivocal/borderline result was stored histopathological tumour samples to investigate for LS in obtained. For abnormal germline MMR gene test records, the patients who were not investigated when they first presented, or raw clinical genetic laboratory submission data were reviewed to for the benefit of relatives. verify the recorded sequence variant and the laboratory variant Our recent analysis of the National Lynch Syndrome Register pathogenicity classification. Where variant pathogenicity classi- suggests that fewer than 5% of MMR PV carriers in England fication was missing, the submitting laboratory was contacted have been diagnosed. Improving the diagnosis and manage- for clarification. ment of LS is an ongoing strategic priority for NHSE. This has Where multiple tests of the same type were identified for a facilitated the recent establishment of infrastructure and data patient, a single result was assigned to the patient according to pipelines for the routine submission of patient- level data for the following hierarchy: abnormal>normal>failed/unknown functional, somatic and germline genetic testing from National for IHC and MSI tumour analyses; unmethylated (suggestive of Health Service (NHS) histopathology, specialist molecular and LS)>methylated>failed/unknown for MLH1 promoter hyper- genomic laboratories, to the National Disease Registration methylation or pathogenic (P)/likely pathogenic (LP)>variant 13 18 19 Service (NDRS). By linking these data at patient-level to of uncertain significance (VUS)>likely benign (LB)/benign (B)/ national cancer registration records we are, for the first time, no variant for germline MMR analyses. Variants classified as P able to describe the English national landscape of known LS and LP are hereafter referred to collectively as PV and LB and B diagnostic testing in patients with EC in England. variants collectively as benign variants. The presented analyses focus on data from 2019, the inaugural Time (in days) was calculated from cancer diagnosis to the year for which the national data collections made this possible first of each type of test recorded for each patient. To examine and the last complete calendar year prior to the introduction of geographic variation, we used the Cancer Alliance in which the the NICE national guidelines on universal reflex LS testing in patient was diagnosed. Cancer Alliances are 20 subregional, EC. The aim of the analyses was to document an informative geographic, collaborative networks of NHS healthcare providers, baseline of practice in 2019 to facilitate the future evaluation We anal- organisations and relevant stakeholders in England. of the impact of implemented national guidance. Specifically ysed the time from cancer diagnosis to functional MMR tumour we analyse: (i) the proportions of patients undergoing testing, test, and difference in median time between Cancer Alliances attrition rates and delays along the diagnostic pathway, (ii) using the Kruskal- Wallis method. Cancer Alliances are pseudony- geographic variations in delays initiating testing and proportions mised in the results, as we seek to investigate variation rather of patients tested and (iii) the association of sociodemographic, than calculate performance metrics in the preguideline period. cancer- related and geographic factors with the likelihood of initi- Date of cancer diagnosis in NCRD is determined by the IARC ating testing, all within the context of the preguideline period. Standards and Guidelines for Cancer Registration. Date of test was determined according to availability using the hierarchy: test report authorisation>test request>sample received>sample METHODS collected. Analyses Multivariable logistic regression was performed to model the A retrospective national population- based observational study relationship between predictor variables (patient age, index of was conducted using data obtained from the NDRS, under an multiple deprivation (IMD) quintile, ethnicity, cancer stage, analytical partnership arrangement with the Institute of Cancer tumour grade and Cancer Alliance) and the binary outcome vari- Research, London, UK. The National Cancer Registration able of whether there was a record of a functional MMR test Dataset (NCRD) covers all malignant neoplasms diagnosed having been conducted or not. Univariable logistic regression from 1971 onwards. National functional MMR tumour testing models for the six predictor variables were conducted first, with (IHC and MSI) and somatic MLH1 promoter hypermethylation statistically significantly associated variables carried through to a testing data are available from 2019 onwards and were quality multivariable model. The multivariable logistic regression model assured as complete to the best of the NDRS’ ability through was constructed with patients with incomplete data variables to the end of 2020. National germline (constitutional) MMR excluded. For patient age category, IMD, cancer stage and grade, gene testing data from English NHS genomic laboratories are p values for linear trend were calculated using linear polynomial available from 2016 onwards, with earlier data available for contrasts. some regions from the year 2000. Due to database issues at All analyses were completed using R Statistical Software genomic laboratories, a small number of germline MMR gene V.4.3.1 (citations in online supplemental table 6). testing records are known to be missing from summer 2019 onwards. The cohort for analysis comprised all patients with a malig- RESULTS nant EC in 2019 (10th revision of the International Classifica- 7938 patients were diagnosed with malignant EC in 2019 in tion of Diseases site code C541) in the NCRD. All tumour-level England. Ten patients had a recorded targeted germline MMR functional MMR tumour testing data, tumour-level somatic test for a known familial variant and/or germline MMR test MLH1 promoter hypermethylation testing data and patient- level before their cancer diagnosis, suggestive in both cases that these germline MMR gene testing data that were available within any patients were previously known to clinical genetic services. timeframe within the NCRD as of 2 March 2024, were used to These patients were excluded from the analysis. The analysed describe the number of tests recorded and results of these tests cohort therefore consisted of 7928 patients (characteristics of for the patient cohort. cohort—online supplemental table 1). 1082 Loong L, et al. J Med Genet 2024;61:1080–1088. doi:10.1136/jmg-2024-110231 Cancer genetics Table 1 Total number of patients receiving functional MMR tumour testing, MLH1 promoter methylation testing and germline MMR gene testing in the endometrial cancer cohort Number of tests Test results Number Per cent Number Per cent Functional MMR tumour testing Immunohistochemistry 1391 17.5 Abnormal 422 30.3 Normal 966 69.4 Failed/Unknown 3 0.2 Microsatellite instability 59 0.7 Abnormal 25 42.4 MSI- high 23 39 MSI- low 2 3.4 Normal 34 57.6 MLH1 promoter methylation testing MLH1 promoter methylation 173 2.2 Unmethylated (suggestive of LS) 23 13.3 Methylated 146 84.4 Failed/Unknown 4 2.3 Germline MMR gene testing Germline MMR gene testing 76 1 Pathogenic/Likely pathogenic 23 30.3 Variant of uncertain significance 4 5.3 Likely benign/Benign/No variant 49 64.5 All tests and results for the cohort are counted, including those undertaken outside of the sequential three-step diagnostic testing pathw ay. For total tests in the cohort, percentages are presented as the number of tests/total cohort patients (7928). For test results, percentages are presented as result/number of patients tested. LS, Lynch syndrome; MMR, mismatch repair; MSI, microsatellite instability. Cancer Alliance and younger age at diagnosis (p trend <0.0001) Functional MMR tumour testing were most strongly associated with there being a functional Of the analysed cohort, 17.5% (1391 patients) were recorded MMR tumour test recorded. Higher cancer grade was also as having received IHC testing and 0.7% (59 patients) were associated with an increased likelihood of there being a test recorded as having received MSI testing. Combined, there was a recorded (p trend=0.045). The associations for IMD quintile (p record of 17.8% (1408) of patients having received at least one trend=0.083) and ethnicity were attenuated, and cancer stage type of functional MMR tumour testing (0.5% (42 patients) had largely unchanged (table 2, online supplemental table 4 and both IHC and MSI testing), meaning there was an 82.2% attri- online supplemental figure 1). tion of patients reaching this first step of the diagnostic testing pathway (table 1, figure 1). Of patients receiving IHC testing, 30.3% (422) had an Somatic MLH1 promoter hypermethylation testing abnormal result, of which 79.9% had MLH1 deficiency (with or Of patients with MLH1 protein IHC loss or MSI in the first without PMS2, MSH2, MSH6 deficiencies), 8.8% had isolated step of the diagnostic pathway, there was an MLH1 promoter MSH6 deficiency, 7.1% had combined MSH2 and MSH6 defi- hypermethylation test recorded for 43.1% (149/346), meaning ciencies, 3.3% had isolated PMS2 deficiency, 0.5% had isolated there was a 56.9% attrition of patients at this step. The yield MSH2 deficiency and 0.5% had combined MSH6 and PMS2 for unmethylated (suggestive of LS) results was 12.8% (19/149) deficiency. Of all patients receiving MSI testing, 42.4% (25) had (figure 1). an abnormal result (23 MSI-high and two MSI- low) (table 1). Within the entire EC cohort, 173 patients were recorded as Median calculated time from cancer diagnosis to the earliest having received MLH1 promoter hypermethylation testing, known functional MMR test was 44 days (IQR 11–108) indicating that 24 patients had this test outside of the three-step (figure 2, online supplemental table 2). The median time varied diagnostic pathway. The median time from cancer diagnosis significantly by Cancer Alliance, ranging from 13 days up to 837 to MLH1 promoter hypermethylation test was 223 days (IQR days (Kruskal- Wallis p<0.0001). The proportion of patients 117–570) (table 1, online supplemental table 2). diagnosed with EC that were recorded as having received func- tional MMR testing varied by Cancer Alliance from 1.4% to 61.2%. For 8/20 Cancer Alliances, ≥75% of the recorded func- Germline MMR gene testing tional MMR testing performed was within 4 months (122 days) 104 patients were eligible for germline MMR gene testing at from the date of cancer diagnosis (figure 3, online supplemental the end of the three- step diagnostic pathway: 85 as a result of table 3). their MSH2, MSH6 and isolated PMS2 IHC deficiency result To examine the factors influencing initiation of LS testing in and 19 as a result of their unmethylated MLH1 promoter hyper- patients with EC, univariable and multivariable logistic regres- methylation result. Of these, only 25% (26/104) were recorded sion analyses were undertaken. On univariable logistic regres- as having received germline MMR testing, meaning there was sion analyses, age at diagnosis, IMD quintile, ethnicity, stage 2 a 75% attrition of patients at this step. The age distribution of and 3 cancer, grade of tumour and Cancer Alliance were asso- patients recorded as having received or not received a germline ciated with the likelihood of there being a functional MMR MMR gene test for which they were eligible was statistically tumour test recorded (table 2). A multivariable regression anal- significantly different: mean 54.5 (SD 11.1) and 62.6 (12.5), ysis was conducted using 5200 patients with complete demo- respectively, p=0.0038 (t- test). There was no statistically signif- graphic and tumour data. Following multivariable adjustment, icant difference in the number of patients who had died within Loong L, et al. J Med Genet 2024;61:1080–1088. doi:10.1136/jmg-2024-110231 1083 Cancer genetics Figure 2 Number of days between cancer diagnosis and first test of each type. Number of days between endometrial cancer diagnosis and earliest test of each type for each patient (in days). Purple cross=mean, n=number of patients with a recorded test. IHC, immunohistochemistry; MMR, mismatch repair; MSI, microsatellite instability. 2 years following their EC diagnosis between the two groups, recommendations and provide an informative description of the p=0.55 (χ test). effects of different testing practices (reflex and post hoc order- The yield of PVs among patients eligible for germline MMR initiated) observed regionally in England in 2019. gene testing at the end of the three- step diagnostic pathway was There was significant attrition of patients progressing along 57.7% (15/26), with a notably high yield of 14/21 PVs in the the three- step diagnostic pathway. Within the diagnostic MSH2/MSH6/isolated PMS2 IHC deficiency group compared pathway, only 17.8% of patients with EC were recorded as with 1/5 in the unmethylated MLH1 promoter methylation having received functional MMR tumour testing, only 43.1% group (figure 1). of eligible patients received MLH1 promoter hypermethylation Within the entire cohort, a further 50 patients were recorded testing and of patients with EC eligible from tumour-testing only as having received germline MMR gene testing outside of the 25% were recorded as having received a germline MMR gene three- step diagnostic pathway. PVs were identified in 8/50 (16%) test. of these tests. In total, 1.0% (76/7928) of patients had a germ- Among patients receiving a germline MMR gene test at the line MMR gene test recorded following an EC diagnosis in this end of the three-step diagnostic pathway, 57.7% (15/26) had cohort. a PV (consistent with a diagnosis of LS). A further 50 patients Out of the 76 patients recorded as having received a germline had germline MMR gene testing despite this either not being MMR gene test in this cohort, 23 patients (30.3%) were found indicated by the results of the three- step diagnostic pathway or to have a PV, of which 12 (52.2%) were in MSH6, 6 (26.1%) despite not having completed it. This is explained by the fact that were in MSH2, 3 (13.0%) were in PMS2 and 2 (8.7%) were many clinical genetics services in 2019 offered germline MMR in MLH1. The median time from cancer diagnosis to germline gene testing as the first test to patients with EC with a personal MMR gene test was 315 days (IQR 222–486) (online supple- or family history of cancer suggestive of LS. Among this group, mental tables 2,5). a further eight patients with a PV were identified. Ten patients who were likely known to clinical genetics services prior to their EC diagnosis were excluded from the main analysis. Among DISCUSSION them seven PV carriers were identified (online supplemental We present an overview of the first systematically assembled table 5). In total, 30 patients with an MMR PV were recorded national data collection of functional, somatic (tumour) and among 7938 patients with EC. Thus, only approximately 12.6% germline (constitutional) testing for MMR deficiency/LS in (30 out of an anticipated 238) of potential MMR PV carriers patients with EC. The collection of functional, somatic and were identified, given an estimated prevalence of LS in unse- germline MMR testing data as part of the NCRD provides lected EC of 3%. ongoing opportunities for (i) audit of guideline adherence, (ii) There was striking regional variation between Cancer Alli- review of future diagnostic pathway changes and (iii) research ances in known functional MMR tumour testing, in both the into endometrial and LS cancer outcomes. The data presented proportion of EC cases tested (range 1.4%–61.2%) and the time here describe the testing performed for all EC diagnosed in from cancer diagnosis to testing (range 13–837 median days). England in 2019 and reflect the testing landscape prior to the In 8/20 Cancer Alliances, the majority (≥75%) of testing was publication of NICE recommendations for universal reflex func- tional MMR tumour testing of all EC in 2020. The data serve performed within 4 months of diagnosis, suggestive of a policy of as a valuable baseline for evaluating the impact of the NICE reflex testing at least for some patients and/or in some hospitals 1084 Loong L, et al. J Med Genet 2024;61:1080–1088. doi:10.1136/jmg-2024-110231 Cancer genetics Figure 3 Number of days between cancer diagnosis and functional MMR tumour testing. Box plots of time in days to earliest functional MMR tumour test from date of endometrial cancer diagnosis by Cancer Alliance. n=number of patients with a recorded functional MMR tumour test within a Cancer Alliance. Fill colour=percentage of patients with a recorded functional MMR tumour test out of all patients with endometrial cancer within a Cancer Alliance (% tested) from high (orange) to low (blue). Box plots are also ordered by % tested from high (top) to low (bottom). constituting the Cancer Alliances. These eight Cancer Alliances the release of NICE guidelines on universal diagnostic LS testing account for the majority of functional MMR testing (74%) in CRC, only 44% of CRCs received functional MMR tumour conducted in this cohort. The remaining 12/20 Cancer Alliances testing. A concerted national collaborative effort is currently tested a lower proportion of their EC cases with a predomi- underway in England to address the variation and low testing nantly longer time-to- test, suggestive of post hoc order-initiated levels for LS in patients with CRC and ECs by engaging key testing (figure 3, online supplemental table 3). Previous studies stakeholders, providing workforce training, addressing funding comparing universal reflex versus post hoc order- initiated MMR and system barriers and extending germline MMR gene test tumour testing in patients with EC have shown that universal requesting to healthcare professionals outside of clinical genetics reflex testing leads to increased proportions of patients with EC clinics. The national datasets and methods described in this receiving testing and greater uptake of downstream germline analysis will be crucial for monitoring the continued implemen- 23–26 MMR gene testing. tation of the national guidelines. It is anticipated that implementation of the 2020 NICE recom- Performance of functional MMR tumour testing did not appear mendations will address the attrition of patients progressing along to be associated with ethnicity or deprivation quintile following the three- step diagnostic pathway and the regional disparities in multivariable adjustment. This likely reflects the majority of England. A baseline survey of EC (and CRC) multidisciplinary testing being performed in centres undertaking reflex testing as teams (MDTs) in England reported that, for example, only 62% part of the histopathological assessment, removing many of the of EC MDTs discussed MMR testing results at their meetings, demographic biases that influence being referred to a clinical only 66% stated they offered ‘universal testing’ and 88% did not genetics service for consideration of post hoc investigation for have a systematic way of referring patients for germline genetic LS. Younger age at EC diagnosis was associated with receiving testing. The main barriers to the delivery of testing cited by those functional MMR tumour testing following multivariable adjust- surveyed were local funding, service commissioning structures ment, and previous studies have shown that even in healthcare and time pressure. Another study revealed that 2 years after systems with established universal reflex LS diagnostic testing Loong L, et al. J Med Genet 2024;61:1080–1088. doi:10.1136/jmg-2024-110231 1085 Cancer genetics Table 2 Univariable and multivariable logistic regression model for functional MMR tumour testing in patients with endometrial cancer Functional MMR test Univariable Multivariable n=5200 Not tested Tested OR (95% CI) P value OR (95% CI) P value P trend Age group (years) 70+ 3037 (86.4) 477 (13.6) – – <0.0001 50–69 3151 (80.9) 743 (19.1) 1.50 (1.32 to 1.70) <0.0001 1.48 (1.24 to 1.77) <0.0001 30–49 323 (64.3) 179 (35.7) 3.53 (2.87 to 4.33) <0.0001 6.60 (4.87 to 8.95) <0.0001 0–29 9 (50.0) 9 (50.0) 6.37 (2.47 to 16.4) 0.0001 14.5 (3.65 to 59.3) 0.0001 IMD quintile Q1—most deprived 1209 (85.4) 207 (14.6) – – 0.083 Q2 1233 (79.4) 319 (20.6) 1.51 (1.25 to 1.83) <0.0001 1.29 (0.97 to 1.71) 0.077 Q3 1385 (82.7) 290 (17.3) 1.22 (1.01 to 1.49) 0.042 1.18 (0.89 to 1.56) 0.25 Q4 1363 (81.3) 313 (18.7) 1.34 (1.11 to 1.63) 0.0027 1.52 (1.15 to 2.00) 0.0029 Q5—least deprived 1330 (82.7) 279 (17.3) 1.23 (1.01 to 1.49) 0.042 1.21 (0.91 to 1.62) 0.18 Ethnicity White 5444 (83.2) 1101 (16.8) – – Asian 252 (73.7) 90 (26.3) 1.77 (1.37 to 2.26) <0.0001 0.55 (0.38 to 0.79) 0.0017 Black 140 (70.7) 58 (29.3) 2.05 (1.49 to 2.79) <0.0001 0.84 (0.48 to 1.46) 0.55 Chinese 15 (60.0) 10 (40.0) 3.30 (1.43 to 7.28) 0.0036 1.72 (0.59 to 4.81) 0.31 Mixed 28 (65.1) 15 (34.9) 2.65 (1.38 to 4.90) 0.0025 3.03 (1.23 to 7.45) 0.015 Other 93 (75.0) 31 (25.0) 1.65 (1.08 to 2.46) 0.017 0.59 (0.32 to 1.05) 0.080 Stage at diagnosis 1 4189 (83.4) 836 (16.6) – – 0.22 2 353 (77.4) 103 (22.6) 1.46 (1.15 to 1.84) 0.0013 1.41 (1.03 to 1.91) 0.027 3 444 (75.5) 144 (24.5) 1.63 (1.32 to 1.98) <0.0001 1.75 (1.32 to 2.30) 0.0001 4 408 (82.3) 88 (17.7) 1.08 (0.84 to 1.37) 0.53 1.20 (0.82 to 1.73) 0.34 Grade of tumour G1—well differentiated 2938 (84.0) 559 (16.0) – – 0.045 G2—moderately differentiated 1364 (79.3) 357 (20.7) 1.38 (1.19 to 1.59) <0.0001 1.51 (1.24 to 1.83) <0.0001 G3—poorly differentiated 1041 (77.8) 297 (22.2) 1.50 (1.28 to 1.75) <0.0001 1.95 (1.57 to 2.43) <0.0001 G4—undifferentiated/anaplastic 33 (66.0) 17 (34.0) 2.71 (1.46 to 4.83) 0.00098 2.34 (0.91 to 5.71) 0.067 Cancer Alliance (pseudonym) MM 213 (98.6) 3 (1.4) – – PP 248 (97.3) 7 (2.7) 2.00 (0.55 to 9.39) 0.32 1.73 (0.37 to 9.02) 0.48 OO 358 (96.0) 15 (4.0) 2.97 (0.97 to 13.0) 0.088 2.42 (0.72 to 11.0) 0.19 … … … … … … … II 317 (64.0) 178 (36.0) 39.9 (14.9 to 163) <0.0001 34.9 (12.6 to 145) <0.0001 RR 154 (38.8) 243 (61.2) 112 (41.7 to 458) <0.0001 210 (73.7 to 886) <0.0001 Unadjusted ORs are presented from univariable regression models including each single variable in turn. Missing data variables are excluded. Adjusted ORs are presented from a multivariable regression model including all variables in the table. Patients with missing data in any of the variables are excluded (n=2728), resulting in inclusion of 5200 patients in the multivariable model. Abbreviated results (highest and lowest ORs) are presented for the Cancer Alliance (full results available in online supplemental table 4). P values <0.05 are highlighted in bold. ORs and p values are presented to three and two significant figures, respectively. IMD, index of multiple deprivation; MMR, mismatch repair. pathways for EC, older age is a factor for non- adherence to stages, with the incidence of CRC between 60 and 70 years of those pathways. age being 11.9% and 15.7% for MLH1 and MSH2 female PV There were marked delays between each step of the diagnostic carriers, respectively. pathway and the total duration of the diagnostic pathway, from The 2020 NICE guidance for EC recommends the use of EC diagnosis to germline MMR test report, was a median of 315 IHC not MSI, based on the higher sensitivity of IHC and health 12 30 days (IQR 222–486). Implementation of the NICE recommen- economic modelling analysis. These analyses offer support dations (with added clarity regarding roles and responsibilities) to that recommendation. In addition to demonstrating dMMR, would be anticipated to shorten the duration of the diagnostic IHC provides additional information regarding the specific gene pathway and ultimately time to LS diagnosis for probands and causing dMMR. In this analysis, 20.1% (85/422) of tumours their relatives. The median age of EC diagnosis in this cohort with IHC abnormality had MSH2/MSH6/isolated PMS2 loss. was 68 (IQR 59–75). Given the relatively high 10- year survival These patients did not require the additional step (and attrition of EC in England of 71.6%, the identification of LS provides and time delay it entails) of MLH1 promoter hypermethylation valuable opportunities for the prevention of further primary analysis, compared with if their dMMR had been diagnosed via 7 28 29 cancers. For example, delays in commencing aspirin MSI analysis. Yield for PVs among patients with MSH2/MSH6/ prophylaxis and colonoscopy screening for female LS carriers isolated PMS2 IHC loss was higher (66.7%, 14/21) compared in this age range could lead to CRCs being diagnosed at later with those with MLH1 IHC loss or MSI with unmethylated 1086 Loong L, et al. J Med Genet 2024;61:1080–1088. doi:10.1136/jmg-2024-110231 Cancer genetics Applied Health Research Unit, Big Data Institute, Nuffield Department of MLH1 promoter methylation status (20%, 1/5), consistent with Population Health, University of Oxford, Oxford, UK the higher penetrance for EC in MSH6- associated and MSH2- Translational and Clinical Research Institute, Newcastle University, Newcastle upon associated LS. Tyne, UK Limitations of these analyses include reliance on complete- The Lynch Syndrome and Family Cancer Clinic, St Mark’s Hospital and Academic ness and comparability of local data submissions. That a small Institute, London, UK Imperial College London, London, UK number of germline MMR gene test records are known to be missing from summer 2019 onwards means that the proportion X Katie Snape @genetikos of patients who received germline tests may be slightly underes- Acknowledgements CT, LL, SA, KS, FL, SG and BT acknowledge grant support timated. However, in a comparable analysis of the CRC LS diag- from Cancer Research UK (C8620/A8372). CH is supported by a Wellcome Trust nostic testing pathway using Danish registry data, 20% of eligible Clinical Research Training Fellowship (ref 203924/Z/16/Z). This work uses data that patients received genetic counselling/germline testing, which has been provided by patients and collected by the NHS as part of their care and is comparable to the 25% we demonstrate here. Inclusion support. The data are collated, maintained and quality assured by the National of potentially nationally incomplete functional MMR tumour Disease Registration Service, which is part of NHS England. testing data beyond the end of 2020 allowed the demonstration Contributors Conceptualisation: LL, CH, JP, FMcR, CT. Formal analysis: CH, LL, JP. of post hoc order- initiated tumour testing further away from Accessed underlying data: CH and LL. Visualisation: LL. Supervision: CT, SH, ML, MT, ACA, PP, EM. Funding acquisition: CT, JB. Data collation and curation: FMcR, SH, JP, the original EC diagnosis. However, it means that the amount FS, BS, OT, SG. Clinical interpretation: LL, CT, KS, AG, FL, GN, DME, MT, AS, JB, KM. of post hoc order- initiated testing could be underestimated. It Project administration: FMcR, BT, SA. Writing—original draft: LL, CH, CT. Writing— is likely that post hoc testing makes up only a small amount review and editing: all authors. Guarantor: CT. of all functional MMR tumour testing conducted in EC, as it Funding This work was funded by Cancer Research UK (C8620/A8372), the usually requires the referral of the patient to a clinical genetics Wellcome Trust (203924/Z/16/Z) and Bowel Cancer UK (18PG0019). service. 84.4% (1224/1450) of the functional MMR tumour Disclaimer The funders of this study had no role in study design, data collection, tests recorded in this analysis were conducted within 1 year data analysis, data interpretation or writing of the report. of the date of EC diagnosis (online supplemental table 7). The Competing interests None declared. relatively small numbers of EC diagnosed in each hospital trust Patient consent for publication Not applicable. necessitated analysis by Cancer Alliance. Therefore, hospital Ethics approval Ethical approval for the data analyses was granted to Can- Gene trust- level variation in practice is not captured in these analyses. Can- Var (REC: 18/WS/0192). Data used in these analyses are collected and stored Lastly, personal or family history for LS- related cancers were not securely within NDRS under the legal permissions afforded by section 254 of the captured in these analyses. Health and Social Care Act 2012, which permits the collection of patient data Overall, there is a baseline picture, prior to the publication without requiring informed consent. of the NICE national guidelines on universal reflex functional Provenance and peer review Not commissioned; externally peer reviewed. MMR tumour testing in EC, of considerable missed opportu- Data availability statement Data are available on reasonable request. All nity, delay and regional variation in the diagnosis of LS among data relevant to the study are included in the article or uploaded as supplementary patients with EC. This may also be reflective of missed diag- information. Summary data relevant to the study are included in the article and nostic opportunities in other health systems in countries that supplementary material. Patient- level data used in this study are held within NDRS and available to access following application. Summary statistics for somatic Lynch have not moved to universal reflex testing. The results of these syndrome testing are available at https://digital.nhs.uk/ndrs/data/data-outputs/ analyses provide an important baseline for measuring the impact cancer-data-hub/somatic-molecular-dashboard. Germline coding DNA sequence of implementing the NICE national guidelines on the number variants are made publicly available for clinical variant interpretation purposes, as of patients tested, testing delays, attrition of patients along the variant- specific observation frequencies on public database https://canvaruk.org/. testing pathway and regional variation. Furthermore, the data- Supplemental material This content has been supplied by the author(s). It sets and methods in this study facilitate ongoing assessment of has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have diagnostic yield and provide opportunities to evaluate cancer been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and outcomes by functional phenotypes and somatic and germline responsibility arising from any reliance placed on the content. Where the content genotypes—key for continuously appraising the diagnostic accu- includes any translated material, BMJ does not warrant the accuracy and reliability racy and cost- effectiveness of implemented testing pathways. of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error Author affiliations and/or omissions arising from translation and adaptation or otherwise. Institute of Cancer Research Division of Genetics and Epidemiology, Sutton, UK 2 Open access This is an open access article distributed in accordance with the National Disease Registration Service, London, UK Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits Health Data Insight, Cambridge, UK others to copy, redistribute, remix, transform and build upon this work for any Cancer Epidemiology and Cancer Services Research, Centre for Cancer, Society & purpose, provided the original work is properly cited, a link to the licence is given, Public Health, Comprehensive Cancer Centre, King’s College London, London, UK and indication of whether changes were made. See: https://creativecommons.org/ Department of Clinical Genetics, St George’s University Hospitals NHS Foundation licenses/by/4.0/. Trust, London, UK Gynaecology Unit, Royal Marsden NHS Foundation Trust, London, UK ORCID iDs The Institute of Cancer Research—Sutton, London, UK Sophie Allen http://orcid.org/0000-0003-4928-2240 Clinical Genetics Service, Manchester Centre for Genomic Medicine, Central Bethany Torr http://orcid.org/0000-0003-3487-9749 Manchester University Hospitals NHS Foundation Trust, Manchester, UK Katie Snape http://orcid.org/0000-0002-1739-7986 South East Genomic Laboratory Hub, Guy’s and St Thomas’ Hospitals NHS Trust, Diana M Eccles http://orcid.org/0000-0002-9935-3169 London, UK Antonis C Antoniou http://orcid.org/0000-0001-9223-3116 Human Genetics and Genomic Medicine, University of Southampton Faculty of Adam Shaw http://orcid.org/0000-0003-3046-3092 Medicine, Southampton, UK Clare Turnbull http://orcid.org/0000-0002-3797-7398 Department of Medical Genetics, Cambridge Biomedical Research Centre, National Institute for Health Research, University of Cambridge, Cambridge, UK Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary REFERENCES Care, University of Cambridge, Cambridge, UK 1 Dominguez- Valentin M, Sampson JR, Seppälä TT, et al. 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A registry- based study on universal Cancer Inst 2004;96:261–8. screening for defective mismatch repair in colorectal cancer in Denmark 17 Huntley C, Loong L, Mallinson C, et al. The comprehensive English National Lynch Syndrome Registry: development and description of a new genomics data resource. highlights disparities in screening uptake and counselling referrals. Transl Oncol EClinMed 2024;69:102465. 2024;46:102013. 1088 Loong L, et al. J Med Genet 2024;61:1080–1088. doi:10.1136/jmg-2024-110231 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Medical Genetics British Medical Journal

Lynch syndrome diagnostic testing pathways in endometrial cancers: a nationwide English registry-based study

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British Medical Journal
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Abstract

Cancer genetics Original research Lynch syndrome diagnostic testing pathways in endometrial cancers: a nationwide English registry- based study 1,2 1,2 2 2 Lucy Loong, Catherine Huntley, Joanna Pethick, Fiona McRonald, 2,3 2 2 2,3 Francesco Santaniello, Brian Shand, Oliver Tulloch, Shilpi Goel, 2,4 1,2 1 5 Margreet Lüchtenborg, Sophie Allen , Bethany Torr , Katie Snape , 6,7 8 9 10 Angela George, Fiona Lalloo, Gail Norbury, Diana M Eccles , 11 12 13 14 Marc Tischkowitz, Antonis C Antoniou , Paul Pharoah, Adam Shaw , 15 16 17,18 2 1,2 Eva Morris, John Burn, Kevin Monahan, Steven Hardy, Clare Turnbull ► Additional supplemental ABSTRACT WHAT IS ALREADY KNOWN ON THIS TOPIC material is published online Background For female patients with Lynch syndrome only. To view, please visit the ⇒ Existing evidence describes how universal reflex (LS), endometrial cancer (EC) is often their first cancer journal online (https:// doi. org/ mismatch repair tumour testing, compared diagnosis. A testing pathway of somatic tumour testing 10. 1136/ jmg- 2024- 110231). with post hoc order- initiated testing, leads triage followed by germline mismatch repair (MMR) gene For numbered affiliations see to increased proportions of patients with testing is an effective way of identifying the estimated end of article. endometrial cancer receiving testing for Lynch 3% of EC caused by LS. syndrome. Methods A retrospective national population- based Correspondence to observational study was conducted using comprehensive Professor Clare Turnbull; WHAT THIS STUDY ADDS national data collections of functional, somatic and turnbull. lab@ icr. ac. uk ⇒ This study is the first national evaluation of the germline MMR tests available via the English National diagnostic testing pathway for Lynch syndrome LL and CH contributed equally. Cancer Registration Dataset. For all EC diagnosed in in patients with endometrial cancer, and the 2019, the proportion tested, median time to test, yield of Received 11 July 2024 first to examine delays between diagnosis and abnormal results and factors influencing testing pathway Accepted 18 September 2024 test receipt. initiation were examined. Published Online First 21 October 2024 Results There was an immunohistochemistry (IHC) or HOW THIS STUDY MIGHT AFFECT RESEARCH, microsatellite instability (MSI) test recorded for 17.8% PRACTICE OR POLICY (1408/7928) of patients diagnosed with EC in 2019. ⇒ This study highlights regional variation, delays Proportions tested varied by Cancer Alliance and age. and missed opportunities to diagnose Lynch There was an MLH1 promoter hypermethylation test syndrome in England in 2019, which may recorded for 43.1% (149/346) of patients with MLH1 also be reflective of other health systems in protein IHC loss or MSI. Of patients with EC eligible from countries which have not moved to universal tumour- testing, 25% (26/104) had a germline MMR test reflex testing. recorded. Median time from cancer diagnosis to germline MMR test was 315 days (IQR 222–486). Conclusion This analysis highlights the regional variation in recorded testing, patient attrition, delays reduce the chance of lethal cancers through colo- and missed opportunities to diagnose LS, providing an noscopy surveillance, aspirin chemoprophylaxis, informative baseline for measuring the impact of the risk- reducing gynaecological surgeries and cascade 3–6 national guidance from the National Institute for Health testing of relatives. EC is one of the canonical and Care Excellence on universal reflex LS testing in EC, cancers associated with LS and for many females implemented in 2020. is the first LS cancer to be diagnosed. For females with LS, the life-time risk of EC is comparable to that of CRC for MSH2-associated LS, and is double the risk of CRC for MSH6- associated LS. INTRODUCTION Tumours arising due to LS typically exhibit Lynch syndrome (LS) is characterised by an elevated deficient dMMR, which can be detected via genetic risk of gastrointestinal and gynaecological immunohistochemistry (IHC) staining and/or cancers, in particular colorectal cancer (CRC) and microsatellite instability (MSI) testing, hereafter © Author(s) (or their employer(s)) 2024. Re- use endometrial cancer (EC). LS is caused by germ- collectively referred to as functional MMR tumour permitted under CC BY. line inactivation of one of four genes acting in testing. IHC analysis comprises examination for Published by BMJ. DNA mismatch repair (dMMR) pathways (MLH1, loss of staining of one or more MMR proteins. To cite: Loong L, Huntley C, MSH2, MSH6 and PMS2), typically due to inher- MSI is a DNA manifestation of dMMR that can be 1 2 8 Pethick J, et al. J Med Genet ited pathogenic variants (PVs). Early identifi- quantified via a laboratory tissue assay. In series 2024;61:1080–1088. cation of patients with LS offers opportunities to of unselected EC, approximately 26% of tumours 1080 Loong L, et al. J Med Genet 2024;61:1080–1088. doi:10.1136/jmg-2024-110231 Cancer genetics were reported to exhibit dMMR on IHC and 22% showed MSI samples and excluding tumours exhibiting hypermethylation can (either at ≥2/5 tested loci (MSI-high) or 1/5 tested loci (MSI- further refine the subset of EC cases that are enriched for LS. low)). Of these tumours showing dMMR on either IHC or Thus, typically diagnostic pathways for LS testing in EC MSI, approximately 10% were the result of an inherited PV in comprise three sequential steps: (i) functional MMR tumour an MMR gene (ie, LS). This equates to approximately 3% of testing (via IHC or MSI), followed by (ii) somatic MLH1 unselected EC being attributable to LS. Thus, functional MMR promoter hypermethylation analysis of tumours exhibiting tumour testing can identify a subset of EC cases that are enriched MLH1 protein loss on IHC or MSI and then (iii) germline genetic for LS. sequencing of MMR genes to identify PVs (figure 1). In England The majority of dMMR arises as a somatic (non-inherited) in October 2020, the National Institute for Health and Care event. Loss of function of both alleles of an MMR gene is required Excellence (NICE) issued guidance recommending universal to result in dMMR. In sporadic tumours with dMMR, both reflex functional MMR tumour testing in all EC. Subsequently, mutational events have arisen somatically. Somatic hypermeth- National Health Service England (NHSE) published a handbook ylation of the MLH1 promoter region accounts for the majority to support local implementation. These documents recommend of somatic events in sporadic dMMR tumours. In LS, the first that initial tumour testing be performed using IHC as part of mutational event is inherited and the second is somatic, typi- standard pathology, MLH1 promoter hypermethylation should cally deletion of a large region of the second allele. Performing be conducted by genomic laboratories and routine germline assays for MLH1 promoter hypermethylation in dMMR tumour testing should be offered by cancer treating teams, with clinical Figure 1 Consolidated Standards of Reporting Trials diagram showing progression of patients with endometrial cancer through the Lynch syndrome diagnostic pathway. The cohort includes patients diagnosed with endometrial cancer in 2019. The sequential three-step diagnostic pathw ay is depicted within the yellow outline. All patients with loss of MLH1 staining on immunohistochemistry (IHC) are included in the MLH1 def. (deficiency) category regardless of the presence or absence of other mismatch repair (MMR) protein deficits on IHC. The results of germline MMR gene testing for patients following different routes within and outside of the three- step diagnostic pathway are displayed at the bottom separated by result. Where patients have >1 test result for a test, the result is selected according to the hierarchies described in ‘Methods’ section. Attrition and yield for each of the sequential three testing steps within the diagnostic pathway are displayed on the left. Attrition: (patients with no test recorded)/(patients eligible for a test). Yield: (abnormal results)/(patients tested). Not all possible combinations of tests are shown. BV/None, benign variant or no variant identified; MSI, microsatellite instability, pMLH1 Meth. Test, MLH1 promoter hypermethylation test; PV, pathogenic variant; VUS, variant of uncertain significance. Loong L, et al. J Med Genet 2024;61:1080–1088. doi:10.1136/jmg-2024-110231 1081 Cancer genetics genetics managing families with PVs and conducting testing for IHC tumour analyses were considered abnormal if an 13 14 those with more complex family histories. For example, abnormal or equivocal/borderline result was obtained. MSI patients with EC with a family history of cancer fulfilling revised tumour analyses were considered abnormal if an MSI-high or Amsterdam clinical diagnostic criteria for LS may also progress MSI- low result was obtained. Somatic MLH1 promoter hyper- to germline MMR gene testing as a first- line test. Additionally, methylation analyses were considered unmethylated (suggestive functional MMR tumour testing may be initiated post hoc on of LS), if an unmethylated or equivocal/borderline result was stored histopathological tumour samples to investigate for LS in obtained. For abnormal germline MMR gene test records, the patients who were not investigated when they first presented, or raw clinical genetic laboratory submission data were reviewed to for the benefit of relatives. verify the recorded sequence variant and the laboratory variant Our recent analysis of the National Lynch Syndrome Register pathogenicity classification. Where variant pathogenicity classi- suggests that fewer than 5% of MMR PV carriers in England fication was missing, the submitting laboratory was contacted have been diagnosed. Improving the diagnosis and manage- for clarification. ment of LS is an ongoing strategic priority for NHSE. This has Where multiple tests of the same type were identified for a facilitated the recent establishment of infrastructure and data patient, a single result was assigned to the patient according to pipelines for the routine submission of patient- level data for the following hierarchy: abnormal>normal>failed/unknown functional, somatic and germline genetic testing from National for IHC and MSI tumour analyses; unmethylated (suggestive of Health Service (NHS) histopathology, specialist molecular and LS)>methylated>failed/unknown for MLH1 promoter hyper- genomic laboratories, to the National Disease Registration methylation or pathogenic (P)/likely pathogenic (LP)>variant 13 18 19 Service (NDRS). By linking these data at patient-level to of uncertain significance (VUS)>likely benign (LB)/benign (B)/ national cancer registration records we are, for the first time, no variant for germline MMR analyses. Variants classified as P able to describe the English national landscape of known LS and LP are hereafter referred to collectively as PV and LB and B diagnostic testing in patients with EC in England. variants collectively as benign variants. The presented analyses focus on data from 2019, the inaugural Time (in days) was calculated from cancer diagnosis to the year for which the national data collections made this possible first of each type of test recorded for each patient. To examine and the last complete calendar year prior to the introduction of geographic variation, we used the Cancer Alliance in which the the NICE national guidelines on universal reflex LS testing in patient was diagnosed. Cancer Alliances are 20 subregional, EC. The aim of the analyses was to document an informative geographic, collaborative networks of NHS healthcare providers, baseline of practice in 2019 to facilitate the future evaluation We anal- organisations and relevant stakeholders in England. of the impact of implemented national guidance. Specifically ysed the time from cancer diagnosis to functional MMR tumour we analyse: (i) the proportions of patients undergoing testing, test, and difference in median time between Cancer Alliances attrition rates and delays along the diagnostic pathway, (ii) using the Kruskal- Wallis method. Cancer Alliances are pseudony- geographic variations in delays initiating testing and proportions mised in the results, as we seek to investigate variation rather of patients tested and (iii) the association of sociodemographic, than calculate performance metrics in the preguideline period. cancer- related and geographic factors with the likelihood of initi- Date of cancer diagnosis in NCRD is determined by the IARC ating testing, all within the context of the preguideline period. Standards and Guidelines for Cancer Registration. Date of test was determined according to availability using the hierarchy: test report authorisation>test request>sample received>sample METHODS collected. Analyses Multivariable logistic regression was performed to model the A retrospective national population- based observational study relationship between predictor variables (patient age, index of was conducted using data obtained from the NDRS, under an multiple deprivation (IMD) quintile, ethnicity, cancer stage, analytical partnership arrangement with the Institute of Cancer tumour grade and Cancer Alliance) and the binary outcome vari- Research, London, UK. The National Cancer Registration able of whether there was a record of a functional MMR test Dataset (NCRD) covers all malignant neoplasms diagnosed having been conducted or not. Univariable logistic regression from 1971 onwards. National functional MMR tumour testing models for the six predictor variables were conducted first, with (IHC and MSI) and somatic MLH1 promoter hypermethylation statistically significantly associated variables carried through to a testing data are available from 2019 onwards and were quality multivariable model. The multivariable logistic regression model assured as complete to the best of the NDRS’ ability through was constructed with patients with incomplete data variables to the end of 2020. National germline (constitutional) MMR excluded. For patient age category, IMD, cancer stage and grade, gene testing data from English NHS genomic laboratories are p values for linear trend were calculated using linear polynomial available from 2016 onwards, with earlier data available for contrasts. some regions from the year 2000. Due to database issues at All analyses were completed using R Statistical Software genomic laboratories, a small number of germline MMR gene V.4.3.1 (citations in online supplemental table 6). testing records are known to be missing from summer 2019 onwards. The cohort for analysis comprised all patients with a malig- RESULTS nant EC in 2019 (10th revision of the International Classifica- 7938 patients were diagnosed with malignant EC in 2019 in tion of Diseases site code C541) in the NCRD. All tumour-level England. Ten patients had a recorded targeted germline MMR functional MMR tumour testing data, tumour-level somatic test for a known familial variant and/or germline MMR test MLH1 promoter hypermethylation testing data and patient- level before their cancer diagnosis, suggestive in both cases that these germline MMR gene testing data that were available within any patients were previously known to clinical genetic services. timeframe within the NCRD as of 2 March 2024, were used to These patients were excluded from the analysis. The analysed describe the number of tests recorded and results of these tests cohort therefore consisted of 7928 patients (characteristics of for the patient cohort. cohort—online supplemental table 1). 1082 Loong L, et al. J Med Genet 2024;61:1080–1088. doi:10.1136/jmg-2024-110231 Cancer genetics Table 1 Total number of patients receiving functional MMR tumour testing, MLH1 promoter methylation testing and germline MMR gene testing in the endometrial cancer cohort Number of tests Test results Number Per cent Number Per cent Functional MMR tumour testing Immunohistochemistry 1391 17.5 Abnormal 422 30.3 Normal 966 69.4 Failed/Unknown 3 0.2 Microsatellite instability 59 0.7 Abnormal 25 42.4 MSI- high 23 39 MSI- low 2 3.4 Normal 34 57.6 MLH1 promoter methylation testing MLH1 promoter methylation 173 2.2 Unmethylated (suggestive of LS) 23 13.3 Methylated 146 84.4 Failed/Unknown 4 2.3 Germline MMR gene testing Germline MMR gene testing 76 1 Pathogenic/Likely pathogenic 23 30.3 Variant of uncertain significance 4 5.3 Likely benign/Benign/No variant 49 64.5 All tests and results for the cohort are counted, including those undertaken outside of the sequential three-step diagnostic testing pathw ay. For total tests in the cohort, percentages are presented as the number of tests/total cohort patients (7928). For test results, percentages are presented as result/number of patients tested. LS, Lynch syndrome; MMR, mismatch repair; MSI, microsatellite instability. Cancer Alliance and younger age at diagnosis (p trend <0.0001) Functional MMR tumour testing were most strongly associated with there being a functional Of the analysed cohort, 17.5% (1391 patients) were recorded MMR tumour test recorded. Higher cancer grade was also as having received IHC testing and 0.7% (59 patients) were associated with an increased likelihood of there being a test recorded as having received MSI testing. Combined, there was a recorded (p trend=0.045). The associations for IMD quintile (p record of 17.8% (1408) of patients having received at least one trend=0.083) and ethnicity were attenuated, and cancer stage type of functional MMR tumour testing (0.5% (42 patients) had largely unchanged (table 2, online supplemental table 4 and both IHC and MSI testing), meaning there was an 82.2% attri- online supplemental figure 1). tion of patients reaching this first step of the diagnostic testing pathway (table 1, figure 1). Of patients receiving IHC testing, 30.3% (422) had an Somatic MLH1 promoter hypermethylation testing abnormal result, of which 79.9% had MLH1 deficiency (with or Of patients with MLH1 protein IHC loss or MSI in the first without PMS2, MSH2, MSH6 deficiencies), 8.8% had isolated step of the diagnostic pathway, there was an MLH1 promoter MSH6 deficiency, 7.1% had combined MSH2 and MSH6 defi- hypermethylation test recorded for 43.1% (149/346), meaning ciencies, 3.3% had isolated PMS2 deficiency, 0.5% had isolated there was a 56.9% attrition of patients at this step. The yield MSH2 deficiency and 0.5% had combined MSH6 and PMS2 for unmethylated (suggestive of LS) results was 12.8% (19/149) deficiency. Of all patients receiving MSI testing, 42.4% (25) had (figure 1). an abnormal result (23 MSI-high and two MSI- low) (table 1). Within the entire EC cohort, 173 patients were recorded as Median calculated time from cancer diagnosis to the earliest having received MLH1 promoter hypermethylation testing, known functional MMR test was 44 days (IQR 11–108) indicating that 24 patients had this test outside of the three-step (figure 2, online supplemental table 2). The median time varied diagnostic pathway. The median time from cancer diagnosis significantly by Cancer Alliance, ranging from 13 days up to 837 to MLH1 promoter hypermethylation test was 223 days (IQR days (Kruskal- Wallis p<0.0001). The proportion of patients 117–570) (table 1, online supplemental table 2). diagnosed with EC that were recorded as having received func- tional MMR testing varied by Cancer Alliance from 1.4% to 61.2%. For 8/20 Cancer Alliances, ≥75% of the recorded func- Germline MMR gene testing tional MMR testing performed was within 4 months (122 days) 104 patients were eligible for germline MMR gene testing at from the date of cancer diagnosis (figure 3, online supplemental the end of the three- step diagnostic pathway: 85 as a result of table 3). their MSH2, MSH6 and isolated PMS2 IHC deficiency result To examine the factors influencing initiation of LS testing in and 19 as a result of their unmethylated MLH1 promoter hyper- patients with EC, univariable and multivariable logistic regres- methylation result. Of these, only 25% (26/104) were recorded sion analyses were undertaken. On univariable logistic regres- as having received germline MMR testing, meaning there was sion analyses, age at diagnosis, IMD quintile, ethnicity, stage 2 a 75% attrition of patients at this step. The age distribution of and 3 cancer, grade of tumour and Cancer Alliance were asso- patients recorded as having received or not received a germline ciated with the likelihood of there being a functional MMR MMR gene test for which they were eligible was statistically tumour test recorded (table 2). A multivariable regression anal- significantly different: mean 54.5 (SD 11.1) and 62.6 (12.5), ysis was conducted using 5200 patients with complete demo- respectively, p=0.0038 (t- test). There was no statistically signif- graphic and tumour data. Following multivariable adjustment, icant difference in the number of patients who had died within Loong L, et al. J Med Genet 2024;61:1080–1088. doi:10.1136/jmg-2024-110231 1083 Cancer genetics Figure 2 Number of days between cancer diagnosis and first test of each type. Number of days between endometrial cancer diagnosis and earliest test of each type for each patient (in days). Purple cross=mean, n=number of patients with a recorded test. IHC, immunohistochemistry; MMR, mismatch repair; MSI, microsatellite instability. 2 years following their EC diagnosis between the two groups, recommendations and provide an informative description of the p=0.55 (χ test). effects of different testing practices (reflex and post hoc order- The yield of PVs among patients eligible for germline MMR initiated) observed regionally in England in 2019. gene testing at the end of the three- step diagnostic pathway was There was significant attrition of patients progressing along 57.7% (15/26), with a notably high yield of 14/21 PVs in the the three- step diagnostic pathway. Within the diagnostic MSH2/MSH6/isolated PMS2 IHC deficiency group compared pathway, only 17.8% of patients with EC were recorded as with 1/5 in the unmethylated MLH1 promoter methylation having received functional MMR tumour testing, only 43.1% group (figure 1). of eligible patients received MLH1 promoter hypermethylation Within the entire cohort, a further 50 patients were recorded testing and of patients with EC eligible from tumour-testing only as having received germline MMR gene testing outside of the 25% were recorded as having received a germline MMR gene three- step diagnostic pathway. PVs were identified in 8/50 (16%) test. of these tests. In total, 1.0% (76/7928) of patients had a germ- Among patients receiving a germline MMR gene test at the line MMR gene test recorded following an EC diagnosis in this end of the three-step diagnostic pathway, 57.7% (15/26) had cohort. a PV (consistent with a diagnosis of LS). A further 50 patients Out of the 76 patients recorded as having received a germline had germline MMR gene testing despite this either not being MMR gene test in this cohort, 23 patients (30.3%) were found indicated by the results of the three- step diagnostic pathway or to have a PV, of which 12 (52.2%) were in MSH6, 6 (26.1%) despite not having completed it. This is explained by the fact that were in MSH2, 3 (13.0%) were in PMS2 and 2 (8.7%) were many clinical genetics services in 2019 offered germline MMR in MLH1. The median time from cancer diagnosis to germline gene testing as the first test to patients with EC with a personal MMR gene test was 315 days (IQR 222–486) (online supple- or family history of cancer suggestive of LS. Among this group, mental tables 2,5). a further eight patients with a PV were identified. Ten patients who were likely known to clinical genetics services prior to their EC diagnosis were excluded from the main analysis. Among DISCUSSION them seven PV carriers were identified (online supplemental We present an overview of the first systematically assembled table 5). In total, 30 patients with an MMR PV were recorded national data collection of functional, somatic (tumour) and among 7938 patients with EC. Thus, only approximately 12.6% germline (constitutional) testing for MMR deficiency/LS in (30 out of an anticipated 238) of potential MMR PV carriers patients with EC. The collection of functional, somatic and were identified, given an estimated prevalence of LS in unse- germline MMR testing data as part of the NCRD provides lected EC of 3%. ongoing opportunities for (i) audit of guideline adherence, (ii) There was striking regional variation between Cancer Alli- review of future diagnostic pathway changes and (iii) research ances in known functional MMR tumour testing, in both the into endometrial and LS cancer outcomes. The data presented proportion of EC cases tested (range 1.4%–61.2%) and the time here describe the testing performed for all EC diagnosed in from cancer diagnosis to testing (range 13–837 median days). England in 2019 and reflect the testing landscape prior to the In 8/20 Cancer Alliances, the majority (≥75%) of testing was publication of NICE recommendations for universal reflex func- tional MMR tumour testing of all EC in 2020. The data serve performed within 4 months of diagnosis, suggestive of a policy of as a valuable baseline for evaluating the impact of the NICE reflex testing at least for some patients and/or in some hospitals 1084 Loong L, et al. J Med Genet 2024;61:1080–1088. doi:10.1136/jmg-2024-110231 Cancer genetics Figure 3 Number of days between cancer diagnosis and functional MMR tumour testing. Box plots of time in days to earliest functional MMR tumour test from date of endometrial cancer diagnosis by Cancer Alliance. n=number of patients with a recorded functional MMR tumour test within a Cancer Alliance. Fill colour=percentage of patients with a recorded functional MMR tumour test out of all patients with endometrial cancer within a Cancer Alliance (% tested) from high (orange) to low (blue). Box plots are also ordered by % tested from high (top) to low (bottom). constituting the Cancer Alliances. These eight Cancer Alliances the release of NICE guidelines on universal diagnostic LS testing account for the majority of functional MMR testing (74%) in CRC, only 44% of CRCs received functional MMR tumour conducted in this cohort. The remaining 12/20 Cancer Alliances testing. A concerted national collaborative effort is currently tested a lower proportion of their EC cases with a predomi- underway in England to address the variation and low testing nantly longer time-to- test, suggestive of post hoc order-initiated levels for LS in patients with CRC and ECs by engaging key testing (figure 3, online supplemental table 3). Previous studies stakeholders, providing workforce training, addressing funding comparing universal reflex versus post hoc order- initiated MMR and system barriers and extending germline MMR gene test tumour testing in patients with EC have shown that universal requesting to healthcare professionals outside of clinical genetics reflex testing leads to increased proportions of patients with EC clinics. The national datasets and methods described in this receiving testing and greater uptake of downstream germline analysis will be crucial for monitoring the continued implemen- 23–26 MMR gene testing. tation of the national guidelines. It is anticipated that implementation of the 2020 NICE recom- Performance of functional MMR tumour testing did not appear mendations will address the attrition of patients progressing along to be associated with ethnicity or deprivation quintile following the three- step diagnostic pathway and the regional disparities in multivariable adjustment. This likely reflects the majority of England. A baseline survey of EC (and CRC) multidisciplinary testing being performed in centres undertaking reflex testing as teams (MDTs) in England reported that, for example, only 62% part of the histopathological assessment, removing many of the of EC MDTs discussed MMR testing results at their meetings, demographic biases that influence being referred to a clinical only 66% stated they offered ‘universal testing’ and 88% did not genetics service for consideration of post hoc investigation for have a systematic way of referring patients for germline genetic LS. Younger age at EC diagnosis was associated with receiving testing. The main barriers to the delivery of testing cited by those functional MMR tumour testing following multivariable adjust- surveyed were local funding, service commissioning structures ment, and previous studies have shown that even in healthcare and time pressure. Another study revealed that 2 years after systems with established universal reflex LS diagnostic testing Loong L, et al. J Med Genet 2024;61:1080–1088. doi:10.1136/jmg-2024-110231 1085 Cancer genetics Table 2 Univariable and multivariable logistic regression model for functional MMR tumour testing in patients with endometrial cancer Functional MMR test Univariable Multivariable n=5200 Not tested Tested OR (95% CI) P value OR (95% CI) P value P trend Age group (years) 70+ 3037 (86.4) 477 (13.6) – – <0.0001 50–69 3151 (80.9) 743 (19.1) 1.50 (1.32 to 1.70) <0.0001 1.48 (1.24 to 1.77) <0.0001 30–49 323 (64.3) 179 (35.7) 3.53 (2.87 to 4.33) <0.0001 6.60 (4.87 to 8.95) <0.0001 0–29 9 (50.0) 9 (50.0) 6.37 (2.47 to 16.4) 0.0001 14.5 (3.65 to 59.3) 0.0001 IMD quintile Q1—most deprived 1209 (85.4) 207 (14.6) – – 0.083 Q2 1233 (79.4) 319 (20.6) 1.51 (1.25 to 1.83) <0.0001 1.29 (0.97 to 1.71) 0.077 Q3 1385 (82.7) 290 (17.3) 1.22 (1.01 to 1.49) 0.042 1.18 (0.89 to 1.56) 0.25 Q4 1363 (81.3) 313 (18.7) 1.34 (1.11 to 1.63) 0.0027 1.52 (1.15 to 2.00) 0.0029 Q5—least deprived 1330 (82.7) 279 (17.3) 1.23 (1.01 to 1.49) 0.042 1.21 (0.91 to 1.62) 0.18 Ethnicity White 5444 (83.2) 1101 (16.8) – – Asian 252 (73.7) 90 (26.3) 1.77 (1.37 to 2.26) <0.0001 0.55 (0.38 to 0.79) 0.0017 Black 140 (70.7) 58 (29.3) 2.05 (1.49 to 2.79) <0.0001 0.84 (0.48 to 1.46) 0.55 Chinese 15 (60.0) 10 (40.0) 3.30 (1.43 to 7.28) 0.0036 1.72 (0.59 to 4.81) 0.31 Mixed 28 (65.1) 15 (34.9) 2.65 (1.38 to 4.90) 0.0025 3.03 (1.23 to 7.45) 0.015 Other 93 (75.0) 31 (25.0) 1.65 (1.08 to 2.46) 0.017 0.59 (0.32 to 1.05) 0.080 Stage at diagnosis 1 4189 (83.4) 836 (16.6) – – 0.22 2 353 (77.4) 103 (22.6) 1.46 (1.15 to 1.84) 0.0013 1.41 (1.03 to 1.91) 0.027 3 444 (75.5) 144 (24.5) 1.63 (1.32 to 1.98) <0.0001 1.75 (1.32 to 2.30) 0.0001 4 408 (82.3) 88 (17.7) 1.08 (0.84 to 1.37) 0.53 1.20 (0.82 to 1.73) 0.34 Grade of tumour G1—well differentiated 2938 (84.0) 559 (16.0) – – 0.045 G2—moderately differentiated 1364 (79.3) 357 (20.7) 1.38 (1.19 to 1.59) <0.0001 1.51 (1.24 to 1.83) <0.0001 G3—poorly differentiated 1041 (77.8) 297 (22.2) 1.50 (1.28 to 1.75) <0.0001 1.95 (1.57 to 2.43) <0.0001 G4—undifferentiated/anaplastic 33 (66.0) 17 (34.0) 2.71 (1.46 to 4.83) 0.00098 2.34 (0.91 to 5.71) 0.067 Cancer Alliance (pseudonym) MM 213 (98.6) 3 (1.4) – – PP 248 (97.3) 7 (2.7) 2.00 (0.55 to 9.39) 0.32 1.73 (0.37 to 9.02) 0.48 OO 358 (96.0) 15 (4.0) 2.97 (0.97 to 13.0) 0.088 2.42 (0.72 to 11.0) 0.19 … … … … … … … II 317 (64.0) 178 (36.0) 39.9 (14.9 to 163) <0.0001 34.9 (12.6 to 145) <0.0001 RR 154 (38.8) 243 (61.2) 112 (41.7 to 458) <0.0001 210 (73.7 to 886) <0.0001 Unadjusted ORs are presented from univariable regression models including each single variable in turn. Missing data variables are excluded. Adjusted ORs are presented from a multivariable regression model including all variables in the table. Patients with missing data in any of the variables are excluded (n=2728), resulting in inclusion of 5200 patients in the multivariable model. Abbreviated results (highest and lowest ORs) are presented for the Cancer Alliance (full results available in online supplemental table 4). P values <0.05 are highlighted in bold. ORs and p values are presented to three and two significant figures, respectively. IMD, index of multiple deprivation; MMR, mismatch repair. pathways for EC, older age is a factor for non- adherence to stages, with the incidence of CRC between 60 and 70 years of those pathways. age being 11.9% and 15.7% for MLH1 and MSH2 female PV There were marked delays between each step of the diagnostic carriers, respectively. pathway and the total duration of the diagnostic pathway, from The 2020 NICE guidance for EC recommends the use of EC diagnosis to germline MMR test report, was a median of 315 IHC not MSI, based on the higher sensitivity of IHC and health 12 30 days (IQR 222–486). Implementation of the NICE recommen- economic modelling analysis. These analyses offer support dations (with added clarity regarding roles and responsibilities) to that recommendation. In addition to demonstrating dMMR, would be anticipated to shorten the duration of the diagnostic IHC provides additional information regarding the specific gene pathway and ultimately time to LS diagnosis for probands and causing dMMR. In this analysis, 20.1% (85/422) of tumours their relatives. The median age of EC diagnosis in this cohort with IHC abnormality had MSH2/MSH6/isolated PMS2 loss. was 68 (IQR 59–75). Given the relatively high 10- year survival These patients did not require the additional step (and attrition of EC in England of 71.6%, the identification of LS provides and time delay it entails) of MLH1 promoter hypermethylation valuable opportunities for the prevention of further primary analysis, compared with if their dMMR had been diagnosed via 7 28 29 cancers. For example, delays in commencing aspirin MSI analysis. Yield for PVs among patients with MSH2/MSH6/ prophylaxis and colonoscopy screening for female LS carriers isolated PMS2 IHC loss was higher (66.7%, 14/21) compared in this age range could lead to CRCs being diagnosed at later with those with MLH1 IHC loss or MSI with unmethylated 1086 Loong L, et al. J Med Genet 2024;61:1080–1088. doi:10.1136/jmg-2024-110231 Cancer genetics Applied Health Research Unit, Big Data Institute, Nuffield Department of MLH1 promoter methylation status (20%, 1/5), consistent with Population Health, University of Oxford, Oxford, UK the higher penetrance for EC in MSH6- associated and MSH2- Translational and Clinical Research Institute, Newcastle University, Newcastle upon associated LS. Tyne, UK Limitations of these analyses include reliance on complete- The Lynch Syndrome and Family Cancer Clinic, St Mark’s Hospital and Academic ness and comparability of local data submissions. That a small Institute, London, UK Imperial College London, London, UK number of germline MMR gene test records are known to be missing from summer 2019 onwards means that the proportion X Katie Snape @genetikos of patients who received germline tests may be slightly underes- Acknowledgements CT, LL, SA, KS, FL, SG and BT acknowledge grant support timated. However, in a comparable analysis of the CRC LS diag- from Cancer Research UK (C8620/A8372). CH is supported by a Wellcome Trust nostic testing pathway using Danish registry data, 20% of eligible Clinical Research Training Fellowship (ref 203924/Z/16/Z). This work uses data that patients received genetic counselling/germline testing, which has been provided by patients and collected by the NHS as part of their care and is comparable to the 25% we demonstrate here. Inclusion support. The data are collated, maintained and quality assured by the National of potentially nationally incomplete functional MMR tumour Disease Registration Service, which is part of NHS England. testing data beyond the end of 2020 allowed the demonstration Contributors Conceptualisation: LL, CH, JP, FMcR, CT. Formal analysis: CH, LL, JP. of post hoc order- initiated tumour testing further away from Accessed underlying data: CH and LL. Visualisation: LL. Supervision: CT, SH, ML, MT, ACA, PP, EM. Funding acquisition: CT, JB. Data collation and curation: FMcR, SH, JP, the original EC diagnosis. However, it means that the amount FS, BS, OT, SG. Clinical interpretation: LL, CT, KS, AG, FL, GN, DME, MT, AS, JB, KM. of post hoc order- initiated testing could be underestimated. It Project administration: FMcR, BT, SA. Writing—original draft: LL, CH, CT. Writing— is likely that post hoc testing makes up only a small amount review and editing: all authors. Guarantor: CT. of all functional MMR tumour testing conducted in EC, as it Funding This work was funded by Cancer Research UK (C8620/A8372), the usually requires the referral of the patient to a clinical genetics Wellcome Trust (203924/Z/16/Z) and Bowel Cancer UK (18PG0019). service. 84.4% (1224/1450) of the functional MMR tumour Disclaimer The funders of this study had no role in study design, data collection, tests recorded in this analysis were conducted within 1 year data analysis, data interpretation or writing of the report. of the date of EC diagnosis (online supplemental table 7). The Competing interests None declared. relatively small numbers of EC diagnosed in each hospital trust Patient consent for publication Not applicable. necessitated analysis by Cancer Alliance. Therefore, hospital Ethics approval Ethical approval for the data analyses was granted to Can- Gene trust- level variation in practice is not captured in these analyses. Can- Var (REC: 18/WS/0192). Data used in these analyses are collected and stored Lastly, personal or family history for LS- related cancers were not securely within NDRS under the legal permissions afforded by section 254 of the captured in these analyses. Health and Social Care Act 2012, which permits the collection of patient data Overall, there is a baseline picture, prior to the publication without requiring informed consent. of the NICE national guidelines on universal reflex functional Provenance and peer review Not commissioned; externally peer reviewed. MMR tumour testing in EC, of considerable missed opportu- Data availability statement Data are available on reasonable request. All nity, delay and regional variation in the diagnosis of LS among data relevant to the study are included in the article or uploaded as supplementary patients with EC. This may also be reflective of missed diag- information. Summary data relevant to the study are included in the article and nostic opportunities in other health systems in countries that supplementary material. Patient- level data used in this study are held within NDRS and available to access following application. Summary statistics for somatic Lynch have not moved to universal reflex testing. The results of these syndrome testing are available at https://digital.nhs.uk/ndrs/data/data-outputs/ analyses provide an important baseline for measuring the impact cancer-data-hub/somatic-molecular-dashboard. Germline coding DNA sequence of implementing the NICE national guidelines on the number variants are made publicly available for clinical variant interpretation purposes, as of patients tested, testing delays, attrition of patients along the variant- specific observation frequencies on public database https://canvaruk.org/. testing pathway and regional variation. Furthermore, the data- Supplemental material This content has been supplied by the author(s). It sets and methods in this study facilitate ongoing assessment of has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have diagnostic yield and provide opportunities to evaluate cancer been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and outcomes by functional phenotypes and somatic and germline responsibility arising from any reliance placed on the content. Where the content genotypes—key for continuously appraising the diagnostic accu- includes any translated material, BMJ does not warrant the accuracy and reliability racy and cost- effectiveness of implemented testing pathways. of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error Author affiliations and/or omissions arising from translation and adaptation or otherwise. Institute of Cancer Research Division of Genetics and Epidemiology, Sutton, UK 2 Open access This is an open access article distributed in accordance with the National Disease Registration Service, London, UK Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits Health Data Insight, Cambridge, UK others to copy, redistribute, remix, transform and build upon this work for any Cancer Epidemiology and Cancer Services Research, Centre for Cancer, Society & purpose, provided the original work is properly cited, a link to the licence is given, Public Health, Comprehensive Cancer Centre, King’s College London, London, UK and indication of whether changes were made. See: https://creativecommons.org/ Department of Clinical Genetics, St George’s University Hospitals NHS Foundation licenses/by/4.0/. Trust, London, UK Gynaecology Unit, Royal Marsden NHS Foundation Trust, London, UK ORCID iDs The Institute of Cancer Research—Sutton, London, UK Sophie Allen http://orcid.org/0000-0003-4928-2240 Clinical Genetics Service, Manchester Centre for Genomic Medicine, Central Bethany Torr http://orcid.org/0000-0003-3487-9749 Manchester University Hospitals NHS Foundation Trust, Manchester, UK Katie Snape http://orcid.org/0000-0002-1739-7986 South East Genomic Laboratory Hub, Guy’s and St Thomas’ Hospitals NHS Trust, Diana M Eccles http://orcid.org/0000-0002-9935-3169 London, UK Antonis C Antoniou http://orcid.org/0000-0001-9223-3116 Human Genetics and Genomic Medicine, University of Southampton Faculty of Adam Shaw http://orcid.org/0000-0003-3046-3092 Medicine, Southampton, UK Clare Turnbull http://orcid.org/0000-0002-3797-7398 Department of Medical Genetics, Cambridge Biomedical Research Centre, National Institute for Health Research, University of Cambridge, Cambridge, UK Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary REFERENCES Care, University of Cambridge, Cambridge, UK 1 Dominguez- Valentin M, Sampson JR, Seppälä TT, et al. 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Journal

Journal of Medical Genetics – British Medical Journal

Published: Oct 21, 2024

Keywords: databases, genetic; genetic predisposition to disease; genetic testing; gynecology; health services research

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