Cost-effectiveness analysis of reflex testing for Lynch syndrome in women with endometrial cancer in the UK setting

Snowsill, Tristan; Ryan, Neil; Crosbie, Emma J.; Frayling, Ian Martin; Evans, D. Gareth; Hyde, Chris

doi:10.1371/journal.pone.0221419

Cited by 25 publications

(28 citation statements)

References 57 publications

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“…Our data provide strong evidence that MMR-IHC with targeted MLH1 -methylation testing is superior to MSI-based testing in EC. It reduces the proportion of women requiring germline sequencing without missing any cases, lowering costs [ 37 ], and improving cost-effectiveness [ 38 , 39 ]. The identification of MMR deficient EC is of clinical importance.…”

Section: Discussionmentioning

confidence: 99%

The proportion of endometrial tumours associated with Lynch syndrome (PETALS): A prospective cross-sectional study

et al. 2020

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Background Lynch syndrome (LS) predisposes to endometrial cancer (EC), colorectal cancer, and other cancers through inherited pathogenic variants affecting mismatch-repair (MMR) genes. Diagnosing LS in women with EC can reduce subsequent cancer mortality through colonoscopic surveillance and aspirin chemoprevention; it also enables cascade testing of relatives. A growing consensus supports LS screening in EC; however, the expected proportion of test positives, and optimal testing strategy is uncertain. Previous studies from insurance-based healthcare systems were limited by narrow selection criteria, failure to apply reference standard tests consistently, and poor conversion to definitive testing. The aim of this study was to establish the prevalence of LS and the diagnostic accuracy of LS testing strategies in an unselected EC population. Methods and findings This was a prospective cross-sectional study carried out at a large United Kingdom gynaecological cancer centre between October 2015 and January 2017. Women diagnosed with EC or atypical hyperplasia (AH) were offered LS testing. Tumours underwent MMR immunohistochemistry (IHC), microsatellite instability (MSI), and targeted MLH1 -methylation testing. Women <50 years, with strong family histories and/or indicative tumour molecular features, underwent MMR germline sequencing. Somatic MMR sequencing was performed when indicative molecular features were unexplained by LS or MLH1 -hypermethylation. The main outcome measures were the prevalence of LS in an unselected EC population and the diagnostic accuracy of clinical and tumour testing strategies for risk stratifying women with EC for MMR germline sequencing. In total, 500 women participated in the study; only 2 (<1%) declined. Germline sequencing was indicated and conducted for 136 and 135 women, respectively. A total of 16/500 women (3.2%, 95% CI 1.8% to 5.1%) had LS, and 11 more (2.2%) had MMR variants of uncertain significance. Restricting testing to age <50 years, indicative family history (revised Bethesda guidelines or Amsterdam II criteria) or endometrioid histology alone would have missed 9/16 (56%), 8/13 (62%) or 9/13 (69%), and 5/16 (31%) cases of LS, respectively. In total 132/500 tumours were MMR deficient by IHC of which 83/132 (63%) had MLH1 -hypermethylation, and 16/49 (33%) of the remaining patients had LS (16/132 with MMR deficiency, 12%). MMR-IHC with targeted MLH1 -methylation testing was more discriminatory for LS than MSI with targeted methylation testing, with 100% versus 56.3% (16/16 versus 9/16) sensitivity ( p = 0.016) and equal 97.5% (468/484) specificity; 64% MSI-H and 73% MMR deficient tumours unexplained by LS or MLH1- hypermethylation had somatic MMR mutations. The main limitation of the study was failure to conduct MMR germline sequencing for the whole study population, w...

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Section: Discussionmentioning

confidence: 99%

The proportion of endometrial tumours associated with Lynch syndrome (PETALS): A prospective cross-sectional study

et al. 2020

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“…When an endometrial cancer patient (proband) is diagnosed with Lynch syndrome, cascade testing of their relatives is simulated. For each proband, we modelled on average six relatives having an appointment with a general practitioner in relation to Lynch syndrome, of whom 4.7 attended genetic counselling, 3.3 underwent predictive genetic testing, and 1.5 were diagnosed with Lynch syndrome [ 13 ]. The relatives were modelled irrespective of the true Lynch syndrome status and diagnostic outcome for the proband, so that there was a consistent population across interventions.…”

Section: Methodsmentioning

confidence: 99%

“…More recent evidence has emerged that reflex testing of endometrial cancer cases for Lynch syndrome may also be cost-effective [ 9 , 10 , 11 , 12 , 13 ], but much of this evidence is limited in its scope, for example, most have not included the option of not testing for Lynch syndrome as a comparator and have only compared testing strategies [ 9 , 10 , 11 , 12 ]. We recently published a model-based economic evaluation using prevalence and diagnostic accuracy data estimated from published literature [ 13 ], but this cannot adequately address that different testing strategies may not only have different performance characteristics, but may also identify different Lynch syndrome cases and face different challenges in a heterogeneous population. For example, MSI testing may both be less specific in older patients (where somatic MLH1 hypermethylation is known to be more common in colorectal cancer [ 14 ]) and may be less sensitive to identify path_MSH6 and path_PMS2 cases (i.e., pathogenic variants in MSH6 and PMS2 ) [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Cost-Effectiveness of the Manchester Approach to Identifying Lynch Syndrome in Women with Endometrial Cancer

Snowsill

Ryan

Crosbie

2020

JCM

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Lynch syndrome (LS) is a hereditary cancer syndrome responsible for 3% of all endometrial cancer and 5% in those aged under 70 years. It is unclear whether universal testing for LS in endometrial cancer patients would be cost-effective. The Manchester approach to identifying LS in endometrial cancer patients uses immunohistochemistry (IHC) to detect mismatch repair (MMR) deficiency, incorporates testing for MLH1 promoter hypermethylation, and incorporates genetic testing for pathogenic MMR variants. We aimed to assess the cost-effectiveness of the Manchester approach on the basis of primary research data from clinical practice in Manchester. The Proportion of Endometrial Tumours Associated with Lynch Syndrome (PETALS) study informed estimates of diagnostic performances for a number of different strategies. A recent microcosting study was adapted and was used to estimate diagnostic costs. A Markov model was used to predict long-term costs and health outcomes (measured in quality-adjusted life years, QALYs) for individuals and their relatives. Bootstrapping and probabilistic sensitivity analysis were used to estimate the uncertainty in cost-effectiveness. The Manchester approach dominated other reflex testing strategies when considering diagnostic costs and Lynch syndrome cases identified. When considering long-term costs and QALYs the Manchester approach was the optimal strategy, costing £5459 per QALY gained (compared to thresholds of £20,000 to £30,000 per QALY commonly used in the National Health Service (NHS)). Cost-effectiveness is not an argument for restricting testing to younger patients or those with a strong family history. Universal testing for Lynch syndrome in endometrial cancer patients is expected to be cost-effective in the U.K. (NHS), and the Manchester approach is expected to be the optimal testing strategy.

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“…The potential for these interventions to save lives supports routine Lynch syndrome testing for all endometrial cancer patients, especially because selecting women by age, family history or tumour characteristics misses cases of Lynch syndrome [ 8 ]. The routine use of sequential tumour-based tests to triage women for definitive germline testing has been proposed as the most effective and cost-effective method of identifying the 3% of women with Lynch syndrome-associated endometrial cancer [ 9 , 10 ]. Initial tumour-based tests, routinely performed to diagnose, stage and inform individualized treatment plans, do not require explicit patient consent.…”

Section: Introductionmentioning

confidence: 99%

Feasibility of Gynaecologist Led Lynch Syndrome Testing in Women with Endometrial Cancer

Ryan

Donnelly

Stocking

et al. 2020

JCM

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A barrier to Lynch syndrome testing is the need for prior genetic counselling, a resource demanding process for both patients and healthcare services. We explored the impact of gynaecologist led Lynch syndrome testing in women with endometrial cancer. Women were approached before surgery, on the day of surgery or during routine follow up. Lynch syndrome testing was offered irrespective of age, family history or tumour characteristics. Women’s reasons for being tested were explored using the Motivations and Concerns for GeNEtic Testing (MACGNET) instrument. The short form State-Trait Anxiety Inventory (STAI-6) was used to measure anxiety levels. Only 3/305 women declined Lynch syndrome testing. In total, 175/220 completed MACGNET and STAI-6 psychological instruments. The consent process took an average of 7 min 36 s (SD 5 min 16 s) to complete. The point of care at which consent was taken (before, day of surgery, during follow up) did not influence motivation for Lynch syndrome testing. Anxiety levels were significantly lower when women were consented during follow up (mean reversed STAI-6 score 32 vs. 42, p = 0.001). Anxiety levels were not affected by familial cancer history (p = 0.41). Gynaecologist led Lynch syndrome testing is feasible and may even be desirable in endometrial cancer, especially when offered during routine follow up.

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Cost-effectiveness analysis of reflex testing for Lynch syndrome in women with endometrial cancer in the UK setting

Cited by 25 publications

References 57 publications

The proportion of endometrial tumours associated with Lynch syndrome (PETALS): A prospective cross-sectional study

The proportion of endometrial tumours associated with Lynch syndrome (PETALS): A prospective cross-sectional study

Cost-Effectiveness of the Manchester Approach to Identifying Lynch Syndrome in Women with Endometrial Cancer

Feasibility of Gynaecologist Led Lynch Syndrome Testing in Women with Endometrial Cancer

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