The case for screening all endometrial cancer patients for Lynch syndrome

Neil Ryan1,2, Raymond McMahon3, Tristan Snowsill4, Niall Davison5, Kate Stocking6, Louise Donnelly7, Simon Tobi8, Andrew Wallace8, Katherine Payne5, D Gareth Evans2,8,9, Emma Crosbie1,9,10

1Gynaecological Oncology Research Group, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester,, Manchester, United Kingdom. 2Division of Evolution and Genomic Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary’s Hospital, Manchester, United Kingdom. 3Department of Pathology, Manchester Academic Health Science Centre, Manchester University Foundation Trust, Manchester, United Kingdom. 4Health Economics Group, University of Exeter Medical School, University of Exeter, , Exeter, United Kingdom. 5Manchester Centre for Health Economics, Division of Population Health, Health Services Research and Primary Care, University of Manchester, , Manchester, United Kingdom. 6Department of Medical Statistics, Manchester University NHS Foundation Trust, Manchester, Manchester, United Kingdom. 7Nightingale and Prevent Breast Cancer Research Unit, Manchester University NHS Foundation Trust, Southmoor Road, Manchester, United Kingdom. 8Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom. 9NIHR Manchester Biomedical Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, , Manchester, United Kingdom. 10Department of Obstetrics and Gynaecology, St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom

Abstract

Objectives: 

We aimed to define the incidence of Lynch syndrome (LS) in an endometrial cancer population. We also explored the acceptability for women and the costs for health care providers for such testing.

 

Methods:

We performed a systematic review with meta-analysis of the incidence of LS-EC. Next, we offered LS testing to all women presenting with EC to our institution between 2015-2017. We tested tumours for microsatellite instability (MSI) and mismatch repair (MMR) deficiency by immunohistochemistry (IHC), with MLH1hypermethylation and/or germline sequencing by next generation sequencing (NGS) as indicated; spurious results we defined with somatic genomic analysis. We assessed the acceptability of LS testing at various stages of treatment. Costs were identified using a micro-costing approach.

 

Results:

The systematic review included 12,633 EC cases and found 3% to be LS-associated. We recruited 300 prospective women with EC. Two women recruited on the day of surgery declined testing. Consenting women for LS testing in follow-up was associated with less cancer worry. Of the 500 EC tested, 108 (22%) showed complete MMR loss, 88 (18%) MSI and 16 (3%) were ultimately diagnosed with LS by germline NGS. Somatic analysis explained all but one sample. Of those with LS, many did not meet established criteria (e.g. age) for testing. MSI was less sensitive and specific than IHC testing. The cheapest testing strategy cost just £42.01/EC.

 

Conclusion:

Unselected testing of EC for LS is cheap, acceptable to women and by directing tailored treatment and risk-reducing interventions, will save lives.

 

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