Lynch syndrome associated endometrial cancer: screening and novel biology.

Abstract

Background: Lynch syndrome (LS) is the most common inherited cause of Endometrial Cancer (EC), however testing for LS in EC is not routine. Identifying LS determines eligibility for immunotherapy trials, enables surveillance to reduce colorectal cancer deaths, and promotes cascade testing of relatives. Methods: I performed a systematic review with meta-analysis of the prevalence of LS associated EC. Next, LS testing was offered to all women presenting with EC to our institution between 2015- 2017. Tumours were tested for microsatellite instability (MSI) and mismatch repair (MMR) deficiency immunohistochemistry (IHC), with MLH1 hypermethylation testing and/or germline next generation sequencing (NGS) as indicated. I assessed the acceptability of LS testing at various stages of the cancer pathway. Costs were identified using micro-costing, whereby clinical/laboratory staff time and consumables/capital equipment costs were calculated. The immunological and molecular landscape of proven LS-EC was compared to sporadic EC by IHC and NGS. Results: The systematic review included 12,633 EC cases and found 3% were LS-associated. This was supported by our prospective cohort study of 500 patients, of whom only less than 1% declined testing, when offered on the day of surgery. Consenting women for LS testing in follow-up was associated with less cancer worry. Sensitivity and specificity for microsatellite instability testing with targeted MLH1 promotor hypermethylation analysis was 62.5% and 97.3% respectively. For immunohistochemistry with targeted MLH1 promotor hypermethylation analysis the sensitivity and specificity were 100% and 98.6% respectively. Sixteen women had LS-EC, of whom only three were known to have LS. Eleven variants of unknown significance were found. Of those tumours with unexplained microsatellite instability or immunohistochemistry mismatch protein loss, 16% and 92% were found to have a somatic path_MMR mutation. The cheapest testing strategy cost just £42.01/EC. LS15 EC (n=63) had significantly higher densities of infiltrating immune cells than sporadic MMR-deficient (n=95)/proficient EC (n=402), and its distinct molecular profile reflected its unique heritage. Conclusion: Unselected testing of EC for LS is cheap, acceptable to women and by directing tailored treatment and risk-reducing interventions, will save lives. The immunological and somatic mutational landscape of LS associated EC is distinct from other etiologies of EC MMR deficiency; this should inform clinical treatment trials exploring the efficacy of checkpoint inhibition in MMR deficient cancers. These results pioneered international LS-EC guidance and opened discussion with UK policy makers.

Date of Award	1 Aug 2020
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Dafydd Evans (Supervisor) & Emma Crosbie (Supervisor)