Search

Objective To explore the impact of molecular subtype in endometrial cancer (EC) on CD8+T cell densities. Furthermore, this work will test the assumption that all mismatch repair deficient (MMRd) tumours are immunologically similar which would enable current trial data to be generalised to all MMRd ECs.Methods and analysis All tumours were characterised into the four clinical molecular subtypes. For analysis, the TP53 mutant and no-specific molecular profile tumours were grouped together and described as the low mutational burden (LMB) cohort. CD8+T cell counts were taken from four regions of interest which sampled the tumour-stromal interface and the tumour core. CD8+T cell counts were analysed as mean averages.Results In total, 607 ECs contributed to the analysis. CD8+T cell counts in confirmed Lynch syndrome (LS) ECs were significantly higher than MLH1-methylated ECs in all tumour locations excluding the tumour stroma. Confirmed LS and path_POLE ECs had significantly higher CD8+T cell counts across all tumour locations when compared with LMB ECs. There were limited significant differences in CD8+T cell counts between path_POLE versus confirmed LS ECs. There was no significant difference in the CD8+T cells counts and gene (MLH1, MSH2, MSH6, PMS2) in which the LS pathogenic variant was found; however, this analysis was limited by small numbers.Conclusion These data indicate that CD8+T cell numbers and distribution is not equal between MLH1-methylated and confirmed LS ECs. This is relevant when interpreting current trial data looking to the application of checkpoint inhibition treatments in MMRd cancers.

Objective In England, through the Genomic Medicine Service Alliances (GMSAs), a national transformation project aims to embed robust pathways to deliver universal Lynch syndrome (LS) testing for patients with colorectal and endometrial cancers. Prior to commencement of the project, there was evidence of variation and low testing levels in eligible patients which is consistent with other health systems; however, we believe this is amenable to systematic improvement with responsibility for testing delivery by local cancer teams supported by regional infrastructure.Methods and analysis A project team and national oversight group was formed in May 2021 with membership including 21×cancer alliances, 7×GMSAs, charities and other stakeholders who agreed key performance indicators. ‘LS champions’ within each cancer team were identified and surveyed. Workforce training focused on effective identification of eligible patients, overcoming barriers and mainstreamed constitutional genetic testing. Comprehensive pathway data analysis was performed in conjunction with the National Disease Registration Service.Results Survey and baseline testing data illustrated variation, and a disparity between practice and perception, in levels of testing. The main reported barriers related to funding streams and systematic approaches. Multifaceted training programmes were produced to support workforce development. Champions responsible for testing delivery were appointed in >95% of cancer teams. We identified >9000 historically diagnosed LS patients to support ascertainment for a nationally coordinated screening programme.Conclusion This ongoing transformational project is strongly supported by stakeholders in England. Significant quality improvement has been implemented, facilitating systematic delivery of universal testing for LS nationally and reduction in variation in care.