Prevalence and clinical implications of mismatch repair (MMR) deficiency in unselected endometrial cancer (EC) patients

Abstract

Background: Endometrial cancer (EC) is the most common gynaecological malignancy worldwide. The TCGA data suggested up to 30% of EC pts have aMMRdeficient (MMRd) tumours, however the exact concordance of this with the presence of a germline mutation (Lynch syndrome) in an unselected population is unclear. Lynch-associated tumours appear to have a better prognosis, however the implications for prognosis and survival in all MMRd tumours are less known. Methods: 396 pts with primary endometrial cancer, treated at RMHwere evaluated for MMRproteins by immunohistochemistry (IHC). Tumours with loss of at least one protein were considered MMRd, those with intact expression wereMMRproficient (MMRp). Clinico-pathological characteristics and survival data was collected from electronic records. Progression free survival (PFS) and overall survival (OS) were assessed using Kaplan Meier and log-rank tests. Results: Of 396 samples tested to date, 29% (114 pts) were MMRd. Frequencies of IHC MMRloss of expression were: MLH1/PMS2 loss: 80, MSH2/MSH6 loss: 10, MSH6 loss: 12, PMS2 loss: 9, other patterns: 3. Germline testing has been completed in 37% (42 pts) thus far; 14pts had a concordant germline mutation: MLH1 (2/25), MSH2 (3/7), MSH6 (7/8), PMS2 (2/2) respectively. Mean age varied significantly, at 66 yrs (MMRd), 65yrs (MMRp) and 58 yrs (Lynch mutation carriers, LS) p=0.022: as did mean BMI: 33 (MMRd), 26 (LS) and 36 (MMRp), p=0.023. Stage at diagnosis did not differ significantly between the groups but MMRd and LS patients were significantly more likely to have LVSI than MMRp (p=0.01), and to be high EORTC risk (p=0.006). OS for the entire cohort was 160mths (75-244.9) and PFS was 51.6mths (32.4-70.7). MMRd pts had a shorter OS (96.4mths, 95%CI 65.7 - 127) than MMRp (160mo, 54.9 - 265) and a shorter PFS median PFS 41.4mo (IC 95% 18.9- 64) vs 51.6mo (IC 95% 30- 72), p.021]. Conclusions: Almost one in three EC tumours are MMRd, with concordance between IHC loss and presence of a germline mutation varying by gene. Those with somatically derived MLH1/PMS2 loss may have a poorer prognosis, and as a group may potentially benefit from checkpoint inhibitors. Further exploration of the clinical correlations and outcome withMMRstatus is warranted.