Substratification of mismatch repair deficient endometrial cancers based on mechanism of MMR loss can provide prognostic and predictive refinement

BACKGROUND: Mismatch repair deficient (MMRd) endometrial carcinomas (EC) encompass 25-30% of ECs. Identifying MMRd directs Lynch Syndrome testing and immune checkpoint inhibitor (ICI) therapy. Our aim was to characterize the clinicopathologic and molecular features of MMRd ECs treated in the pre-ICI era. METHODS: MMRd ECs were identified retrospectively and tumors underwent selective immunohistochemistry and hotspot panel sequencing. RESULTS: MMRd ECs (n = 899) were predominantly FIGO 2009 stage I (77%), endometrioid histotype (92%), with 14% lymph node metastases (LNM). Lymphovascular invasion and myoinvasion were prognostic in MMRd ECs, but grade and histotype were not. Patients with MLH1 loss (80%) were older with higher BMI, had more deeply invasive tumors and more LNM compared to patients with MSH2/MSH6/isolated PMS2 loss (20%). Worse outcomes were observed with MLH1 loss; 18% of patients recurred and 10% died of disease compared to 7% and 4% with MSH2/MSH6/isolated PMS2 loss. MLH1 loss tumors had lower CD8+ tumor infiltrating lymphocyte densities, which were associated with worse prognosis. ER, PR, L1CAM and CTNNB1 were not associated with outcomes in MMRd ECs. There was no difference in outcomes between patients with MMRd-p53abn (N = 150, multiple classifiers) and MMRd ECs with wildtype p53 expression. Outcomes were identical for chemoradiation vs radiation alone for ESMO high risk or high/advanced/metastatic risk groups combined. CONCLUSION: MLH1 loss identifies a subset of MMRd ECs with worse outcomes and lower CD8+ densities supporting substratification of this molecular subtype. Grade, histotype, ER, PR, L1CAM, CTNNB1 and p53 status do not add prognostic refinement within MMRd EC.