Redefining Prognosis In Early-Stage High-Grade Endometrial Cancer

Current clinicopathological risk stratification methods in endometrial cancer (EC) are not considered sufficiently accurate tools to address prognosis and adjuvant therapy. There is a high interobserver variation in the assignment of histotype, especially in high grade (HG) tumors. We investigate if molecular classification can be used to refine prognosis in early-stage HG-EC despite histological subtypes. An early-stage (FIGO I & II) HG-EC patients cohort between 2003 to 2015 was collected in a Spanish hospital. Molecular surrogate classification was performed using immunohistochemistry for p53 (p53 wild-type “p53wt” or p53 aberrant “p53abn” expression) and mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), considering MMR deficiency (MMRd) when a loss of MMR nuclear staining for at least one protein was identified. Identification of POLE mutations (POLE-EDM) was made by sequencing exons 9–14. Only pathogenic variants described in COSMIC database were considered for further analysis. Clinicopathological variables and survival ([RFS, relapse free survival; OS, overall survival]) correlations were assessed by the Kaplan Meier method and log rank. A cohort of 54 patients fulfilled clinical and pathological criteria. Distribution by histological subtype was: endometrioid (46.3%), serous (33.3%), undifferentiated (11.1%), mixed (5.6%), and clear cell (3.7%). Molecular profile was fully evaluable in 49 samples: MMRd (26.5%), POLE-EDM (12.2%), p53wt (22.5%), p53abn (38.8%). Regardless of molecular subtype, 5 year relapse rate was: POLE 0%, MMRd 31.6%, p53wt 35.7%, p53abn 48.9% (p=0.23), and 5 year OS rate was: POLE-EDM 100%, MMRd 76.2%, p53wt 48% and p53abn 38.5% (p=0.18). Considering only endometrioid subtype, there was a statistically significant correlation of the molecular classification with 5 year OS (p=0.02). To our knowledge, this is the first series that has evaluated the molecular classification focused on early-stage HG-EC, including all histologies. Patients with POLE-EDM have an excellent prognosis, with no relapses in this subgroup, whereas patients with p53abn have the worst prognosis. The application of molecular classification in daily practice could be useful in a better design of adjuvant therapy.