Molecular classification of endometrial carcinoma: Analysis of a multicentre Portuguese cohort.
Authors: Moreira Inês , Ferreira Marta , Garcia Sofia , Novais Pedro , Gama João , Ferro Beatriz , Leite-Silva Pedro , Frutuoso Cristina , Pires Monica , Barbosa Ana , Pinto Carla , Teixeira Manuel , Pereira Deolinda , Bartosch Carla 
Published: June 2023

e17615 Background: Management of endometrial carcinoma (EC) relies on prognostic risk group classification to help to determine the individual risk of recurrence and the need for adjuvant treatment after surgery. A molecular classification with four distinct prognostic EC subtypes based on genomic abnormalities - DNA polymerase epsilon ( POLE) mutated ( POLEmut), mismatch repair deficient (MMRd), p53 abnormal (p53abn) and no specific molecular profile (NSMP) - has emerged, that raises the possibility of a more precise tailoring of adjuvant therapy. This study aimed to describe the clinicopathological and molecular characteristics of an EC Portuguese cohort, assess its potential impact in patient management and evaluate its prognostic value. Methods: Multicentre, retrospective cohort study of 230 patients with EC diagnosed between 2019 and 2022. Sample processing, clinicopathological, treatment and follow-up data was collected. Molecular classification was obtained by p53 and mismatch repair proteins immunohistochemistry, and POLE next-generation sequencing. Results: Overall, 230 patients from two institutions were included. Median age at diagnosis was 68 years. The most frequent histology was endometrioid (n=163; 70.9%) and most were low-grade (n=129, 56.1%).At diagnosis, disease was confined to the uterus in the majority of patients (FIGO stage I/II, n=153, 66.5%). Most had surgery upfront (n=196, 85.2%) and, of those, 120 (52.2%) received adjuvant treatment. 26 (11.3%) had metastatic disease. Median follow-up time was 15.4 months. Regarding molecular subgroups, the majority were classified as NSMP (n=87, 37.8%), followed by p53abn (n=73, 31.7%), MMRd (n=56, 24.3%), and POLEmut (n=14, 6.1%); 11 (4.8%) were multiple-classifier. Integration of these results led to a change in adjuvant treatment in 3 patients. Median disease-specific survival (DSS) was 108 months. Factors that significantly influenced survival included age (p=0.030), histological type (p<0.001), grade (p<0.001) and FIGO stage (p=0.006). Overall, 35 (15.2%) patients developed recurrences. Median recurrence-free survival (RFS) was 46.7 months. Kaplan-Meier survival analysis showed that molecular alterations were significantly associated both with DSS and RFS (p=0.0092 and p=0.0139, respectively). Tumours with p53abn had the worst prognosis, and patients with POLEmut tumours experienced an excellent prognosis. Comparative measures (BIC, C-index, log-likelihood) showed that considering the molecular classification in establishing risk groups for adjuvant treatment had prognostic significance. Conclusions: The molecular classification has prognostic value and should be considered in adjuvant treatment decisions. It allows for a more personalised approach, helps to reduce under and overtreatment, and therefore reduce patient morbidity associated with treatment toxicities, and healthcare related costs.