Risk stratification of stage I grade 3 endometrioid endometrial carcinoma (083)

Abstract

<b>Objectives:</b> We sought to assess the role of adjuvant therapy in stage I grade 3 endometrioid endometrial carcinomas (EC). The primary objective was to define the agreement between PORTEC-1 high intermediate risk (HIR), GOG 99 HIR, and TCGA molecular subtype classification for these patients. Secondary outcomes included adjuvant treatment received and progression-free survival (PFS). <b>Methods:</b> We retrospectively reviewed all patients with stage I grade 3 endometrioid ECs who underwent surgical staging at our institution from 1/1/2014-1/4/2020. Patients were stratified into PORTEC-1 HIR (yes/no), GOG 99 HIR (yes/no), and TCGA molecular subtypes. Clinical characteristics were compared. The agreement was assessed using Cohen's kappa. PFS was compared between groups in a time-to-event analysis. <b>Results:</b> Seventy-five patients met the inclusion criteria: 15 (20%) were of copy number (CN)-high, 26 (35%) of microsatellite instability-high (MSI-H), 24 (32%) of polymerase epsilon (<i>POLE</i>), and 10 (13%) of CN-low molecular subtype. While the overall number of stage I grade 3 endometrioid ECs classified into the PORTEC-1 HIR and GOG 99 HIR was similar (52/75, 69% and 38/75, 51%, respectively), the agreement between PORTEC-1 and GOG 99 HIR classification was only 68% (95% CI: 56.2-78.3) with a kappa value of 0.36 (p=0.001). When comparing PORTEC-1 or GOG 99 HIR classification with a dichotomized molecular classification (CN-high vs all other subtypes), the agreement proportions were 40% (95%CI: 28.9-52) and 48% (95%CI: 36.3%-59.8%), respectively, with kappa values of 0.03 (p=0.39) and -0.03 (p=0.61), respectively. Patients with stage I grade 3 endometrioid ECs classified as GOG 99 HIR or of MSI-H molecular subtype were significantly more likely to have received adjuvant chemotherapy. There were ten progressions and four deaths among 75 patients, with a median follow-up of 25.3 months (range: 7-66.5 months). Patients with ECs of CN-high molecular subtype experienced a 2-year PFS of 65% (95% CI: 35.1-83.7) compared with patients with CN-low (HR: 0.54, 95% CI: 0.11-2.8), MSI-H (HR: 0.2, 95% CI: 0.04-1.05) and <i>POLE</i> (HR: 0.09, 95% CI: 0.01-0.8) molecular subtypes. <b>Conclusions:</b> In this cohort of patients with stage I grade 3 endometrioid EC, PORTEC-1 and GOG 99 HIR criteria are not in agreement and do not identify CN-high patients. Patients with tumors of CN-high molecular subtype experienced worse PFS than all other classified tumors. Molecular classification may play a role in tailoring adjuvant therapy in this population.Fig. 1