Introduction Endometroid endometrial cancers (EECs) are clinically and molecularly heterogeneous. We sought to investigate the molecular landscape of stage I, grade 3 EECs.

Methods Patients with stage I, grade 3 EECs who underwent surgical staging from 1/2014–1/2020 were identified. Clinicopathologic data were curated from electronic medical records. All EECs underwent tumor-normal targeted panel sequencing of up to 505 cancer-related genes and were classified by molecular subtype. POLE-mutated ECCs were excluded from mutational analyses, as they are ultramutated tumors.

Results Seventy-five patients were identified. Unlike stage I, grade 1 EECs, which are mostly of copy number (CN)-low molecular subtype, most of our stage I, grade 3 EECs were of POLE (25/75, 33%) or microsatellite instability (MSI)-high (24/75, 32%) molecular subtypes; 20% (15/75) were CN-high and 15% (11/75) CN-low. Patients with MSI-high EECs, compared to other subtypes, were more likely to have deep myometrial invasion (p=0.02) and to have received chemotherapy (p=0.01). After exclusion of POLE EECs, 50 patients met criteria for mutational analyses. The most common alterations affected PTEN (68%), ARID1A (46%), PIK3CA (42%), and PIK3R1 (38%). Stage I, grade 3 EECs with positive lymphovascular space invasion, compared to those without, more frequently harbored PTEN (86% vs 56%, p=0.03), PIK3R1 (57% vs 28%, p=0.04), and MAP2K4 (19% vs 0%, p=0.03) mutations. Stage IB cases, compared to stage IA cases, were more likely to harbor FBXW7 (29% vs 6%, p=0.04) and KMT2D (64% vs 25%, p=0.02) mutations.

Conclusion/Implications Stage I, grade 3 EECs are a heterogenous group of tumors with varying mutational profiles and molecular subtypes.