A monocentric analysis of ESCAT gene actionability detection in non-specific molecular profile (NSMP) endometrial cancer.

e17634 Background: The non-specific molecular profile (NSMP) subtype accounts for 50% of endometrial carcinoma (EC). It's a heterogeneous group of tumors, characterized by minimal cell mutations and low copy number variations, including both aggressive and clinically low-risk ECs. Methods: In January 2022 our institution launched a comprehensive cancer genome profiling (CGP) (FPG500 IRB approval 3837; NCT06020625) enrolling also EC patients. Oncogenic and likely oncogenic alterations were reported according to OncoKB and classified as Tier I-II-III according to ESCAT classification. The aim of the current analysis was to describe ESCAT gene actionability findings. Results: From January 1 st 2022 to December 31 st 2023, 253 patients with any FIGO stage, NSMP ECs were enrolled. Median age was 62 years and the most frequent histotype was endometrioid (96.9%). Estrogen receptors were positive in 94.5%. Overall, 233 patients (92%) had at least one tier III ESCAT alteration. The more frequent variants were found in PTEN (88%), PIK3CA (43%), FGFR2 (15%) and AKT1 (6%). 18% of patients had an ESR1 variant, while a KRAS G12C variant was found in 11% of patients. The majority of PTEN variants were R130X: R130G (40 pts, 17.2%), R130Q (17 pts, 7.3%) and R130* (10 pts, 4.3%). The PIK3CA's more frequently altered hotspots were H1047R (21 pts, 9.0%), E545D/K/Q/A (13 pts, 5.6%) and E542K (9 pts, 3.9%). The most frequent FGFR2 hotspot was S252W (16 pts, 6.9%). Mutually exclusive genes (p<0.05) were AKT and PTEN, PIK3CA and PIK3R1, FGFR2 with CTNNB1 and KRAS. Significant co-occurrence (p<0.05). was found between PTEN and PIK3CA and ARID1A. Considering ESCAT Tiers, the PI3K pathway was altered in 85% of patients. Conclusions: Our descriptive analysis aligns with existing literature data. Further investigation correlating survival and recurrence rates with molecular findings could unveil prognostic subgroups and potentially targetable variants.