740P - A monocentric analysis of ESCAT gene actionability detection in non-specific molecular profile (NSMP) early-stage endometrial cancer

Background

The non-specific molecular profile (NSMP) subtype accounts for 50% of endometrial carcinomas (EC). It's a heterogeneous group of tumors characterized by low tumor mutational burden (TMB) and low copy number variation (CNV), 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 early stage EC (I-II according to FIGO). A VAF cut-off of 0.05 was used. 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 1st 2022 to December 31st 2023, 209 patients with FIGO stage I-II NSMP ECs were enrolled. Median age was 62 years and the most frequent histotype was endometrioid (96%, of which 90% were low grade). Estrogen receptors and progesterone receptors were positive in 97% and 95% of patients, respectively. Median TMB was 5.5. Overall, 181 patients (87%) had at least one ESCAT alteration (all Tier III). The more frequent variants were in PTEN (75%), PIK3CA (36%), FGFR2 (10%) and AKT1 (6%). 4% of patients had a ESR1 variant, while a KRAS G12C variant was found in 2% of patients and ERBB2 was mutated in 1% of patients. The majority of PTEN variants were R130X: R130G (29 pts, 14%), R130Q (12 pts, 6%) and R130* (9pts, 4%). The PIK3CA's more frequently altered hotspots were H1047R (18 pts, 9%), E545D/K/Q/A (14 pts, 7%) and E542K (7 pts, 3%). The most frequent FGFR2 hotspot was S252S (14 pts, 7%). 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.

Clinical trial identification

NCT06020625.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

C. Nero: Financial Interests, Personal, Other: MSD, Illumina. G. Scambia: Financial Interests, Personal, Invited Speaker, Speaker: Baxter Healthcare, GSK, Intuitive Surgical Inc., AstraZeneca & MSD, Olympus Europa, GSK, AstraZeneca & MSD, Olympus Europa; Financial Interests, Personal, Advisory Board, Trainer: Covidien AG (Medtronic company); Financial Interests, Institutional, Coordinating PI, ‘IsoMSLN’ in Ovarian Cancer and Malignant Pleural Mesothelioma: Kiromic; Financial Interests, Institutional, Coordinating PI, Roll-over study for patients who have completed a previous cancer study with olaparib and who the investigator believes can benefit from continued treatment - ROSY-O: AstraZeneca; Financial Interests, Institutional, Coordinating PI, CATCH-R: Roll-over study to provide continuous access to clinical therapy with rucaparib.: Clovis Oncology; Financial Interests, Institutional, Coordinating PI, Phase 3, multicenter, placebo-controlled clinical study comparing chemo-immunotherapy (paclitaxel-carboplatin-oregovomab) versus chemotherapy (paclitaxel-carboplatin-placebo) in patients with advanced epithelial ovarian, tubal cancer of fallopian or peritoneal (FLORA-5): Oncoquest Pharmaceuticals Inc.; Financial Interests, Institutional, Coordinating PI, Phase 2b randomized, open-label, active comparator, parallel-group, multicenter study designed to evaluate the efficacy and safety of three different doses of the P2X3 receptor antagonist (BAY 1817080) versus placebo and Elagolix 150 mg in women with symptomatic endometriosis: Bayer AG; Financial Interests, Institutional, Coordinating PI, Usability of ITE transducers for sending electric fields for tumor treatment (TTFields): Novocure Ltd; Financial Interests, Institutional, Coordinating PI, Phase III, multicentre, open-label extension trial to evaluate long-term safety and efficacy in patients with advanced cancers currently undergoing treatment or in follow-up in a pembrolizumab trial.: Merck. All other authors have declared no conflicts of interest.