GLP-1 receptor expression in a molecularly characterized cohort of endometrial carcinoma: Results from the GEICO 163-T/SPECTRUM study.

5625 Background: The glucagon-like peptide-1 receptor (GLP-1R) plays a central role in metabolic, and hormonal signaling and has gained increasing clinical relevance due to the widespread use of GLP-1R agonists. Given the strong link between obesity and endometrial carcinoma (EC), data on GLP-1R expression in EC are of clinical interest. We aimed to evaluate GLP-1R expression in a large, molecularly classified EC cohort and analyze its association with clinicopathological and molecular features. Methods: GLP-1R immunohistochemistry was performed on tissue microarrays from 192 ECs included in the SPECTRUM cohort. This cohort included 111 low grade endometrioid and 81 high grade ECs. 187 tumors were successfully classified according to WHO 2020 criteria, including 3% POLE-mutated (POLEmut), 25% mismatch repair–deficient (dMMR), 43% no specific molecular profile (NSMP), and 29% p53 abnormal (p53abn) carcinomas. Additionally, CTNNB1 mutation status was available in 168 tumors (16% mutated). GLP-1R expression was evaluated using the Allred scoring system (range 0–8). GLP-1R positivity was defined as Allred ≥6 according to previously published criteria (Kanda et al. 2018). Associations were evaluated using univariable analyses and multivariable logistic regression, reporting ORs with 95% confidence intervals; p<0.05 was considered statistically significant. Results: GLP-1R expression was evaluated in 172 EC. GLP-1R positivity was observed in 32.0% of the overall cohort and differed across molecular subtypes: 41.9% in NSMP, 40.0% in POLEmut, 28.9% in p53abn and 20.5% in dMMR tumors (p=0.099). Progesterone receptor (PR) levels were significantly higher in GLP-1R–positive compared with GLP-1R–negative tumors (median 55% vs 20%, p=0.015), whereas a non-significant trend toward higher estrogen receptor (ER) expression was observed (median 50% vs 25%, p=0.18). GLP-1R positivity was more frequent in CTNNB1 mutated tumors (50.0% vs 28.9%; p=0.041). In multivariable logistic regression including PR (continuous), CTNNB1 mutation status and molecular classification, only PR levels remained independently associated with GLP-1R positivity (OR per 10% increase 1.15, 95% CI 1.02–1.30; p = 0.019). Conclusions: GLP-1R is frequently expressed in EC, particularly in PR positive tumors and within the NSMP molecular subtype, suggesting that the underlying pathway of carcinogenesis may influence GLP-1R expression. These findings may inform the design of future translational and clinical studies exploring GLP-1R–targeted strategies in endometrial carcinoma.