INTEGRATING Β-CATENIN AND AKT INTO THE SURROGATE MOLECULAR CLASSIFICATION OF ENDOMETRIAL CARCINOMA: AN IMMUNOHISTOCHEMICAL APPROACH FOR PROGNOSTIC RE-STRATIFICATION

Background: The molecular classification of endometrial cancer (EC) has revolutionized risk stratification; however, the impact of novel biomarkers across subgroups remains to be fully elucidated. This study evaluates the clinical and molecular implications of activation of the PI3K/AKT and Wnt/β-catenin pathways. Methods: We analyzed p-AKT and nuclear β-catenin expression via immunohistochemistry (IHC) in 60 EC cases. Findings were correlated with surrogate molecular subgroups (MMRd, NSMP, p53abn), clinicopathological features, and oncological outcomes. Cases were categorized by protein expression into three groups: double-positive (both proteins), single-positive, and double-negative.Results: β-catenin expression was observed in 33 (55%) cases, p-AKT overexpression in 46 (76.6%) cases and a dual overexpression in 26 patients (43.3%). β-catenin expression and the double-positive profile were almost exclusively associated with endometrioid histology (97%, p<0.001 and p=0.011, respectively). These proteins and their co-occurrence were equally distributed across molecular classes (p=0.4). p-AKT hyperexpression was significantly associated with a shorter median Disease-Free Survival (DFS) (36 vs. 40 months, p=0.013) and a trend toward deeper myometrial invasion (p=0.080). Conclusions: Proteomic activation of AKT and β-catenin may be helpful to identifies tumors with a more rapid recurrence independently of standard molecular subclasses. Combined IHC profiling could offer a functional and cost-effective supplement to genomic classification, potentially refining post-operative surveillance strategies. Further studies with larger cohorts and longer follow-up are warranted.