Prognostic impact of AXL expression in upper gastrointestinal cancer in MONSTAR-SCREEN-2: An international collaborative study between United States and Japan.

4032 Background: AXL, a receptor tyrosine kinase of the TAM family, promotes epithelial-mesenchymal transition (EMT) and tumor progression. Elevated AXL expression is reported as poor prognostic factor with immunosuppressive features in colorectal cancer (Karam Ashouri, et al. J Immunother Cancer. 2025). We investigated the prognostic impact of AXL expression and its associated molecular and tumor microenvironment (TME) features in upper gastrointestinal (GI) cancers. Methods: Treatment-naïve patients with gastric cancer (GC) and esophageal cancer (EC) enrolled in MONSTAR-SCREEN-2 with available RNA-seq data (Caris MI TumorSeek) were analyzed. AXL expression was dichotomized by median into high and low groups within each cancer type. Molecular alteration, including somatic mutations and copy number alterations, and expression of receptor tyrosine kinases, including FGFRs, VEGFRs, and EGFR were compared between groups. Overall survival (OS) was evaluated using Kaplan-Meier analysis and Cox proportional hazards models. Tumor microenvironment (TME) cell infiltration, assessed using xCell deconvolution and gene set enrichment analysis (GSEA) performed using Hallmark gene sets, was compared between AXL-high and AXL-low groups. Results: A total of 320 patients were analyzed (GC: n = 270; EC: n = 50). In GC, AXL-high patients were older than AXL-low patients (median 71 vs 66 years, p = 0.012), while no other baseline characteristics, including sex, histology, primary site, metastatic sites, microsatellite instability-high, and tumor mutation burden-high status, differed between groups. ARID1A mutations were enriched in AXL-high GC (p < 0.05), while CCNE1 amplification was associated with AXL-low (p < 0.05). Across both cancer types, AXL-high tumors exhibited significantly higher expression of FGFR1, VEGFR1-3, and MET (p < 0.01). In GC, AXL-high was associated with significantly shorter OS compared to AXL-low (median 12.9 vs 16.6 months; HR 1.44, 95%CI 1.03-2.02; p = 0.034). Similarly in EC, AXL-high showed worse OS compared to AXL-low (median 10.4 vs not reached; HR 2.46, 95%CI 1.08-5.62; p = 0.027). TME analysis revealed increased stromal scores, endothelial cells, M1/M2 macrophages, and regulatory T cells, along with higher expression of immune checkpoint molecules, including PD-L2 and CTLA4, in AXL-high tumors. GSEA showed enrichment of EMT, IFN-γ response, and PI3K/AKT/mTOR pathways in AXL-high GC. Conclusions: AXL overexpression is a prognostic biomarker in upper GI cancers, and is associated with worse survival and a distinct molecular and immune landscape characterized by EMT activation and immune-suppressive TME. These findings support AXL as a potential therapeutic target and warrant further investigation of AXL-targeted therapy in upper GI cancers.