High AXL Expression and Stromal–Angiogenic Immune Phenotypes in Upper Gastrointestinal Cancers

AXL, a receptor tyrosine kinase, has been implicated in epithelial-mesenchymal transition, angiogenesis, immune evasion, and therapeutic resistance, but its relevance in upper gastrointestinal cancers remains incompletely defined. We analyzed 337 patients with advanced gastric (n = 287) or esophageal (n = 50) cancer enrolled in SCRUM-Japan MONSTAR-SCREEN-2, whose tumors were profiled by whole-exome and whole-transcriptome sequencing. Patients were classified as AXL-high (n = 169) or AXL-low (n = 168) using cancer type-specific median transcripts-per-million cutoffs. Median follow-up was 14.1 months. AXL-high tumors were associated with shorter overall survival than AXL-low tumors (median, 12.9 versus 17.1 months; hazard ratio, 1.58; 95% confidence interval, 1.17-2.14; p = 0.003), consistently in gastric (hazard ratio, 1.47; p = 0.020) and esophageal (hazard ratio, 2.46; p = 0.027) cancer. This association persisted after adjustment for cancer type, age, sex, number of metastatic sites, microsatellite instability status, and tumor mutational burden (hazard ratio, 1.59; 95% confidence interval, 1.14-2.22; p = 0.007). Among microsatellite stable patients treated with immune checkpoint blockade, AXL expression was not associated with progression-free survival (hazard ratio, 0.83; 95% confidence interval, 0.61-1.14; p = 0.255). AXL-high tumors showed stromal and vascular expansion, regulatory T-cell enrichment, higher expression of fibroblast growth factor receptor 1, vascular endothelial growth factor receptors 1-3, and MET, and enrichment of epithelial-mesenchymal transition, angiogenesis, and transforming growth factor beta signaling. High AXL expression identifies a poor-prognosis stromal-angiogenic phenotype in upper gastrointestinal cancers and warrants prospective validation as a prognostic, rather than predictive, biomarker. Trial Registration: UMIN Clinical Trials Registry, UMIN000043899.