High AXL Expression and Stromal–Angiogenic Immune Phenotypes in Upper Gastrointestinal Cancers
Year: 2026
Type: article
Abstract: 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.
Source: Cancer Science
DOI: 10.1111/cas.70594
Authors: Kyosuke Seguchi, Tadayoshi Hashimoto, Takao Fujisawa, Akitaka Makiyama, Toshihiro Kudo, Kentaro Yamazaki, Koushiro Ohtsubo, Taroh Satoh, Chigusa Morizane, Shogen Boku, Eiji Oki, Naoki Takahashi, Fumio Nagashima, Shigenori Kadowaki, Takeshi Kato, Yoshito Komatsu, Yohei Kubota, Akihito Tsuji, Yukiko Fukuda, Naoko Iida, Taro Shibuki, Hideaki Bando, Karam Ashouri, Sandra Algaze, Heinz‐Josef Lenz, Takayuki Yoshino
Institutions: National Cancer Centre Japan, National Cancer Center Hospital East, Gifu University Hospital, Osaka International Cancer Institute, Shizuoka Cancer Center, Kanazawa University Hospital, Osaka University Hospital, The University of Osaka, National Cancer Center Hospital, Kansai Medical University, Kansai Medical University Hospital, Kyushu University Hospital, Saitama Cancer Center, Kyorin University, Aichi Cancer Center, Aichi Cancer Center Hospital, Osaka National Hospital, Hokkaido University Hospital, St. Marianna University School of Medicine, Kagawa University, Kagawa University Hospital, Tokyo University of Science, University of Southern California, USC Norris Comprehensive Cancer Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,600
OpenAlex ID: W7225788751