Systematic review and meta-analysis of the prognostic role of fibroblast-activation protein in gastrointestinal cancers

Background: Gastrointestinal (GI) cancers, particularly pancreatic cancer, are characterized by a dense stromal tumor microenvironment where cancer-associated fibroblasts (CAFs) predominate. CAFs comprise highly heterogeneous subpopulations with different functions, which can be both tumor-promoting and tumor-restraining. This systematic review and meta-analysis aims to comprehensively assess the impact of the CAF marker fibroblast-activation protein (FAP) expression on clinical outcomes in GI cancers. Methods: Adhering to PRISMA guidelines, we systematically searched PubMed/MEDLINE, Web of Science, Cochrane Library, and ClinicalTrials.gov for relevant articles. Inclusion criteria involved studies comparing GI cancer patients with and without FAP overexpression. Meta-analysis evaluated overall survival (OS), histological differentiation, local tumor invasion, lymph node metastases, and distant metastases. For each observational study, the risk of bias was assessed using the risk of bias in non-randomized studies of Results: The meta-analysis included 31 cohort studies from six countries, comprising 3,976 patients. Patients without FAP overexpression exhibited a favorable OS [hazard ratio (HR) =1.74; 95% confidence interval (CI): 1.51-2.01]. Subgroup analyses revealed consistent results across esophageal, pancreatic, colorectal, and gastric cancers. While one-year survival rates showed no significant difference, subsequent years displayed lower rates for FAP-overexpressing groups. Lymph node metastases were more frequent in FAP-overexpressing patients, whereas distant metastases did not differ. None of 31 studies systematically controlled confounding and adjusted data so that all studies were categorized as "high risk of bias" for the domain "risk of bias due to confounding". For domains "risk of bias arising from measurement of exposure", "risk of bias due to post-exposure interventions", "risk of bias arising from measurement of outcomes", and "risk of bias in selection of the reported result", all studies were categorized as "low risk of bias". Conclusions: This meta-analysis underscores the potential adverse prognostic significance of FAP expression in GI cancers. Limitations include heterogeneity in FAP expression cutoffs and definitions. Future research should focus on delineating the precise roles and clinical implications of FAP in GI cancers.