Renin–angiotensin system inhibitor exposure and survival outcomes in gastroesophageal cancers: A meta-analysis of observational studies

Background Gastroesophageal cancers are associated with poor prognosis, necessitating effective adjunctive strategies. Renin–angiotensin system (RAS) inhibitors have demonstrated potential antineoplastic effects in preclinical models, but their clinical impact remains uncertain. Objectives To evaluate the association between RAS inhibitor exposure and survival outcomes in patients with gastroesophageal cancers. Design Meta-analysis of observational studies. Data Sources and Methods PubMed, Embase, and Web of Science were searched from inception to May 5, 2026. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using random-effects models. Prespecified subgroup and sensitivity analyses were performed to explore heterogeneity and robustness. Publication bias was assessed by funnel plots and Egger’s test, with trim-and-fill analysis used as an exploratory assessment of the potential impact of funnel-plot asymmetry. Results Twelve studies comprising 14 cohort-level estimates ( N = 15,062) were included. RAS inhibitor exposure was associated with improved overall survival (HR = 0.79, 95% CI: 0.71–0.88; I 2 = 40.8%). Consistent associations were observed for cancer-specific survival (HR = 0.83, 95% CI: 0.75–0.91; I 2 = 0%) and disease-free survival (HR = 0.67, 95% CI: 0.49–0.90; I 2 = 0%). Subgroup analyses showed directionally consistent associations in both gastric and esophageal cancers. Evidence of small-study effects was detected ( p = 0.003), and trim-and-fill analysis attenuated the pooled OS estimate to HR 0.84 (95% CI: 0.74–0.96). Conclusions RAS inhibitor exposure was associated with improved survival outcomes in gastroesophageal cancers. However, given the observational nature of the evidence, substantial heterogeneity in exposure definitions and treatment settings, and evidence of small-study effects, these findings should be interpreted as hypothesis-generating. They do not support routine clinical use of RAS inhibitors for anticancer purposes outside established indications. Prospective studies are warranted to determine whether these associations reflect causal effects and to identify clinical contexts in which RAS inhibition may be beneficial.