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Introduction: The relationship of CYP2A6 polymorphisms with S-1 therapy outcomes in gastric cancer is unclear. This review aimed to assess the association between CYP2A6 gene polymorphisms (CYP2A6*4, *7, *9, *10) and S-1 therapy outcomes in gastric cancer, aiming to identify predictive markers for S-1 efficacy and adverse reactions. Methods: We searched seven databases, using random or fixed-effect models to calculate hazard ratio (HR) and 95% confidence interval (CI) based on study heterogeneity. Results: A total of 1,143 articles were retrieved from multiple online databases as of March 28, 2023. After screening, seven articles containing seven investigations were included in the meta-analysis. Our results revealed a significant association between the CYP2A6 polymorphism site and the overall survival (OS) of variant/variant group (V/V) patients compared to wild-type/wild-type (W/W) or wild-type/variant (W/V) patients (HR = 2.73, 95% CI: 1.45–5.14, p = 0.002). S-1 was more beneficial for W/W or W/V patients than V/V patients in terms of progression-free survival (PFS) (HR = 3.15, 95% CI: 1.47–6.75, p = 0.003). There was no association between CYP2A6 polymorphism and hematological adverse reactions (OR = 0.52, 95% CI: 0.23–1.15, p = 0.104). Conclusion: CYP2A6 polymorphisms correlate with S-1 efficacy (OS and PFS) in gastric cancer, suggesting their potential as predictive markers. However, the generalizability of findings is limited by the small number of studies from Eastern countries and variations in chemotherapy regimens and detection methods. Further, large-scale studies are needed to confirm these associations.

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