Microsatellite instability combined with PD-L1 expression in prognosis of gastric cancer: an integrated analysis based on individual patient data.

Abstract

Objective This study aimed to systematically assess the predictive value of microsatellite instability (MSI) combined with programmed death-ligand 1 (PD-L1) expression for prognosis and immunotherapy response in patients with gastric cancer (GC). Methods An individual patient data (IPD) meta-analysis was performed in accordance with the PICOS framework and PRISMA 2020 guidelines. A comprehensive literature search was performed across English and Chinese databases to identify cohort studies or randomized controlled trials (RCTs) that simultaneously evaluated MSI status and PD-L1 expression, and reported overall survival (OS), disease-free survival (DFS) with 95% confidence intervals (CIs) were used as pooled effect measures. Fixed-effect or random-effects models were applied based on heterogeneity assessed by the I² statistic. Subgroup analyses were stratified by ethnicity, pathological stage, Lauren classification, chemotherapy timing, MSI detection platform, and PD-L1 antibody clone. The interactive effect of MSI-H and PD-L1 expression was evaluated using radar plots. Results Nine studies involving 6,667 GC patients were included. For OS, MSI-H alone (HR = 0.500, 95%CI: 0.357-0.700, P < 0.001), and MSI-H/MSI-L combined (HR = 0.641, 95%CI: 0.437-0.939, P = 0.025) were associated with better outcomes than MSS; PD-L1 positivity predicted poorer OS (HR = 1.517, 95%CI: 1.077-2.137, P = 0.017); MSI-H+PD-L1 negative patients had the most favorable OS (HR = 0.380, 95%CI: 0.255-0.566, P < 0.001), while MSI-H+PD-L1 positive patients had poorer OS than MSS+PD-L1 negative patients (HR = 2.076, 95%CI: 1.238-3.479, P = 0.006). For DFS, MSI-H alone (HR = 0.506, 95%CI: 0.360-0.710, P < 0.001) and MSI-H/MSI-L combined (HR = 0.530, 95%CI: 0.402-0.698, P < 0.001) outperformed MSS, but PD-L1 expression showed no significant DFS association (HR = 1.189, 95%CI: 0.472-2.998, P = 0.709). Subgroup analyses identified TNM stage, Lauren classification, chemotherapy timing, and MSI detection method as significant effect modifiers (all interaction P < 0.05). Pooled immunotherapy data showed that MSI-H patients had higher ORR than MSS (OR = 3.580, P < 0.001), and MSI-H+PD-L1 positive patients achieved the highest response rates (OR = 4.100 vs. MSI-H+PD-L1 negative, P < 0.001). Sensitivity analysis confirmed result stability, and publication bias was minimal. Conclusion MSI-H status is a robust favorable prognostic factor for GC, while PD-L1 positivity indicates adverse OS prognosis. The combination of MSI and PD-L1 expression enables refined prognostic stratification of GC patients.