Microsatellite Instability and Programmed Cell Death-Ligand 1 Expression in Stage II/III Gastric Cancer

<jats:sec> <jats:title>Objective:</jats:title> <jats:p>We investigated microsatellite instability (MSI) status and programed cell death ligand 1 (PD-L1) expression as predictors of prognosis and responsiveness to chemotherapy for stage II/III gastric cancer.</jats:p> </jats:sec> <jats:sec> <jats:title>Background:</jats:title> <jats:p>The clinical implications of MSI status and PD-L1 expression in gastric cancer have not been well-elucidated.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>Tumor specimens and clinical information were collected from patients enrolled in the CLASSIC trial—a randomized controlled study of capecitabine plus oxaliplatin-based adjuvant chemotherapy. Five quasi-monomorphic mononucleotide markers were used to assess tumor MSI status. PD-L1 expressions of tumor and stromal immune cells were evaluated using immunohistochemistry.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>Of 592 patients, 40 (6.8%) had MSI-high (MSI-H) tumors. Among 582 patients available for immunohistochemistry evaluation, PD-L1 was positive in tumor cells (tPD-L1) of 16 patients (2.7%) and stromal immune cells (sPD-L1) of 165 patients (28.4%). Multivariable analysis of disease-free survival (DFS) showed that MSI-H and sPD-L1-positivity were independent prognostic factors [hazard ratio 0.301 (0.123–0.736), 0.714 (0.514–0.991); <jats:italic toggle="yes">P</jats:italic> = 0.008, 0.044), as were receiving chemotherapy, age, tumor grade, and TNM stage. Although adjuvant chemotherapy improved DFS in the microsatellite-stable (MSS) group (5-year DFS: 66.8% vs 54.1%; <jats:italic toggle="yes">P</jats:italic> = 0.002); no benefit was observed in the MSI-H group (5-year DFS: 83.9% vs 85.7%; <jats:italic toggle="yes">P</jats:italic> = 0.931). In the MSS group, sPD-L1-negative patients, but not sPD-L1-positive patients, had significant survival benefit from adjuvant chemotherapy compared with surgery only (5-year DFS: 66.1% vs 50.7%; <jats:italic toggle="yes">P</jats:italic> = 0.001).</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>MSI status and PD-L1 expression are clinically actionable biomarkers for stratifying patients and predicting benefit from adjuvant chemotherapy after D2 gastrectomy for stage II/III gastric cancer.</jats:p> </jats:sec>