Microsatellite Instability and Programmed Cell Death-Ligand 1 Expression in Stage II/III Gastric Cancer: Post Hoc Analysis of the CLASSIC Randomized Controlled study

Ann Surg. 2019 Aug;270(2):309-316. doi: 10.1097/SLA.0000000000002803.


Objective: 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.

Background: The clinical implications of MSI status and PD-L1 expression in gastric cancer have not been well-elucidated.

Methods: 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.

Results: 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); P = 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%; P = 0.002); no benefit was observed in the MSI-H group (5-year DFS: 83.9% vs 85.7%; P = 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%; P = 0.001).

Conclusion: 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use
  • Apoptosis
  • B7-H1 Antigen / biosynthesis
  • B7-H1 Antigen / genetics*
  • Biomarkers, Tumor / biosynthesis
  • Biomarkers, Tumor / genetics
  • Chemotherapy, Adjuvant
  • DNA, Neoplasm / genetics*
  • Follow-Up Studies
  • Gastrectomy
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunohistochemistry
  • Microsatellite Instability
  • Neoplasm Grading*
  • Prognosis
  • Retrospective Studies
  • Stomach Neoplasms / diagnosis
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / therapy


  • Antineoplastic Agents
  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • DNA, Neoplasm