New Clues to Mismatch Repair and PD-1/PD-L1 Status and Survival in Patients with Gastric or Esophageal Cancer

Charles Bankhead

June 2018, Vol 8, No 6 - Gastrointestinal Cancers


Understanding the complex relationship between the PD-1 receptor, its ligand 1 (PD-L1), and mismatch repair deficiency (dMMR) status may help to improve treatment outcomes in patients with resectable gastric and esophageal cancer, according to a retrospective tissue-based analysis.

Examination of tumor specimens from 174 patients showed that high expression of PD-L1 in tumor cells and tumor-infiltrating lymphocytes (TILs) correlated with dMMR, but expression of PD-1 did not. High expression of PD-1/PD-L1 or PD-1 in TILs was associated with improved survival, most notably in patients with MMR-proficient tumors, as reported at the 2018 Gastrointestinal Cancers Symposium.

“Esophageal and gastric cancers still have a poor prognosis,” said Maria C. Svensson, MD, and current PhD student, Division of Oncology and Pathology, Lund University, Sweden, in explaining the rationale and background of the study. “Neoadjuvant and adjuvant systemic therapy enhances survival, but there is still a great need for new treatment strategies and relevant biomarkers.”

“Immune checkpoint blockade has shown promise in the metastatic setting, and dMMR and expression of PD-L1 are candidate predictive biomarkers. We wanted to examine the prognostic value of dMMR and PD-L1 and PD-1 in tumor cells and tumor-infiltrating immune cells in chemoradiotherapy-naïve esophageal and gastric adenocarcinoma,” Dr Svensson said.

The retrospective cohort study involved patients with resected esophageal or gastric cancer. None of the patients had a history of neoadjuvant chemoradiotherapy, but 13 patients had received adjuvant chemotherapy. The investigators determined tumor MMR status and PD-1/PD-L1 expression by immuno­histochemistry, and they validat­ed data for PD-1/PD-L1 by com­paring with 354 gastric cancer specimens in The Cancer Genome Atlas (TCGA).

The results showed that PD-1 expression did not have a significant association with MMR status but PD-L1 expression did, in tumor cells and in TILs (P <.001 for both associations). Neither MMR status nor PD-L1 expression in tumor cells had a prognostic association with survival. In an unadjusted analysis, high PD-L1 expression (>10%; P = .023) and PD-1 (>50%; P = .004) in TILs was associated with significantly longer survival.

“The association of PD-L1 and prolonged survival remained significant after adjustment for other prognostic factors and mismatch repair status (hazard ratio 0.39, 95% confidence interval 0.15-0.99),” Dr Svensson said. “High PD-1 expression in tumor-infiltrating immune cells also was associated with improved survival, but not after adjusting for other prognostic factors and mismatch repair status.”

The validation comparison with specimens from TCGA yielded mixed results, as high PD-1 expression had a significant association with prolonged overall survival in patients with gastric adenocarcinoma (P = .012) but PD-L1 expression did not have a significant association with survival.