Five-gene signature for the prediction of response to immune checkpoint inhibitors in patients with gastric and urothelial carcinomas

Abstract

Background: Ample evidence supports the potential of programmed death-ligand 1 (PD-L1) expression, detected by immunohistochemistry, as a predictive biomarker for immunotherapy in patients with advanced cancers. To predict the response to immune checkpoint inhibitors in patients with gastric and urothelial carcinomas, we aimed to replace PD-L1 combined positive score (CPS) with CD274 mRNA in the original four-gene signature and PD-L1 CPS model developed by us.

Method: We used quantitative real-time polymerase chain reaction (qRT-PCR) to measure the expression levels of five target genes in a cohort of 49 patients (33 with gastric cancer and 16 with urothelial carcinoma) who had received immunotherapy and whose therapeutic responses were available. The predictive performance was evaluated using R package maxstat.

Results: Cutoff values of mRNA expression level were measured using the log-rank statistics for progression-free survival (PFS). Based on these cutoffs, immunotherapy responses were predicted and sorted into responder (n = 12, 24.5%) and non-responder (n = 37, 75.5%) groups. The median PFS values of predicted responders and non-responders were 14.8 months (95% confidence interval [CI]: 0-34.7) and 4.7 months (95% CI: 1.0-8.4, p = 0.02), respectively. Among the 12 predicted responders, 10 had microsatellite-stable tumors with a low tumor mutational burden. The actual clinical responses (complete and partial) were higher in the responder group than those in the non-responder group: 83.3% and 16.2%, respectively.

Conclusion: We modified a predictive biomarker for CD274 mRNA expression to predict the response to immunotherapy in patients with gastric or urothelial carcinomas.

Keywords: Biomarker; CD274; Gastric; Immune checkpoint inhibitors; Prediction; Urothelial.