Programmed Death-Ligand 1 (PD-L1) Positivity and Factors Associated with Poor Prognosis in Patients with Gastric Cancer: An Umbrella Meta-Analysis

Abstract

Gastric cancer (GC) is one of the most common malignancies throughout the world with late diagnosis and poor prognosis. The expression of programmed death-ligand 1 (PD-L1) in GC is attributed to immune evasion and tumor progression. PD-L1 positivity has both predictive and prognostic biomarker potential. Aiming to summarize a large amount of research and to provide a definitive conclusion to the conflicting results on the prognostic significance of PD-L1 expression in GC, we performed an umbrella review based on existing meta-analyses which were published recently (2016-2021) and indexed in the PubMed database. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was used in August 2021 to screen articles, and data extraction with quality assessment was performed on the selected meta-analyses. Review Manager (RevMan) 5.3 software was used to analyze the HR and OR with a 95% confidence interval (CI) among PD-L1 positive GC patients. We also assessed the between-study heterogeneity (I ²). Forest and Funnel plots were obtained, and a P-value of <0.05 was considered statistically significant. A total of 567 articles were screened, and we selected three meta-analyses with a total of 40 studies conducted over a period of 14 years. In our umbrella review, a total of 8,419 GC patients with an average PD-L1 positivity of 39% were analyzed. We found that PD-L1 positivity in GC patients is associated with poor prognosis (pooled HR =1.44, 95% CI: 1.24-1.68, P<0.00001) having higher mortality reducing the chances of overall survival (OS). However, there are no significant differences in PD-L1 expression among different lymph node (LN) metastases (OR=1.31, 95% CI: 0.98-1.74, P=0.07) and tumor, node, and metastasis (TNM) stages (OR=1.13, 95% CI: 0.80-1.58, P=0.50). Early identification of PD-L1 expression may help tailor cost-effective and targeted immunotherapy among GC patients. More research is needed to further understand how PD-L1 affects LN metastasis and tumor invasion.

Keywords: clinicopathological; gastric cancer; hazard ratio; lymph node metastasis; meta-analysis; overall survival (os); pd-l1; poor prognosis; tumor stage; umbrella review.

Figure 1. PRISMA 2020 flow chart of study selection

PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Figure credit: Urvish K. Patel and Nidhi Jain.

Figure 2. Forest plot describing PD-L1 expression and mortality among patients with GC

CI, confidence interval; GC, gastric cancer; PD-L1, programmed death-ligand 1. Figure credit: Urvish K. Patel.

Figure 3. Forest plot for the association between PD-L1 expression and LN metastasis

CI, confidence interval; LN, lymph node; PD-L1, programmed death-ligand 1. Figure credit: Urvish K. Patel.

Figure 4. Forest plots for the association between PD-L1 expression and the TNM stage

CI, confidence interval; PD-L1, programmed death-ligand 1; TNM, tumor, node, and metastasis. Figure credit: Urvish K. Patel.

Figure 5. Sensitivity analysis of LN Metastasis and PD-L1 expression for heterogeneity.

CI, confidence interval; LN, lymph node; PD-L1, programmed death-ligand 1. Figure credit: Urvish K. Patel.

Figure 6. Funnel plot after sensitivity analysis using leave one out in the case of LN metastasis and the presence of PD-L1 in GC patients

OR, odds ratio; LN, lymph node; PD-L1, programmed death-ligand 1. Figure credit: Urvish K. Patel.

Figure 7. Funnel plot of PD-L1 presence and OS in GC patients

OR, odds ratio; PD-L1, programmed death-ligand 1; GC, gastric cancer. Figure credit: Urvish K. Patel.

Figure 8. Funnel plot for LN metastasis and the presence of PD-L1 in GC patients

OR, odds ratio; LN, lymph node; PD-L1, programmed death-ligand 1; GC, gastric cancer. Figure credit: Urvish K. Patel.

Figure 9. Funnel plot for TNM staging and PD-L1 in GC patients

OR, odds ratio; TNM, tumor, node, and metastasis; PD-L1, programmed death-ligand 1; GC, gastric cancer. Figure credit: Urvish K. Patel.