PD-L1 testing in advanced gastric cancer—what physicians who treat this disease must know—a literature review

Abstract

Background and Objective Immune checkpoint inhibition has shed light on a new era in cancer therapy, and randomized clinical trials have demonstrated that a meaningful portion of the overall population of metastatic gastric cancer (GC) patients may derive clinical benefit from immunotherapy, which raises the relevance in identifying predictive biomarkers. Programmed cell death-ligand 1 (PD-L1) expression has demonstrated a significant association between level of expression and the magnitude of benefit derived from immune checkpoint inhibition in GC. Nevertheless, this biomarker shows several pitfalls that must be considered in the therapeutic decision to incorporate immune checkpoint inhibition as the standard of care of GC, such as spatial and temporal heterogeneity, interobserver variability, immunohistochemistry (IHC) assay, and influence by chemotherapy or radiation therapy. Methods In the present comprehensive review, we revised the main studies regarding PD-L1 evaluation in GC. Key Content and Findings Here we describe the molecular characteristics of the tumor microenvironment in GC, the obstacles in the interpretation of PD-L1 expression and present the data of the clinical trials that have evaluated the efficacy and safety of immune checkpoint inhibition and the association with the biomarker expression, both in first-line and later lines of therapy. Conclusions From the emerging predictive biomarkers for immune checkpoint inhibition, PD-L1 has demonstrated a meaningful association between level of expression in tumor microenvironment and the magnitude of benefit derived from immune checkpoint inhibition in GC.

Immunotherapy of gastric cancer: Present status and future perspectives

“…Existing data support that PD-L1 exhibits a significant correlation between its expression level and the benefit expected from ICI application in GC. However, its application is not without drawbacks, such as interobserver variability, the immunohistochemical assay used, and the effect of chemotherapy and radiation[ 49 ]. Currently, there are six Food and Drug Administration-approved immunotherapy options for GC (Table 1 ).…”

A Clinical Viewpoint on the Use of Targeted Therapy in Advanced Gastric Cancer

“…The molecular characterization of GC necessitates the inclusion of MSI and MMR testing, which delivers vital details for prognosis, treatment selection, and genetic counseling. Microsatellites, which are sequences of DNA, have a length that ranges from one to six repetitions of nucleotides [68]. Both coding and non-coding regions of the genome contain these DNA motifs, which exhibit high levels of polymorphism among populations but remain stable within individuals [68].…”

“…Microsatellites, which are sequences of DNA, have a length that ranges from one to six repetitions of nucleotides [68]. Both coding and non-coding regions of the genome contain these DNA motifs, which exhibit high levels of polymorphism among populations but remain stable within individuals [68]. The MMR system comprises various proteins, specifically the products of hMLH1, hMSH2, hMSH6, and hPMS2 genes, which supervise the accuracy of DNA replication.…”

Molecular Classifications in Gastric Cancer: A Call for Interdisciplinary Collaboration

“…Additionally, the approval of pembrolizumab for solid tumors with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) included GC cases [ 26 , 27 ]. The indication for immunotherapy also depends on PD-L1 expression or the tumor mutational burden (TMB) [ 28 ]. Therefore, the only established and broadly available biomarkers for GC treatment are HER2 amplification, MSI-H, and PD-L1 expression [ 29 ].…”