Positive Status of Epstein-Barr Virus as a Biomarker for Gastric Cancer Immunotherapy: A Prospective Observational Study

Abstract

Immunotherapy has exhibited promising but controversial results in gastric cancer; determining criteria for choosing the appropriate target population is still problematic. Epstein-Barr virus (EBV)associated gastric carcinoma (EBVaGC) exhibits distinctive genomic aberrations and clinicopathologic features, the positive status of EBV is a potential biomarker. We prospectively recruited 9 patients who were diagnosed with stage-IV EBVaGC, and all of the patients were treated by immune-checkpoint inhibitors. The median age of the patients was 62 years old. The clinicopathologic characteristics demonstrated a male predominance and poor differentiation status of EBVaGC. Lymph nodes were demonstrated to represent the most common metastatic site. Immunochemistry and polymerase chain reaction analysis revealed that all of the patients were proficient mismatch repair, and microsatellite instability-stable and programmed cell death-ligand 1 were detected in 7 patients. Three patients with positive programmed cell death-ligand 1 showed partial response, 5 patients showed stable disease, 1 patient without measurable lesion showed decreasing ascites and tumor marker level after immunotherapy. The longest duration of response was 18 months by the time of the last follow-up. EBVaGC exhibits distinctive clinicopathologic characteristics, and EBV-positive status may be a potential biomarker for gastric cancer immunotherapy.

The clinicopathological significance and predictive value for immunotherapy of programmed death ligand-1 expression in Epstein-Barr virus-associated gastric cancer

“…To date, all clinical reports on immunotherapy in EBVaGC are of small sample numbers, none of which exceeded 10 EBVaGC patients, and the efficacy has been debatable, with ORRs ranging from 25% to 100%. 5,15,16,[24][25][26][27][28][29] Collectively, an ORR of 48.7% was concluded combining available clinical reports, as shown in our study. However, this result was evidently biased, as 30 out of 39 (76.9%) patients were PD-L1 positive, which was far beyond the rates of approximately 50% in unselected EBVaGC population by our immunohistochemistry staining result and literature reports.…”

Clinicopathological and Immunomicroenvironment Characteristics of Epstein–Barr Virus-Associated Gastric Cancer in a Chinese Population

“…The clinical benefit of EBVaGC patients after anti-PD-L1 antibody treatment can be maintained for a longer period of time. In patients with EBV-positive tumors, dramatic responses to pembrolizumab were observed (objective response rate of 100% in EBVaGC), which might be related to EBVaGC-rich immune cell infiltration and increased expression of immune checkpoint pathway genes (3)(4)(5). Therefore, EBV-positive status may be a potential biomarker for GC immunotherapy.…”

The Clinicopathological Features and Genetic Alterations in Epstein–Barr Virus-Associated Gastric Cancer Patients after Curative Surgery

“…However, EBV was found not only in the rare gastric lymphoepithelial carcinoma but also in gastric adenocarcinomas [12,13], including intestinal-type GC and diffuse-type GC [14], which was confirmed by polymerase chain reaction (PCR) and ISH in a variety of studies [15][16][17]. EBV-positive status can serve as a biomarker for immunotherapy in GC patients [18], which might be due to a higher level of PD-L1 [19] and more tumor infiltrating lymphocytes in EBV-associated GC [20]. Previous studies demonstrated that EBV-associated GC was more common in diffuse-type than in intestinal-type GC (9.9 vs. 6.5%) [21].…”

“…Hot tumors are characterized by the accumulation of proinflammatory cytokines and T cell infiltration and have a better response rate to ICB treatment. Indeed, EBV associated lymphoepithelial carcinoma is a typical hot tumor ( Figure 1 D), which can partially explain why EBV associated GC might be a good candidate for ICB [ 18 ].…”