Case Report: Epstein-Barr virus Positive Gastric Carcinoma

In 2014, The Cancer Genome Atlas provided a molecular classification defining Epstein-Barr virus (EBV)-positive gastric cancer as a separate subtype. While its prognostic role is still debatable, emerging potential biomarker role for personalized treatment strategies is already recognized by international guidelines. We report a case with successful combined therapy of a 64-year-old EBV-positive gastric cancer male patient. Patient initially presented with locally advanced gastric cancer, which was treated surgically; three years later patient developed recurrence within the remnant stomach and was treated surgically. Two years after operation patient developed distant metastases and was enrolled in a clinical trials’ (NCT01630083) arm 2: receiving chemotherapy and monoclonal antibody claudiximab. This treatment induced durable disease stabilisation for 34 months. After progression, second line chemotherapy with docetaxel and cisplatin provided additional disease stabilisation and symptom control for 8 months. Patient’s overall survival reached 9.1 years. Presented report shows EBV- ositive gastric cancer case with better overall survival compared to reported average, which contributes to the meaningfulness of its distinction as a separate subtype, evidence that targeted therapy is more effective in selected patient groups, and EBV as an emerging biomarker.

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A pilot study of avelumab in Epstein-Barr virus-associated gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.tps473 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. TPS473-TPS473

Author(s):

Ronan Andrew Mc Laughlin ◽

John Aird ◽

Orla McCormack ◽

C. DeGascun ◽

R. Hussein ◽

...

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

Pilot Study ◽

Epstein Barr Virus ◽

Single Agent ◽

The Cancer Genome Atlas ◽

Eligibility Criteria ◽

Barr Virus ◽

Stage 4 ◽

Epstein Barr

TPS473 Background: Gastric Cancer (GC) is the third most common cause of cancer related deaths worldwide. The median overall survival of patients with stage 4 disease is approximately 1 year. Current accepted treatment approach with chemotherapy is applied with little consideration for known genetic or biologic heterogeneity. Whilst immune-based approaches in GC look promising it is clear that single-agent PD1/PDL1 inhibition benefit a minority. We must clarify a means of identifying prospectively those patients who may benefit from this treatment. A recent landmark paper by The Cancer Genome Atlas (TCGA) proposed a classification of GC into four subtypes: Epstein-Barr-virus (EBV)-positive, microsatellite instable (MSI), chromosomal instable (CI), and genomically stable (GS). Two of the four – EBV and MSI subtypes – are likely to be immunogenic and amenable to PD1/PDL1 inhibition. Recent advances have shown EBV-positive tumors to be infiltrated by lymphocytes and be enriched for PDL1. Methods: This single centre single-arm pilot study in gastric or junctional adenocarcinoma will explore the hypothesis that administering anti-PDL1 therapy (Avelumab) in a prospectively identified population enriched for potential responders will result in improved outcomes. The anticipated frequency of EBV associated-GC (c10%) means that approximately N = 100 patients will be screened to identify N = 10 participants. If a positive signal for efficacy is seen this will provide a basis for a larger, multicentre study. Previously treated Patients with confirmation of stage 4 EBV- positive gastric or oesophago-gastric adenocarcinoma meeting eligibility criteria will be enrolled. Avelumab will be administered at a dose of 10mg/kg IV every 14days. Primary endpoint is to determine the 6-month progression free survival (PFS) of Avelumab in EBV-associated GC. Secondary endpoints include overall response rate, overall survival, median PFS time and feasibility/accrual rate at 12 months. Exploratory endpoints will be to evaluate changes in immune parameters in the peripheral blood over time. Kaplan-Meier methods for primary efficacy endpoint with two-tailed one-sample proportion test will be used to evaluate the evidence to reject the null hypothesis. Clinical trial information: 2018-002085-39.

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Intratumoral CXCR5+CD8+T associates with favorable clinical outcomes and immunogenic contexture in gastric cancer

Nature Communications ◽

10.1038/s41467-021-23356-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jieti Wang ◽

Ruochen Li ◽

Yifan Cao ◽

Yun Gu ◽

Hanji Fang ◽

...

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

T Cells ◽

Epstein Barr Virus ◽

Effector Memory ◽

Feature Identification ◽

Barr Virus ◽

T Cell Infiltration ◽

Epstein Barr ◽

Gastric Cancer Patients

AbstractStudies that examined an association between CD8+T and prognosis in gastric cancer are inconsistent, and a distinct population of CXCR5+CD8+T associated with better overall survival has been reported among various malignancies. Here, we show that the abundance of intratumoral CXCR5+CD8+T cells is associated with better overall survival in patients with gastric cancer. Patients with TNM II + III gastric cancer with higher intratumoral CXCR5+CD8+T cell infiltration are more likely to benefit from adjuvant chemotherapy. Microsatellite-unstable and Epstein–Barr virus positive tumors are enriched with CXCR5+CD8+T cells. Gastric cancer infiltrating CXCR5+CD8+T cells represent a specific subtype of stem-like CD8+T with effector memory feature. Identification of the clinical significance and phenotype of gastric cancer infiltrating CXCR5+CD8+T provides a roadmap for patient stratification and trials of targeted therapies.

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Epstein-Barr Virus miR-BART17-5p Promotes Migration and Anchorage-Independent Growth by Targeting Kruppel-Like Factor 2 in Gastric Cancer

Microorganisms ◽

10.3390/microorganisms8020258 ◽

2020 ◽

Vol 8 (2) ◽

pp. 258 ◽

Cited By ~ 4

Author(s):

Jae Hee Yoon ◽

Kyoungmi Min ◽

Suk Kyeong Lee

Keyword(s):

Gastric Cancer ◽

Gastric Carcinoma ◽

Epstein Barr Virus ◽

The Cancer Genome Atlas ◽

Sequencing Data ◽

Ags Cells ◽

Anchorage Independent Growth ◽

Barr Virus ◽

Epstein Barr ◽

Bart Mirnas

Epstein-Barr virus (EBV) infects more than 90% of the global population and is associated with a variety of tumors including nasopharyngeal carcinoma, Hodgkin lymphoma, natural killer/T lymphoma, and gastric carcinoma. In EBV-associated gastric cancer (EBVaGC), highly expressed EBV BamHI A rightward transcripts (BART) miRNAs may contribute to tumorigenesis with limited viral antigens. Despite previous studies on the targets of BART miRNAs, the functions of all 44 BART miRNAs have not been fully clarified. Here, we used RNA sequencing data from the Cancer Genome Atlas to find genes with decreased expression in EBVaGC. Furthermore, we used AGS cells infected with EBV to determine whether expression was reduced by BART miRNA. We showed that the expression of Kruppel-like factor 2 (KLF2) is lower in AGS-EBV cells than in the AGS control. Using bioinformatics analysis, four BART miRNAs were selected to check whether they suppress KLF2 expression. We found that only miR-BART17-5p directly down-regulated KLF2 and promoted gastric carcinoma cell migration and anchorage-independent growth. Our data suggest that KLF2 functions as a tumor suppressor in EBVaGC and that miR-BART17-5p may be a valuable target for effective EBVaGC treatment.

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Clinicopathological features of Epstein–Barr virus associated gastric carcinoma with submucosal invasion.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4029 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4029-4029

Author(s):

Hiroki Osumi ◽

Hiroshi Kawachi ◽

Toshiyuki Yoshio ◽

Satoshi Ida ◽

Yusuke Horiuchi ◽

...

Keyword(s):

Gastric Cancer ◽

Lymph Node ◽

Epstein Barr Virus ◽

Lymphovascular Invasion ◽

Submucosal Invasion ◽

The Cancer Genome Atlas ◽

Research Network ◽

Barr Virus ◽

Regional Lymph Node Dissection ◽

Epstein Barr

4029 Background: The incidence of lymph node metastasis (LNM) in pathological T1b (pT1b) gastric cancer (GC) is around 20% and the majority of them have no LNM. The Cancer Genome Atlas Research Network proposed the concept of molecular phenotype classifying GC into 4 phenotypes including Epstein-Barr virus-CIMP (EBV). EBV positive gastric cancer (EBVGC) is associated with a low prevalence of LNM; however, EBV status is not considered in the present indication of endoscopic resection (ER). We aimed to clarify the implication of EBV status for ER of pT1b GC. Methods: Consecutive cases of pT1b GCs treated with curative surgery between 2005 and 2014 were retrospectively analyzed. Tissue microarray was made and EBV-encoded RNA in situ hybridization was performed for evaluation of EBV status. Clinicopathological factors and LNM status were compared between EBVGC and non-EBVGC groups. Results: Among the 1221 pT1b GCs that underwent gastrectomy with regional lymph node dissection, 898 pT1bGCs were eligible in this study. EBVGC accounted for 7.9% (71 of 898) cases. Compared to non-EBVGC, EBVGC was more frequent in males (p = 0.0055), the upper third region (p < 0.0001), showed elevated growth features (p = 0.0059), and was associated with a lower frequency of accompanying ulceration (p = 0.002), greater depth of submucosal invasion (p = 0.017), and lower frequency of lymphatic invasion (p < 0.0001). Frequency of LNM was significantly lower in EBVGC than in non-EBVGC (4.2% vs. 21.9%, p < 0.0001). In EBVGC, tumors without lymphovascular invasion showed significantly lower frequency of LNM than those with lymphovascular invasion (0 of 50, 0%; vs 3 of 21, 14.3%; p = 0.023). Histologically, 84.5% (60 of 71) of EBVGC included carcinomas with lymphoid stroma and/or lace pattern components. Conclusions: pT1b EBVGC is a convincing candidate for ER, regardless of risk factors other than lymphovascular invasion.

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MSI and EBV Positive Gastric Cancer’s Subgroups and Their Link with Novel Immunotherapy

Journal of Clinical Medicine ◽

10.3390/jcm9051427 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1427 ◽

Cited By ~ 5

Author(s):

Maria Grazia Rodriquenz ◽

Giandomenico Roviello ◽

Alberto D’Angelo ◽

Daniele Lavacchi ◽

Franco Roviello ◽

...

Keyword(s):

Gastric Cancer ◽

Chromosomal Instability ◽

Epstein Barr Virus ◽

Genetic Alterations ◽

The Cancer Genome Atlas ◽

Gastric Cancers ◽

Barr Virus ◽

Cancer Genome Atlas ◽

Epstein Barr ◽

Genome Atlas

Gastric cancers have been historically classified based on histomorphologic features. The Cancer Genome Atlas network reported the comprehensive identification of genetic alterations associated with gastric cancer, identifying four distinct subtypes— Epstein-Barr virus (EBV)-positive, microsatellite-unstable/instability (MSI), genomically stable and chromosomal instability. In particular, EBV-positive and MSI gastric cancers seem responsive to novel immunotherapies drugs. The aim of this review is to describe MSI and EBV positive gastric cancer’s subgroups and their relationship with novel immunotherapy.

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Clinical Importance of Epstein–Barr Virus-Associated Gastric Cancer

Cancers ◽

10.3390/cancers10060167 ◽

2018 ◽

Vol 10 (6) ◽

pp. 167 ◽

Cited By ~ 20

Author(s):

Jun Nishikawa ◽

Hisashi Iizasa ◽

Hironori Yoshiyama ◽

Kanami Shimokuri ◽

Yuki Kobayashi ◽

...

Keyword(s):

Gastric Cancer ◽

Gastric Carcinoma ◽

Epstein Barr Virus ◽

Low Frequency ◽

Clinical Importance ◽

Molecular Classification ◽

The Cancer Genome Atlas ◽

Barr Virus ◽

Cancer Genome Atlas ◽

Epstein Barr

Epstein–Barr virus-associated gastric carcinoma (EBVaGC) is the most common malignancy caused by EBV infection. EBVaGC has definite histological characteristics similar to gastric carcinoma with lymphoid stroma. Clinically, EBVaGC has a significantly low frequency of lymph node metastasis compared with EBV-negative gastric cancer, resulting in a better prognosis. The Cancer Genome Atlas of gastric adenocarcinomas proposed a molecular classification divided into four molecular subtypes: (1) EBVaGC; (2) microsatellite instability; (3) chromosomal instability; and (4) genomically stable tumors. EBVaGC harbors a DNA methylation phenotype, PD-L1 and PD-L2 overexpression, and frequent alterations in the PIK3CA gene. We review clinical importance of EBVaGC and discuss novel therapeutic applications for EBVaGC.

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PD-L1 Expression Associated with Epstein—Barr Virus Status and Patients’ Survival in a Large Cohort of Gastric Cancer Patients in Northern Brazil

Cancers ◽

10.3390/cancers13133107 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3107

Author(s):

Caroline de Fátima Aquino Moreira-Nunes ◽

Cláudia Nazaré de Souza Almeida Titan Martins ◽

Danielle Feio ◽

Isamu Komatsu Lima ◽

Leticia Martins Lamarão ◽

...

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

Survival Data ◽

Epstein Barr Virus ◽

Gastric Neoplasms ◽

Probability Of Survival ◽

Barr Virus ◽

Kaplan Meier ◽

Epstein Barr ◽

Gastric Cancer Patients

Gastric cancer (GC) is a worldwide health problem, making it one of the most common types of cancer, in fifth place of all tumor types, and the third highest cause of cancer deaths in the world. There is a subgroup of GC that consists of tumors infected with the Epstein–Barr virus (EBV) and is characterized mainly by the overexpression of programmed cell death protein-ligand-1 (PD-L1). In the present study, we present histopathological and survival data of a thousand GC patients, associated with EBV status and PD-L1 expression. Of the thousand tumors analyzed, 190 were EBV-positive and the vast majority (86.8%) had a high relative expression of mRNA and PD-L1 protein (p < 0.0001) in relation to non-neoplastic control. On the other hand, in EBV-negative samples, the majority had a low PD-L1 expression of RNA and protein (p < 0.0001). In the Kaplan–Meier analysis, the probability of survival and increased overall survival of EBV-positive GC patients was impacted by the PD-L1 overexpression (p < 0.0001 and p = 0.004, respectively). However, the PD-L1 low expression was correlated with low overall survival in those patients. Patients with GC positive for EBV, presenting PD-L1 overexpression can benefit from immunotherapy treatments and performing the quantification of PD-L1 in gastric neoplasms should be adopted as routine.

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PD-L1 overexpression in EBV-positive gastric cancer is caused by unique genomic or epigenomic mechanisms

Scientific Reports ◽

10.1038/s41598-021-81667-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hiroshi Nakano ◽

Motonobu Saito ◽

Shotaro Nakajima ◽

Katsuharu Saito ◽

Yuko Nakayama ◽

...

Keyword(s):

Gastric Cancer ◽

Epstein Barr Virus ◽

Tumor Tissue ◽

The Cancer Genome Atlas ◽

Barr Virus ◽

Cancer Genome Atlas ◽

Ifn Γ ◽

Epstein Barr ◽

Dual Mechanism ◽

Irf3 Activation

AbstractEpstein-Barr virus-positive gastric cancer [EBV (+) GC] is a distinct GC subtype with unique genetic and epigenetic aberrations. Here, we examined resected GC samples and publicly available microarray data and The Cancer Genome Atlas (TCGA) database to identify the mechanism underlying overexpression of PD-L1 in EBV (+) GC. We found that high levels of PD-L1 overexpression in EBV (+) GC were caused by focal amplification of CD274. By contrast, relatively high expression of PD-L1 in tumor tissue and infiltrating immune cells correlated with CD8 lymphocyte infiltration and IFN-γ expression via IRF3 activation. Since we reported previously that PD-L1 expression is associated both with the presence of CD8 T cells in the tumor microenvironment and with IFN-γ expression in GC, we examined a database to see whether IFN-γ-associated overexpression of PD-L1 plays a significant role in EBV (+) GC. Immunohistochemical staining showed that expression of the IRF3 signature in clinical GC samples was higher in EBV (+) than in EBV (−) cases. The data presented herein reveal a unique dual mechanism underlying PD-L1 overexpression in EBV (+) GC: high focal amplification of CD274 or IFN-γ-mediated signaling via activation of IRF3.

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Case Report: Favorable Response and Manageable Toxicity to the Combination of Camrelizumab, Oxaliplatin, and Oral S-1 in a Patient With Advanced Epstein–Barr Virus-Associated Gastric Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.759652 ◽

2022 ◽

Vol 11 ◽

Author(s):

Wanrui Lv ◽

Ke Cheng ◽

Xiaofen Li ◽

Lusi Feng ◽

Hancong Li ◽

...

Keyword(s):

Gastric Cancer ◽

Epstein Barr Virus ◽

Integrated Treatment ◽

Combined Approach ◽

First Line ◽

Predictive Capacity ◽

Barr Virus ◽

Potential Biomarker ◽

Multiple Biomarkers ◽

Epstein Barr

Some pertinent studies have demonstrated that Epstein–Barr virus-associated gastric cancer (EBVaGC) patients showed a favorable clinical outcome to immunotherapy and Epstein–Barr virus (EBV)-positive status might be a potential biomarker for immunotherapy in gastric cancer (GC). However, knowledge of given exposure to EBVaGC to the first-line immunotherapy is largely inadequate. Moreover, whether camrelizumab can be as effective as other PD-1 inhibitors in the treatment of advanced EBVaGC has not been reported. We report a case of advanced EBVaGC patient with a positive expression of PD-L1, enriched PD-L1+CD68+macrophages, and high TMB who had a long-term partial response and manageable toxicity to the combined approach of camrelizumab (a novel PD-1 inhibitor) and oxaliplatin plus oral S-1 (SOX). As the first-line treatment of advanced EBVaGC patients, camrelizumab combined with SOX regimen may provide a novel combined approach with favorable response and manageable safety. Combination of multiple biomarkers could have a higher effective predictive capacity to immunotherapy. Integrated treatment (chemo-immunotherapy and radiotherapy) might be the optimal strategy for patients with oligometastasis. It deserves prospective research to further validate the efficacy.

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