Immune Activation and Benefit From Avelumab in EBV-Positive Gastric Cancer

Abstract Response to immune checkpoint therapy can be associated with a high mutation burden, but other mechanisms are also likely to be important. We identified a patient with metastatic gastric cancer with meaningful clinical benefit from treatment with the anti–programmed death–ligand 1 (PD-L1) antibody avelumab. This tumor showed no evidence of high mutation burden or mismatch repair defect but was strongly positive for presence of Epstein-Barr virus (EBV) encoded RNA. Analysis of The Cancer Genome Atlas gastric cancer data (25 EBV+, 80 microsatellite-instable [MSI], 310 microsatellite-stable [MSS]) showed that EBV-positive tumors were MSS. Two-sided Wilcoxon rank-sum tests showed that: 1) EBV-positive tumors had low mutation burden (median = 2.07 vs 3.13 in log10 scale, P < 10-12) but stronger evidence of immune infiltration (median ImmuneScore 2212 vs 1295, P < 10-4; log2 fold-change of CD8A = 1.85, P < 10-6) compared with MSI tumors, and 2) EBV-positive tumors had higher expression of immune checkpoint pathway (PD-1, CTLA-4 pathway) genes in RNA-seq data (log2 fold-changes: PD-1 = 1.85, PD-L1 = 1.93, PD-L2 = 1.50, CTLA-4 = 1.31, CD80 = 0.89, CD86 = 1.31, P < 10-4 each), and higher lymphocytic infiltration by histology (median tumor-infiltrating lymphocyte score = 3 vs 2, P < .001) compared with MSS tumors. These data suggest that EBV-positive low–mutation burden gastric cancers are a subset of MSS gastric cancers that may respond to immune checkpoint therapy.

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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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Immunotherapy for Esophageal and Gastric Cancer

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_175231 ◽

2017 ◽

pp. 292-300 ◽

Cited By ~ 1

Author(s):

Ronan J. Kelly

Keyword(s):

Gastric Cancer ◽

Tumor Cells ◽

Immune Cells ◽

Single Agent ◽

Phase Iii ◽

Immune Checkpoints ◽

Barr Virus ◽

Mutation Burden ◽

Heavily Pretreated ◽

Epstein Barr

PD-L1 upregulation occurs in approximately 40% of gastroesophageal cancers. However, unlike other solid tumors, there is minimal PD-L1 expressed on the cancer cells; rather, expression occurs predominantly on infiltrating myeloid cells. Preliminary clinical data involving single-agent PD-1/PD-L1 inhibitors in metastatic gastroesophageal cancer have reported response rates of 22%–27% for patients with PD-L1+ tumors and 10%–17% for unselected patients. The phase III ONO-4538-12 (ATTRACTION 2) trial has demonstrated an improved overall survival for nivolumab compared with placebo for patients with heavily pretreated gastric cancer. In the future, we will need better biomarkers to select those most likely to respond and/or identify patients who may need combination immunotherapeutics or alternate strategies. A number of subsets of gastric cancer with different immune signatures, most notably tumors positive for Epstein-Barr virus and microsatellite instability, have been identified, with approximately 50% and 94% PD-L1+ staining seen on tumor cells and immune cells in the EBV subtype and approximately 33% and 45% PD-L1+ staining seen on tumor cells and immune cells in MSI high tumors. Both subtypes demonstrate PD-L1+ immune cells with tumor-infiltrating patterns, unlike the more commonly seen PD-L1+ immune cells at the invasive margin. PD-L2 expression has been reported in 52% of esophageal adenocarcinomas but little is known about the expression of other immune checkpoints. Additional factors that suggest gastroesophageal cancers may respond to checkpoint inhibition include the high somatic mutation burden and the link with chronic inflammation. Here we provide a comprehensive review of the checkpoint inhibitor data published to date in advanced esophagogastric cancers and rationalize how the immune microenvironment in these diverse tumors can explain response or resistance to immunotherapeutics.

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New drug developments in metastatic gastric cancer

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284818808072 ◽

2018 ◽

Vol 11 ◽

pp. 175628481880807 ◽

Cited By ~ 6

Author(s):

Aaron C. Tan ◽

David L. Chan ◽

Wasek Faisal ◽

Nick Pavlakis

Keyword(s):

Gastric Cancer ◽

Clinical Trials ◽

Targeted Therapies ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Predictive Biomarkers ◽

Metastatic Gastric Cancer ◽

New Era

Metastatic gastric cancer is associated with a poor prognosis and novel treatment options are desperately needed. The development of targeted therapies heralded a new era for the management of metastatic gastric cancer, however results from clinical trials of numerous targeted agents have been mixed. The advent of immune checkpoint inhibitors has yielded similar promise and results from early trials are encouraging. This review provides an overview of the systemic treatment options evaluated in metastatic gastric cancer, with a focus on recent evidence from clinical trials for targeted therapies and immune checkpoint inhibitors. The failure to identify appropriate predictive biomarkers has hampered the success of many targeted therapies in gastric cancer, and a deeper understanding of specific molecular subtypes and genomic alterations may allow for more precision in the application of novel therapies. Identifying appropriate biomarkers for patient selection is essential for future clinical trials, for the most effective use of novel agents and in combination approaches to account for growing complexity of treatment options.

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Efficacy of Immune Checkpoint Inhibitors in Metastatic Epstein-Barr Virus Associated Gastric Cancer (EBVaGC): A Case Series and Review of Literature

10.21203/rs.3.rs-967167/v1 ◽

2021 ◽

Author(s):

Shimeng Liang ◽

Weibing Leng ◽

Dan Jiang ◽

Ming Liu ◽

Dan Cao ◽

...

Keyword(s):

Gastric Cancer ◽

Gastric Carcinoma ◽

Immune Checkpoint Inhibitors ◽

Epstein Barr Virus ◽

Checkpoint Inhibitors ◽

Case Series ◽

Metastatic Gastric Cancer ◽

Pooled Analysis ◽

Barr Virus ◽

Epstein Barr

Abstract Background Immunotherapy has revolutionized the treatment of malignant tumors. However, limited clinical data are available to report the efficacy of immune checkpoint inhibitors (ICIs) on Epstein-Barr virus-associated gastric carcinoma. Methods In this study, we report a case series of five patients with metastatic Epstein-Barr virus-associated gastric carcinoma who were treated with ICIs and to perform a pooled analysis of published cases to investigate the efficacy of ICIs in Epstein-Barr virus-associated gastric carcinoma patients. Results Between 2018 and 2020, five metastatic gastric cancer patients with EBV positivity who received PD-1 antibodies treatment were included in the analysis at the authors’ institution. Furthermore, we performed a pooled analysis of the contemporary literature. In our case series, two patients experienced partial response (PR); one patient achieved complete response (CR), whereas two patients had progression disease (PD), resulting an ORR of 60%. In the pooled analysis of all 36 patients, ORR was 48.6% (17/35). For the first line and later lines, it was 75% (3/4) and 45.2% (14/31) respectively. The ORR was 46.7% (14/30) for ICIs monotherapy and improved to 60% (3/5) by combination with chemotherapy. Conclusions These results demonstrated that an EBV-positive status was a reliable biomarker for immunotherapy in metastatic gastric cancer, especially for monotherapy. Immunotherapy combined with chemotherapy may be a better strategy, warranting further large-scale clinical trials for validation.

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A Molecular Stratification of Chilean Gastric Cancer Patients with Potential Clinical Applicability

Cancers ◽

10.3390/cancers12071863 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1863

Author(s):

Mauricio P. Pinto ◽

Miguel Córdova-Delgado ◽

Ignacio N. Retamal ◽

Matías Muñoz-Medel ◽

M. Loreto Bravo ◽

...

Keyword(s):

Gastric Cancer ◽

Latin American ◽

Epithelial To Mesenchymal Transition ◽

Low Cost ◽

Molecular Classification ◽

The Cancer Genome Atlas ◽

Mesenchymal Transition ◽

Barr Virus ◽

Clinical Applicability ◽

Stratification System

Gastric cancer (GC) is a complex and heterogeneous disease. In recent decades, The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) defined GC molecular subtypes. Unfortunately, these systems require high-cost and complex techniques and consequently their impact in the clinic has remained limited. Additionally, most of these studies are based on European, Asian, or North American GC cohorts. Herein, we report a molecular classification of Chilean GC patients into five subtypes, based on immunohistochemical (IHC) and in situ hybridization (ISH) methods. These were Epstein–Barr virus positive (EBV+), mismatch repair-deficient (MMR-D), epithelial to mesenchymal transition (EMT)-like, and accumulated (p53+) or undetected p53 (p53−). Given its lower costs this system has the potential for clinical applicability. Our results confirm relevant molecular alterations previously reported by TCGA and ACRG. We confirm EBV+ and MMR-D patients had the best prognosis and could be candidates for immunotherapy. Conversely, EMT-like displayed the poorest prognosis; our data suggest FGFR2 or KRAS could serve as potential actionable targets for these patients. Finally, we propose a low-cost step-by-step stratification system for GC patients. To the best of our knowledge, this is the first Latin American report on a molecular classification for GC. Pending further validation, this stratification system could be implemented into the routine clinic

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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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Case Report: Epstein-Barr virus Positive Gastric Carcinoma

Integrative Gastroenterology and Hepatology ◽

10.18314/igh.v2i1.1632 ◽

2019 ◽

pp. 145-151

Author(s):

Gasenko E ◽

Hegmane A ◽

Plate S ◽

Zvirbule Z ◽

Elsberga E ◽

...

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

Epstein Barr Virus ◽

Symptom Control ◽

Locally Advanced ◽

Disease Stabilisation ◽

The Cancer Genome Atlas ◽

Barr Virus ◽

Potential Biomarker ◽

Epstein Barr

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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Characteristics of Subtypes Within Microsatellite Instability-high Gastric Cancer Based on a Gene Signature Related to Immune Microenvironment Components

10.21203/rs.3.rs-31506/v1 ◽

2020 ◽

Author(s):

Xiaolong Wu ◽

Xiangyu Gao ◽

Xiaofang Xing ◽

Xianzi Wen ◽

Ziyu Li ◽

...

Keyword(s):

Gastric Cancer ◽

Microsatellite Instability ◽

Cancer Patients ◽

Immune Checkpoint ◽

Differentially Expressed Gene ◽

The Cancer Genome Atlas ◽

Immune Microenvironment ◽

Clinical Prognosis ◽

Time Signature ◽

Gastric Cancer Patients

Abstract Background: Gastric cancer patients with microsatellite instability-high (MSI-H) status have a better clinical prognosis and higher response rate to immune checkpoint inhibitors. However, recent studies have suggested that some molecular pathways in MSI-H tumors could affect tumor immune microenvironment (TIME) components, thereby leading to immunotherapy resistance. We aimed to establish subtypes based on the TIME components of MSI-H gastric cancer and analyze the characteristics of each subtype. Methods: Cohorts from the Cancer Genome Atlas, the Asian Cancer Research Group, and Peking University Cancer Hospital were used for this study. CIBERSORT software was used to analyze the TIME components. A set of genes based on the TIME component characteristics, which we named the MSI-TIME signature, was defined using k-means cluster and differentially expressed gene analysis. Results: By using the MSI-TIME signature in the aforementioned cohorts for cluster analysis, the TIME subtypes within MSI-H gastric cancer (MSI-S1, MSI-S2) were established; the differences between the subgroups were reflected in multiple aspects. The MSI-S1 subtype was characterized by a high density of CD8+ T cells, high expression levels of immune checkpoint molecules including PD-L1, PD-L2, CTLA-4, and a high T-cell inflammation level. Patients with the MSI-S1 subtype could also benefit from adjuvant chemotherapy. In contrast, the WNT/β-catenin pathway was enriched in the MSI-S2 subtype. Conclusion: We found that patients with MSI-H gastric cancer showed very different TIME characteristics and could be divided into two subtypes accordingly. These results might benefit MSI-H gastric cancer patients developing individualized treatment strategies in the future.

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