What Will We Expect From Novel Therapies to Esophageal and Gastric Malignancies?

2018 ◽  
pp. 249-261 ◽  
Author(s):  
Ramon Andrade De Mello ◽  
Luis Castelo-Branco ◽  
Pedro Castelo-Branco ◽  
Daniel Humberto Pozza ◽  
Louis Vermeulen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Microsatellite Instability ◽  
Growth Factor Receptor ◽  
The Cancer Genome Atlas ◽  
Novel Therapies ◽  
Pik3ca Mutations ◽  
Barr Virus ◽  
Epstein Barr ◽  
Near Future ◽  
Parp 1

Esophageal cancer and gastric cancer are aggressive diseases for which treatment approaches are facing a new era. Some molecular pathways, such as VEGF, EGFR, fibroblast growth factor receptor, PIK3CA, and PARP-1, have been studied, and novel targeted drugs are presumed to be developed in the near future. From The Cancer Genome Atlas report, 80% of Epstein-Barr virus tumors and 42% of tumors with microsatellite instability have PIK3CA mutations, suggesting that this pathway could be reevaluated as a possible target for new systemic treatment of gastric cancer. Notably, higher PARP-1 expression can be found in gastric cancer, which might be related to more advanced disease and worse prognosis. In addition, PD-L1 expression, high microsatellite instability, and mismatch repair deficiency can be found in gastric cancer, thus suggesting that immunotherapy may also play a role in those patients. We discuss trends related to the potential of novel therapies for patients with esophageal and gastric cancers in the near future.

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

2020 ◽  
Vol 8 (2) ◽  
pp. 258 ◽  
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.

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

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.

scholarly journals Case Report: Epstein-Barr virus Positive Gastric Carcinoma

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.

scholarly journals Clinicopathological features of tumor mutation burden, Epstein-Barr virus infection, microsatellite instability and PD-L1 status in Chinese patients with gastric cancer

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Li Zhang ◽  
Yinkui Wang ◽  
Zhongwu Li ◽  
Dongmei Lin ◽  
Yiqiang Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Microsatellite Instability ◽  
Epstein Barr Virus ◽  
Genetic Alterations ◽  
Chinese Patients ◽  
Epstein Barr Virus Infection ◽  
Tumor Mutation Burden ◽  
Barr Virus ◽  
Mutation Burden ◽  
Epstein Barr

Abstract Objectives Gastric cancer (GC) is the 4th most common type of cancer worldwide. Different GC subtypes have unique molecular features that may have different therapeutic methods. The aim of the present study was to investigate Epstein-Barr virus (EBV) infection, microsatellite instability (MSI) status, the expression of programmed death-ligand 1 (PD-L1) and gene mutations in GC patients. Methods The data of 2504 GC patients, who underwent curative gastrectomy with lymphadenectomy at Peking University Cancer Hospital between 2013 and 2018, were reviewed. We analyzed the clinicopathological factors associated with the immunohistochemistry (IHC) profiles of these patients, and genetic alterations were analyzed using next generation sequencing (NGS). Results Mismatch repair-deficient (d-MMR) GC patients were found to have a higher probability of expressing PD-L1 (p = 0.000, PD-L1 cutoff value = 1%). In addition, 4 and 6.9% of the 2504 gastric cancer patients were EBV-positive and d-MMR, respectively. The number of MLH1/PMS2-negative cases was 126 (6%), and the number of MSH2/MSH6-negative cases was 14 (0.9%). d-MMR status was associated with a intestinal group (p = 0.012), but not with tumor differentiation. Furthermore, MSI and d-MMR GC status (detected by NGS and IHC, respectively) were consistently high, and the rate of MSI was higher in patients with d-MMR GC. A number of genes associated with DNA damage repair were detected in GC patients with MSI, including POLE, ETV6, BRCA and RNF43. In patients with a high tumor mutation burden, the most significantly mutated genes were LRP1B (79.07%), ARID1A (74.42%), RNF43 (69.77%), ZFHX3 (65.12%), TP53 (58.14%), GANS (51.16%), BRCA2 (51.16%), PIK3CA (51.16%), NOTCH1 (51.16%), SMARCA4 (48.84%), ATR (46.51%), POLE (41.86%) and ATM (39.53%). Conclusions Using IHC and NGS, MSI status, protein expression, tumor mutation burden (TMB) and genetic alterations were identified in patients with GC, which provides a theoretical basis for the future clinical treatment of GC.

scholarly journals Clinicopathological features of Epstein-Barr virus infection, microsatellite instability, tumor mutation burden and PD-L1 status in Chinese patients with gastric cancer

2020 ◽  
Author(s):  
Li Zhang ◽  
Aiwen Wu ◽  
Zhongwu Li
Keyword(s):  
Gastric Cancer ◽  
Microsatellite Instability ◽  
Epstein Barr Virus ◽  
Genetic Alterations ◽  
Epstein Barr Virus Infection ◽  
Tumor Mutation Burden ◽  
Barr Virus ◽  
Mutation Burden ◽  
Therapeutic Decisions ◽  
Epstein Barr

Abstract Objectives: Gastric cancer (GC) is the 4th most common type of cancer worldwide. Different GC subtypes exhibit unique molecular features that may potentially guide therapeutic decisions. The aim of the present study was to investigate Epstein-Barr virus (EBV) infection, microsatellite instability (MSI) status, the expression of programmed death-ligand 1 (PD-L1) and gene mutations in patients with surgically-treated GC. Methods: The data of 2,504 GC patients, who underwent potentially curative gastrectomy with lymphadenectomy at Peking University Cancer Hospital between 2013 and 2018, were reviewed from a prospectively collected medical database. We also analyzed the clinicopathological factors associated with the immunohistochemistry (IHC) profiles of these patients, and genetic alterations were analyzed using next generation sequencing (NGS). Results: Mismatch repair-deficient (d-MMR) GC patients were found to have a higher probability of expressing PD-L1 (p<0.001, PD-L1 cutoff value = 1%). In addition, 4 and 6.9% of the 2,504 gastric cancer patients were EBV-positive and d-MMR, respectively. The number of MLH1/PMS2-negative cases was 126 (6%), and the number of MSH2/MSH6-negative cases was 14 (0.9%). d-MMR status was associated with a diffuse/mixed group (p<0.05), but not with tumor differentiation. Furthermore, MSI and d-MMR GC status (detected by NGS and IHC, respectively) were consistently high, and the rate of MSI was higher in patients with d-MMR GC. A number of genes associated with DNA damage repair were detected in GC patients with MSI, including POLE, ETV6, BRCA and RNF43. In patients with a high tumor mutation burden, the most significantly mutated genes were LRP1B (79.07%), ARID1A (74.42%), RNF43 (69.77%), ZFHX3 (65.12%), TP53 (58.14%), GANS (51.16%), BRCA2 (51.16%), PIK3CA (51.16%), NOTCH1 (51.16%), SMARCA4 (48.84%), ATR (46.51%), POLE (41.86%) and ATM (39.53%). Conclusions: Using IHC and NGS, MSI status, protein expression, TMB and genetic alterations were identified in patients with GC, which provides a theoretical basis for the future clinical treatment of GC.

scholarly journals Clinicopathological features of Epstein-Barr virus infection, microsatellite instability, tumor mutation burden and PD-L1 status in Chinese patients with gastric cancer

2020 ◽  
Author(s):  
Li Zhang ◽  
Aiwen Wu ◽  
Zhongwu Li
Keyword(s):  
Gastric Cancer ◽  
Microsatellite Instability ◽  
Epstein Barr Virus ◽  
Genetic Alterations ◽  
Epstein Barr Virus Infection ◽  
Tumor Mutation Burden ◽  
Barr Virus ◽  
Mutation Burden ◽  
Therapeutic Decisions ◽  
Epstein Barr

Abstract Objectives: Gastric cancer (GC) is the 4th most common type of cancer worldwide. Different GC subtypes exhibit unique molecular features that may potentially guide therapeutic decisions. The aim of the present study was to investigate Epstein-Barr virus (EBV) infection, microsatellite instability (MSI) status, the expression of programmed death-ligand 1 (PD-L1) and gene mutations in patients with surgically-treated GC. Methods: The data of 2,504 GC patients, who underwent potentially curative gastrectomy with lymphadenectomy at Peking University Cancer Hospital between 2013 and 2018, were reviewed from a prospectively collected medical database. We also analyzed the clinicopathological factors associated with the immunohistochemistry (IHC) profiles of these patients, and genetic alterations were analyzed using next generation sequencing (NGS). Results: Mismatch repair-deficient (d-MMR) GC patients were found to have a higher probability of expressing PD-L1 (p<0.001, PD-L1 cutoff value = 1%). In addition, 4 and 6.9% of the 2,504 gastric cancer patients were EBV-positive and d-MMR, respectively. The number of MLH1/PMS2-negative cases was 126 (6%), and the number of MSH2/MSH6-negative cases was 14 (0.9%). d-MMR status was associated with a diffuse/mixed group (p<0.05), but not with tumor differentiation. Furthermore, MSI and d-MMR GC status (detected by NGS and IHC, respectively) were consistently high, and the rate of MSI was higher in patients with d-MMR GC. A number of genes associated with DNA damage repair were detected in GC patients with MSI, including POLE, ETV6, BRCA and RNF43. In patients with a high tumor mutation burden, the most significantly mutated genes were LRP1B (79.07%), ARID1A (74.42%), RNF43 (69.77%), ZFHX3 (65.12%), TP53 (58.14%), GANS (51.16%), BRCA2 (51.16%), PIK3CA (51.16%), NOTCH1 (51.16%), SMARCA4 (48.84%), ATR (46.51%), POLE (41.86%) and ATM (39.53%). Conclusions: Using IHC and NGS, MSI status, protein expression, TMB and genetic alterations were identified in patients with GC, which provides a theoretical basis for the future clinical treatment of GC.

scholarly journals Microsatellite Instability, Epstein–Barr Virus, and Programmed Cell Death Ligand 1 as Predictive Markers for Immunotherapy in Gastric Cancer

Cancers ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 218
Author(s):  
Hung-Yuan Yu ◽  
Chung-Pin Li ◽  
Yi-Hsiang Huang ◽  
Shao-Jung Hsu ◽  
Yen-Po Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Microsatellite Instability ◽  
Progression Free Survival ◽  
Negative Group ◽  
Barr Virus ◽  
Positive Score ◽  
Epstein Barr ◽  
Combined Positive Score

Immunotherapy benefits selected cases of gastric cancer (GC), but the correlation between biomarkers and prognosis is still unclear. Fifty-two patients with GC who underwent immunotherapy were enrolled from June 2016 to December 2020. Their clinical features and biomarkers—microsatellite instability-high (MSI-H), programmed cell death ligand 1 (PD-L1) combined positive score (CPS), and Epstein–Barr encoding region (EBER)—were analyzed. Eight patients had MSI-H, five patients had EBER, 29 patients had CPS ≥ 1, and 20 patients had no biomarker. The overall response rates (ORRs) of the MSI-H, EBER, PD-L1 CPS ≥ 1, and all-negative group were 75%, 60%, 44.8%, and 15%, respectively. Compared with that of the all-negative group, progression-free survival (PFS) was better in the MSI-H (p = 0.018), CPS ≥ 5 (p = 0.012), and CPS ≥ 10 (p = 0.006) groups, but not in the EBER (p = 0.2) and CPS ≥ 1 groups (p = 0.35). Ten patients had combined biomarkers, CPS ≥ 1 with either MSI-H or EBER. The ORRs were 66.7% for CPS ≥ 1 and MSI-H and 75% for CPS ≥ 1 and EBER. PFS was better in patients with combined biomarkers (p = 0.01). MSI-H, EBER, and CPS are useful biomarkers for predicting the efficacy of immunotherapy.

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