scholarly journals From Molecular Classification to Targeted Therapeutics: The Changing Face of Systemic Therapy in Metastatic Gastroesophageal Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Adrian Murphy ◽  
Ronan J. Kelly
Keyword(s):  
Gastric Cancer ◽  
Clinical Trials ◽  
Molecular Classification ◽  
Molecular Profiling ◽  
The Cancer Genome Atlas ◽  
Research Network ◽  
Phase Iii ◽  
Molecular Alterations ◽  
Barr Virus ◽  
Therapeutic Decisions

Histological classification of adenocarcinoma or squamous cell carcinoma for esophageal cancer or using the Lauren classification for intestinal and diffuse type gastric cancer has limited clinical utility in the management of advanced disease. Germline mutations in E-cadherin (CDH1) or mismatch repair genes (Lynch syndrome) were identified many years ago but given their rarity, the identification of these molecular alterations does not substantially impact treatment in the advanced setting. Recent molecular profiling studies of upper GI tumors have added to our knowledge of the underlying biology but have not led to an alternative classification system which can guide clinician’s therapeutic decisions. Recently the Cancer Genome Atlas Research Network has proposed four subtypes of gastric cancer dividing tumors into those positive for Epstein-Barr virus, microsatellite unstable tumors, genomically stable tumors, and tumors with chromosomal instability. Unfortunately to date, many phase III clinical trials involving molecularly targeted agents have failed to meet their survival endpoints due to their use in unselected populations. Future clinical trials should utilize molecular profiling of individual tumors in order to determine the optimal use of targeted therapies in preselected patients.

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

Cancers ◽  
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

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 Clinical Importance of Epstein–Barr Virus-Associated Gastric Cancer

Cancers ◽  
2018 ◽  
Vol 10 (6) ◽  
pp. 167 ◽  
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.

Immunotherapy for Esophageal and Gastric Cancer

2017 ◽  
pp. 292-300 ◽  
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.

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.

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.

The Molecular Pathology of Eye Tumors: A 2019 Update Main Interests for Routine Clinical Practice

2019 ◽  
Vol 19 (9) ◽  
pp. 632-664
Author(s):  
Sacha Nahon-Esteve ◽  
Arnaud Martel ◽  
Célia Maschi ◽  
Jean-Pierre Caujolle ◽  
Stéphanie Baillif ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Molecular Pathology ◽  
Biological Diversity ◽  
Locally Advanced ◽  
Molecular Classification ◽  
Molecular Data ◽  
Molecular Alterations ◽  
Molecular Tests ◽  
Advanced Tumor ◽  
Therapeutic Decisions

Over the last few years, we have seen constant development of molecular pathology for the care of patients with cancer. The information obtained from molecular data has transformed our thinking about the biological diversity of cancers, particularly in the field of ophthalmic oncology. It has reoriented the way in which therapeutic decisions and decisions concerning patient surveillance are made, both in the area of pediatric cancers, including rhabdomyosarcoma and retinoblastoma, and adult cancers, such as uveal melanoma and lymphomas. A better definition of the molecular classification of these cancers and of the different biological pathways involved is essential to the understanding of both the pathologist and the onco-ophthalmologist. Molecular tests based on targeted or expanded analysis of gene panels are now available. These tests can be performed with tumor tissue or biofluids (especially blood) to predict the prognosis of tumors and, above all, the benefit of targeted therapies, immunotherapy or even chemotherapy. Looking for the BAP1 mutation in uveal melanoma is essential because of the associated metastatic risk. When treating retinoblastoma, it is mandatory to assess the heritable status of RB1. Conjunctival melanoma requires investigation into the BRAF mutation in the case of a locally advanced tumor. The understanding of genomic alterations, the results of molecular tests and/or other biological tests predictive of a therapeutic response, but also of the limits of these tests with respect to the available biological resources, represents a major challenge for optimal patient management in ophthalmic oncology. In this review, we present the current state of knowledge concerning the different molecular alterations and therapeutic targets of interest in ophthalmic oncology.

scholarly journals Molekulare Pathologie des ösophagogastralen Adenokarzinoms

2018 ◽  
Vol 09 (04) ◽  
pp. 192-193
Author(s):  
Ine Schmale
Keyword(s):  
Epstein Barr Virus ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Research Network ◽  
Molekulare Pathologie ◽  
Barr Virus ◽  
Adenokarzinom Des Ösophagus ◽  
Cancer Genome Atlas ◽  
Epstein Barr ◽  
Genome Atlas

Zusammenfassung Die molekularbiologische Beschreibung des Magenkarzinoms hat sich durch die Arbeit des TCGA (The Cancer Genome Atlas) Research Network stark gewandelt. In einer aktuellen Publikation des TCGA wurden vier genomische Subtypen unterschieden: Epstein-Barr-Virus-infizierte Tumoren (EBV), Mikrosatelliten-instabile Tumoren (MSI), genomisch stabile Tumoren (GS) und chromosomal instabile Tumoren (CIN). Dabei unterscheidet sich das Plattenepithel des Ösophagus fundamental vom dem des Adenokarzinoms Das Adenokarzinom des Ösophagus bzw. des ösophagogastralen Übergangs (ÖGÜ) entspricht eher dem CIN-Subtyp des proximalen Magenkarzinoms, berichtete Prof. Timo Gaiser, Universitätsklinikum Mannheim, auf dem Deutschen Krebs-kongress (DKK) in Berlin.

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

2017 ◽  
Vol 110 (3) ◽  
pp. 316-320 ◽  
Author(s):  
Anshuman Panda ◽  
Janice M Mehnert ◽  
Kim M Hirshfield ◽  
Greg Riedlinger ◽  
Sherri Damare ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Immune Checkpoint ◽  
Lymphocytic Infiltration ◽  
Metastatic Gastric Cancer ◽  
The Cancer Genome Atlas ◽  
Cancer Data ◽  
Gastric Cancers ◽  
Barr Virus ◽  
Mutation Burden ◽  
Repair Defect

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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