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Dislich B, Mertz KD, Gloor B, Langer R. Interspatial Distribution of Tumor and Immune Cells in Correlation with PD-L1 in Molecular Subtypes of Gastric Cancers. Cancers (Basel) 2022; 14:cancers14071736. [PMID: 35406506 PMCID: PMC8996833 DOI: 10.3390/cancers14071736] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 03/24/2022] [Indexed: 12/16/2022] Open
Abstract
(1) Background: EBV-positive and mismatch repair-deficient (MMRd) gastric cancers (GCs) show higher levels of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression and thus a more profound response to immunotherapy. However, the majority of GCs are EBV-negative (EBV−) and MMR proficient (MMRp). We analyzed PD-L1 expression and TILs in EBV-MMRpGCs in comparison to EBV-positive (EBV+) and MMRdGCs to identify an immunogenic phenotype susceptible to immunotherapy. (2) Methods: A next-generation tissue microarray of 409 primary resected GCs was analyzed by Epstein-Barr encoding region (EBER) in situ hybridization for MSH1, PMS2, MSH2, MSH6, PD-L1, and CD8 immunohistochemistry. PD-L1 positivity was defined as a combined positive score (CPS) of ≥1. CD8+ TILs and their proximity to cancer cells were digitally analyzed on the HALO™ image analysis platform. (3) Results: Eleven cases were EBV+, 49 cases MMRd, and 349 cases EBV-MMRpGCs. The highest rate of PD-L1 positivity was seen in EBV+GCs, followed by MMRdGCs and EBV-MMRpGCs (81.8%, 73.5%, and 27.8%, respectively). EBV+ and MMRdGCs also demonstrated increased numbers and proximity of CD8+ TILs to tumor cells compared to EBV-MMRpGCs (p < 0.001 each). PD-L1 status positively correlated with the total numbers of CD8+ TILs and their proximity to tumor cells in all subtypes, including EBV-MMRpGCs (p < 0.001 each). A total of 28.4% of EBV-MMRpGCs showed high CD8+ TILs independent of PD-L1. (4) Conclusions: PD-L1 and CD8 immunohistochemistry, supplemented by digital image analysis, may identify EBV-MMRpGCs with high immunoreactivity indices, indicating susceptibility to immunotherapy.
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Affiliation(s)
- Bastian Dislich
- Institute of Pathology, University of Bern, 3008 Bern, Switzerland
- Correspondence:
| | - Kirsten D. Mertz
- Institute of Pathology, Cantonal Hospital Baselland, 4410 Liestal, Switzerland;
| | - Beat Gloor
- Department of Visceral Surgery and Medicine, Inselspital Bern, University of Bern, 3010 Bern, Switzerland;
| | - Rupert Langer
- Institute of Clinical Pathology and Molecular Pathology, Kepler University Hospital, Johannes Kepler University, 4021 Linz, Austria;
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Bausys A, Gricius Z, Aniukstyte L, Luksta M, Bickaite K, Bausys R, Strupas K. Current treatment strategies for patients with only peritoneal cytology positive stage IV gastric cancer. World J Clin Cases 2021; 9:9711-9721. [PMID: 34877310 PMCID: PMC8610919 DOI: 10.12998/wjcc.v9.i32.9711] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 07/28/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies worldwide and surgery remains the only potentially curative treatment option for it. Although a significant proportion of GC patients are found with distant metastases already at the initial diagnosis. Peritoneal dissemination is the most common site of metastases. Positive peritoneal cytology (Cy1) is associated with poor long-term outcomes; thus, these patients are considered as stage IV even if macroscopic carcinomatosis is absent. Currently, there is no clear evidence for the most optimal treatment for this distinct subpopulation of the stage IV cohort. Available strategies vary from palliative chemotherapy to upfront gastrectomy. This comprehensive review summarized current evidence of different treatment strategies for Cy1 GC including roles of surgery, systemic and intraperitoneal chemotherapy.
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Affiliation(s)
- Augustinas Bausys
- Department of Abdominal Surgery and Oncology, National Cancer Institute, Vilnius 08406, Lithuania
- Clinic of Gastroenterology, Nephrourology and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius 03101, Lithuania
| | - Zilvinas Gricius
- Faculty of Medicine, Vilnius University, Vilnius 08406, Lithuania
| | - Laura Aniukstyte
- Faculty of Medicine, Vilnius University, Vilnius 08406, Lithuania
| | - Martynas Luksta
- Clinic of Gastroenterology, Nephrourology and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius 03101, Lithuania
| | | | - Rimantas Bausys
- Department of Abdominal Surgery and Oncology, National Cancer Institute, Vilnius 08406, Lithuania
| | - Kestutis Strupas
- Clinic of Gastroenterology, Nephrourology and Surgery, Institute of Clinical Medicine, Vilnius University, Vilnius 03101, Lithuania
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Dislich B, Blaser N, Berger MD, Gloor B, Langer R. Preservation of Epstein-Barr virus status and mismatch repair protein status along the metastatic course of gastric cancer. Histopathology 2021; 76:740-747. [PMID: 31898331 DOI: 10.1111/his.14059] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 12/17/2019] [Accepted: 01/02/2020] [Indexed: 12/13/2022]
Abstract
AIMS Epstein-Barr virus (EBV) in-situ hybridisation and mismatch repair (MMR) protein immunohistochemistry identifies two subgroups of gastric cancer (GC) with high immunogenicity and likelihood for response to immune check-point inhibition. As tumour biology may change during the metastatic course, which can negatively influence the success of therapeutic decisions made on primary tissue, we investigated the consistency of GC EBV and MMR status within primary tumours and metastases. METHODS AND RESULTS We investigated a cohort of 415 primary resected GC, including 111 cases with corresponding distant metastases and 297 cases with lymph node metastases. Tumours were analysed by EBV in-situ hybridisation and MLH1, PMS2, MSH2 and MSH6 immunohistochemistry using tissue microarray technique. Primary tumours were grouped as EBV-positive MMR-proficient, EBV-negative MMR-deficient and EBV-negative MMR-proficient. Eleven of 415 (2.7%) of primary tumours were EBV-positive MMR-proficient, whereas 49 of 415 (11.8%) of tumours were EBV-negative MMR-deficient. EBV and MMR protein status showed full concordance with that of the primary tumours. MMR-deficient tumours were of lower pT-category (P < 0.001), had fewer lymph node metastases [24 of 49 (49%) versus 273 of 361 (75.6%) cases; P < 0.001] and a lower rate of distant metastases [six of 49 (12.2%) versus 105 of 366 (28.7%) cases; P = 0.015]. CONCLUSION We demonstrate a strong correlation of EBV and MMR status between primary tumours, lymph node and distant metastases in a large series of primary resected GC. The cases showed the expected frequency of EBV-positive MMR-deficient and EBV-negative MMR-proficient tumours. We conclude that tissue testing for molecular subtyping for therapeutic decision-making can be reliably performed on primary tumours and metastases in GC.
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Affiliation(s)
- Bastian Dislich
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Nicola Blaser
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Martin D Berger
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Beat Gloor
- Department of Visceral Surgery and Medicine, Inselspital Bern, University of Bern, Bern, Switzerland
| | - Rupert Langer
- Institute of Pathology, University of Bern, Bern, Switzerland
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Abstract
BACKGROUND PD-1/PD-L1-Immunotherapy has been approved for gastric carcinoma. PD-L1 assessment by immunohistochemistry is the principle biomarker. Are biopsies able to map the actual PD-L1 status of the entire tumor? METHODS Whole tumor slides of 56 gastric carcinoma were analyzed to determine the distribution of PD-L1 positive cells in the entire tumor areas. Tissue micro arrays with four cores of the tumor surface, which represents the endoscopically accessible biopsy zone, were built from the same tumors. The PD-L1 CPS value was determined separately for each core. Preoperative diagnostic biopsies were available for 22 of the tumors. PD-L1 prevalence, sensitivity and specificity were analyzed using the whole tumor slides as reference scores. Molecular subtyping was performed and related to the PD-L1 status. RESULTS 27.3% of cases were PD-L1 negative (CPS < 1), 43.6% showed low PD-L1 expression (CPS ≥ 1 to < 5), 12.7% moderate (CPS ≥ 5 to < 10) and 16.4% strong expression (CPS ≥ 10). The biopsies showed best test characteristics if four surface biopsies were analyzed combined, i.e., the CPS was calculated across all four biopsies. The prevalence showed a distribution similar to the resection specimens, sensitivity was 0.73 and specificity 1.0. Using fewer surface biopsies decreased sensitivity and specificity and caused false-negative classifications. Compared to the TMAs, the preoperative biopsies showed reduced sensitivity (0.412). CONCLUSIONS This is the first comprehensive study to optimize PD-L1 assessment in gastric cancer using endoscopically available tissue. The obtained PD-L1 prevalence is consistent with data of current clinical studies. Calculation of the test characteristics shows that surface biopsies can be indicative of the true PD-L1 status based on the resection specimen. However, an adequate number of biopsies is required. In this study, n = 4 biopsies yielded best results.
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Derks S, de Klerk LK, Xu X, Fleitas T, Liu KX, Liu Y, Dietlein F, Margolis C, Chiaravalli AM, Da Silva AC, Ogino S, Akarca FG, Freeman GJ, Rodig SJ, Hornick JL, van Allen E, Li B, Liu SX, Thorsson V, Bass AJ. Characterizing diversity in the tumor-immune microenvironment of distinct subclasses of gastroesophageal adenocarcinomas. Ann Oncol 2020; 31:1011-1020. [PMID: 32387455 PMCID: PMC7690253 DOI: 10.1016/j.annonc.2020.04.011] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/11/2020] [Accepted: 04/14/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Gastroesophageal adenocarcinomas (GEAs) are heterogeneous cancers where immune checkpoint inhibitors have robust efficacy in heavily inflamed microsatellite instability (MSI) or Epstein-Barr virus (EBV)-positive subtypes. Immune checkpoint inhibitor responses are markedly lower in diffuse/genome stable (GS) and chromosomal instable (CIN) GEAs. In contrast to EBV and MSI subtypes, the tumor microenvironment of CIN and GS GEAs have not been fully characterized to date, which limits our ability to improve immunotherapeutic strategies. PATIENTS AND METHODS Here we aimed to identify tumor-immune cell association across GEA subclasses using data from The Cancer Genome Atlas (N = 453 GEAs) and archival GEA resection specimen (N = 71). The Cancer Genome Atlas RNAseq data were used for computational inferences of immune cell subsets, which were correlated to tumor characteristics within and between subtypes. Archival tissues were used for more spatial immune characterization spanning immunohistochemistry and mRNA expression analyses. RESULTS Our results confirmed substantial heterogeneity in the tumor microenvironment between distinct subtypes. While MSI-high and EBV+ GEAs harbored most intense T cell infiltrates, the GS group showed enrichment of CD4+ T cells, macrophages and B cells and, in ∼50% of cases, evidence for tertiary lymphoid structures. In contrast, CIN cancers possessed CD8+ T cells predominantly at the invasive margin while tumor-associated macrophages showed tumor infiltrating capacity. Relatively T cell-rich 'hot' CIN GEAs were often from Western patients, while immunological 'cold' CIN GEAs showed enrichment of MYC and cell cycle pathways, including amplification of CCNE1. CONCLUSIONS These results reveal the diversity of immune phenotypes of GEA. Half of GS gastric cancers have tertiary lymphoid structures and are therefore promising candidates for immunotherapy. The majority of CIN GEAs, however, exhibit T cell exclusion and infiltrating macrophages. Associations of immune-poor CIN GEAs with MYC activity and CCNE1 amplification may enable new studies to determine precise mechanisms of immune evasion, ultimately inspiring new therapeutic modalities.
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Affiliation(s)
- S Derks
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands.
| | - L K de Klerk
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands; Dana-Farber Cancer Institute, Boston, USA
| | - X Xu
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - T Fleitas
- Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - K X Liu
- Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, USA
| | - Y Liu
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, USA
| | - F Dietlein
- Dana-Farber Cancer Institute, Boston, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, USA
| | - C Margolis
- Dana-Farber Cancer Institute, Boston, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, USA
| | | | - A C Da Silva
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, USA
| | - S Ogino
- Dana-Farber Cancer Institute, Boston, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA
| | - F G Akarca
- Dana-Farber Cancer Institute, Boston, USA
| | | | - S J Rodig
- Department of Pathology and Center for Immuno-Oncology
| | - J L Hornick
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, USA
| | - E van Allen
- Dana-Farber Cancer Institute, Boston, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, USA
| | - B Li
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, USA
| | - S X Liu
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, USA
| | - V Thorsson
- Institute for Systems Biology, Seattle, USA
| | - A J Bass
- Dana-Farber Cancer Institute, Boston, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, USA.
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Moisseev A, Albert E, Lubarsky D, Schroeder D, Clark J. Transcriptomic and Genomic Testing to Guide Individualized Treatment in Chemoresistant Gastric Cancer Case. Biomedicines 2020; 8:biomedicines8030067. [PMID: 32210001 PMCID: PMC7148467 DOI: 10.3390/biomedicines8030067] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/20/2020] [Accepted: 03/20/2020] [Indexed: 12/20/2022] Open
Abstract
Gastric cancer is globally the fifth leading cause of cancer death. We present a case report describing the unique genomic characteristics of an Epstein–Barr virus-negative gastric cancer with esophageal invasion and regional lymph node metastasis. Genomic tests were performed first with the stomach biopsy using platforms FoundationOne, OncoDNA, and Oncopanel at Dana Farber Institute. Following neoadjuvant chemotherapy, residual tumor was resected and the stomach and esophageal residual tumor samples were compared with the initial biopsy by whole exome sequencing and molecular pathway analysis platform Oncobox. Copy number variation profiling perfectly matched the whole exome sequencing results. A moderate agreement was seen between the diagnostic platforms in finding mutations in the initial biopsy. Final data indicate somatic activating mutation Q546K in PIK3CA gene, somatic frameshifts in PIH1D1 and FBXW7 genes, stop-gain in TP53BP1, and a few somatic mutations of unknown significance. RNA sequencing analysis revealed upregulated expressions of MMP7, MMP9, BIRC5, and PD-L1 genes and strongly differential regulation of several molecular pathways linked with the mutations identified. According to test results, the patient received immunotherapy with anti-PD1 therapy and is now free of disease for 2 years. Our data suggest that matched tumor and normal tissue analyses have a considerable advantage over tumor biopsy-only genomic tests in stomach cancer.
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Affiliation(s)
- Alexey Moisseev
- Institute for personalized medicine, I.M. Sechenov First Moscow State Medical University, 119048 Moscow, Russia;
- Correspondence: ; Tel.: +7(926)1443639
| | - Eugene Albert
- Institute for personalized medicine, I.M. Sechenov First Moscow State Medical University, 119048 Moscow, Russia;
| | | | - David Schroeder
- Wellesley Internal Medicine, 372 Washington St Ste 2, Wellesley Hills, MA 02481, USA;
| | - Jeffrey Clark
- Department of Hematology and Oncology, Massachusetts General Hospital, 55 Fruit Street Boston, MA 02114, USA;
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Ge Y, Westphalen CB, Ma WW, Vega KJ, Weygant N. Implications for Tumor Microenvironment and Epithelial Crosstalk in the Management of Gastrointestinal Cancers. JOURNAL OF ONCOLOGY 2019; 2019:4835318. [PMID: 32082375 PMCID: PMC7012231 DOI: 10.1155/2019/4835318] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 09/23/2019] [Accepted: 10/12/2019] [Indexed: 02/08/2023]
Abstract
Rapid advances in technology are revealing previously unknown organization, cooperation, and limitations within the population of nontumor cells surrounding the tumor epithelium known as the tumor microenvironment (TME). Nowhere are these findings more pertinent than in the gastrointestinal (GI) tract where exquisite cell specialization supports a complex microenvironmental niche characterized by rapid stemness-associated cell turnover, pathogen sensing, epithelial orchestration of immune signaling, and other facets that maintain the complex balance between homeostasis, inflammation, and disease. Here, we summarize and discuss select emerging concepts in the precancerous microenvironment, TME, and tumor epithelial-TME crosstalk as well as their implications for the management of GI cancers.
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Affiliation(s)
- Yang Ge
- Dept of Oncology, Beijing Chao-Yang Hospital, Capital Medical Univ., Beijing, China
| | | | - Wen Wee Ma
- Dept of Oncology, Mayo Clinic, Minneapolis, MN, USA
| | - Kenneth J. Vega
- Dept of Gastroenterology, Augusta University, Augusta, GA, USA
| | - Nathaniel Weygant
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Fujian Key Laboratory of Integrative Medicine in Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, China
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