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Original article
Improved survival of gastric cancer with tumour Epstein–Barr virus positivity: an international pooled analysis
  1. M Constanza Camargo1,
  2. Woo-Ho Kim2,
  3. Anna Maria Chiaravalli3,
  4. Kyoung-Mee Kim4,
  5. Alejandro H Corvalan5,
  6. Keitaro Matsuo6,
  7. Jun Yu7,
  8. Joseph J Y Sung7,
  9. Roberto Herrera-Goepfert8,
  10. Fernando Meneses-Gonzalez9,
  11. Yuko Kijima10,
  12. Shoji Natsugoe10,
  13. Linda M Liao1,
  14. Jolanta Lissowska11,
  15. Sung Kim12,
  16. Nan Hu1,
  17. Carlos A Gonzalez13,
  18. Yashushi Yatabe14,
  19. Chihaya Koriyama10,
  20. Stephen M Hewitt15,
  21. Suminori Akiba10,
  22. Margaret L Gulley16,
  23. Philip R Taylor1,
  24. Charles S Rabkin1
  1. 1Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
  2. 2Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
  3. 3Anatomic Pathology Unit, Ospedale di Circolo and University of Insubria, Varese, Italy
  4. 4Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
  5. 5Department of Hematology and Oncology, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
  6. 6Division of Molecular Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan
  7. 7Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
  8. 8Department of Pathology, National Cancer Institute, Mexico City, Mexico
  9. 9Programa de Residencia en Epidemiología, Dirección General Adjunta de Epidemiología, Secretaría de Salud, México City, México
  10. 10Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
  11. 11Division of Cancer Epidemiology and Prevention, M Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
  12. 12Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
  13. 13Unit of Nutrition, Environment and Cancer, Epidemiology Research Program, Catalan Institute of Oncology, Barcelona, Spain; on behalf of the Euro-gast EPIC study
  14. 14Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan
  15. 15Tissue Array Research Program and Applied Molecular Pathology Laboratory, Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA
  16. 16Department of Pathology and Laboratory Medicine, The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA
  1. Correspondence to Dr M Constanza Camargo, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Blvd, EPS 6116, Rockville, MD 20852, USA; camargomc{at}mail.nih.gov

Abstract

Background and objective About 9% of gastric carcinomas have Epstein–Barr virus (EBV) in the tumour cells, but it is unclear whether viral presence influences clinical progression. We therefore examined a large multicentre case series for the association of tumour EBV status with survival after gastric cancer diagnosis, accounting for surgical stage and other prognostic factors.

Methods We combined individual-level data on 4599 gastric cancer patients diagnosed between 1976 and 2010 from 13 studies in Asia (n=8), Europe (n=3), and Latin America (n=2). EBV positivity of tumours was assessed by in situ hybridisation. Mortality HRs for EBV positivity were estimated by Cox regression models stratified by study, adjusted for distributions of sex (71% male), age (mean 58 years), stage (52% tumour-node-metastasis stages III or IV), tumour histology (49% poorly differentiated, 57% Lauren intestinal-type), anatomic subsite (70% non-cardia) and year of diagnosis. Variations by study and continent were assessed using study-specific HRs for EBV positivity.

Results During median 3.0 years follow-up, 49% of patients died. Stage was strongly predictive of mortality, with unadjusted HRs (vs stage I) of 3.1 for stage II, 8.1 for stage III and 13.2 for stage IV. Tumour EBV positivity was 8.2% overall and inversely associated with stage (adjusted OR: 0.79 per unit change). Adjusted for stage and other confounders, EBV positivity was associated with lower mortality (HR, 0.72; 95% CI 0.61 to 0.86), with low heterogeneity among the study populations (p=0.2). The association did not significantly vary across patient or tumour characteristics. There was no significant variation among the three continent-specific HRs (p=0.4).

Conclusions Our findings suggest that tumour EBV positivity is an additional prognostic indicator in gastric cancer. Further studies are warranted to identify the mechanisms underlying this protective association.

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