FGFR2, HER2 and cMet in gastric adenocarcinoma: detection, prognostic significance and assessment of downstream pathway activation

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• 作者：Guy Betts (1) (7)
  Helen Valentine (1)
  Sue Pritchard (2)
  Richard Swindell (3)
  Victoria Williams (4)
  Shethah Morgan (4)
  Ewen A. Griffiths (5)
  Ian Welch (6)
  Catharine West (1)
  Christopher Womack (4)
  
• 关键词：Gastric adenocarcinoma ; FGFR2 ; HER2 ; cMet ; Tissue microarray
• 刊名：Virchows Archiv
• 出版年：2014
• 出版时间：February 2014
• 年：2014
• 卷：464
• 期：2
• 页码：145-156
• 全文大小：623 KB
• 作者单位：Guy Betts (1) (7)
  Helen Valentine (1)
  Sue Pritchard (2)
  Richard Swindell (3)
  Victoria Williams (4)
  Shethah Morgan (4)
  Ewen A. Griffiths (5)
  Ian Welch (6)
  Catharine West (1)
  Christopher Womack (4)
  
  1. Translational Radiobiology Group, Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
  7. Translational Radiobiology Group, Wilmslow Road, Manchester, M20 4BX, UK
  2. Department of Histopathology, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK
  3. Academic Department of Radiation Oncology, University of Manchester, Christie Hospital, Manchester, UK
  4. Innovative Medicines, R&D, AstraZeneca, Alderley Park, UK
  5. Department of Surgery, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
  6. University Hospital of South Manchester NHS Foundation Trust, Manchester, UK
  
• ISSN：1432-2307

文摘

Receptor tyrosine kinase pathways are potential therapeutic targets in gastric adenocarcinoma patients. We evaluated HER2 and cMet protein expression, and FGFR2 gene amplification to assess their prognostic significance, and downstream mediators pS6 and pERK for their potential utility as pharmacodynamic biomarkers in patients with gastric adenocarcinoma. Tissue microarrays were constructed from resection samples of 184 patients who underwent surgery for gastric/gastro-oesophageal junction adenocarcinoma. Tissue cores were obtained from the tumour body (TB), luminal surface (LS) and invasive edge (IE), and immunohistochemical and fluorescence in situ hybridisation (FGFR2) analysis was performed. FGFR2 amplification was identified in 2?% of cases and associated with worse survival (P--.005). HER2 overexpression was observed in 10?% of cases and associated with increased survival (P--.041). cMet overexpression was observed in 4?% of cases and associated with worse survival (P-lt;-.001). On multivariate analysis, only cMet retained significance (P--.006). pS6 and pERK expression were observed in 73?% and 30?% of tumours, respectively, with no association with survival. HER2 (P--.004) and pERK (P--.001) expression differed between tumour regions with HER2 expression increased in the LS compared with the TB and IE. These findings confirm subpopulations in gastric adenocarcinoma with poor outcome that may benefit from specific therapeutic strategies. However, we found heterogeneous HER2, pS6 and pERK overexpression, which presents challenges for their use as predictive biomarkers in gastric biopsies. The potential downstream pharmacodynamic markers pS6 and pERK were expressed across tumour regions, providing evidence that resections and biopsies would yield comparative results in clinical trials.