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Virchows Archiv

, Volume 464, Issue 2, pp 145–156 | Cite as

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

  • Guy Betts
  • Helen Valentine
  • Sue Pritchard
  • Richard Swindell
  • Victoria Williams
  • Shethah Morgan
  • Ewen A. Griffiths
  • Ian Welch
  • Catharine West
  • Christopher Womack
Original Article

Abstract

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 = 0.005). HER2 overexpression was observed in 10 % of cases and associated with increased survival (P = 0.041). cMet overexpression was observed in 4 % of cases and associated with worse survival (P < 0.001). On multivariate analysis, only cMet retained significance (P = 0.006). pS6 and pERK expression were observed in 73 % and 30 % of tumours, respectively, with no association with survival. HER2 (P = 0.004) and pERK (P = 0.001) 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.

Keywords

Gastric adenocarcinoma FGFR2 HER2 cMet Tissue microarray 

Notes

Acknowledgments

We would like to thank the FGFR2 FISH analysis team at AstraZeneca: Laura Blockley, Grace Harrod and James Stevens, and we also thank Claire Routley PhD, from Mudskipper Business who provided medical writing assistance funded by AstraZeneca. This study was sponsored by AstraZeneca. Additionally, Catharine West was supported by Experimental Cancer Medicine Centre funding.

Conflict of interest

G Betts, H Valentine, S Pritchard, R Swindell, E Griffiths, Ian Welch and C West have no conflicts of interest to disclose. V Williams, S Morgan and C Womack are full-time employees of AstraZeneca and have AstraZeneca shares.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • 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. 1.Translational Radiobiology Group, Institute of Cancer Sciences, Manchester Academic Health Science CentreUniversity of ManchesterManchesterUK
  2. 2.Department of HistopathologyUniversity Hospital of South Manchester NHS Foundation TrustManchesterUK
  3. 3.Academic Department of Radiation OncologyUniversity of Manchester, Christie HospitalManchesterUK
  4. 4.Innovative Medicines, R&DAstraZenecaAlderley ParkUK
  5. 5.Department of SurgeryUniversity Hospitals Birmingham NHS Foundation TrustBirminghamUK
  6. 6.University Hospital of South Manchester NHS Foundation TrustManchesterUK
  7. 7.Translational Radiobiology GroupManchesterUK

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