HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials

Susan D Richman, Katie Southward, Philip Chambers, Debra Cross, Jennifer Barrett, Gemma Hemmings, Morag Taylor, Henry Wood, Gordon Hutchins, Joseph M Foster, Assa Oumie, Karen G Spink, Sarah R Brown, Marc Jones, David Kerr, Kelly Handley, Richard Gray, Matthew Seymour, Philip Quirke

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91 Citations (Scopus)

Abstract

HER2 overexpression/amplification is linked to trastuzumab response in breast/gastric cancers. One suggested anti-EGFR resistance mechanism in colorectal cancer (CRC) is aberrant MEK-AKT pathway activation through HER2 up-regulation. We assessed HER2-amplification/overexpression in stage II-III and IV CRC patients, assessing relationships to KRAS/BRAF and outcome. Pathological material was obtained from 1914 patients in the QUASAR stage II-III trial and 1342 patients in stage IV trials (FOCUS and PICCOLO). Tissue microarrays were created for HER2 immunohistochemistry. HER2-amplification was assessed using FISH and copy number variation. KRAS/BRAF mutation status was assessed by pyrosequencing. Progression-free survival (PFS) and overall survival (OS) data were obtained for FOCUS/PICCOLO and recurrence and mortality for QUASAR; 29/1342 (2.2%) stage IV and 25/1914 (1.3%) stage II-III tumours showed HER2 protein overexpression. Of the HER2-overexpressing cases, 27/28 (96.4%) stage IV tumours and 20/24 (83.3%) stage II-III tumours demonstrated HER2 amplification by FISH; 41/47 (87.2%) also showed copy number gains. HER2-overexpression was associated with KRAS/BRAF wild-type (WT) status at all stages: in 5.2% WT versus 1.0% mutated tumours (p < 0.0001) in stage IV and 2.1% versus 0.2% in stage II-III tumours (p = 0.01), respectively. HER2 was not associated with OS or PFS. At stage II-III, there was no significant correlation between HER2 overexpression and 5FU/FA response. A higher proportion of HER2-overexpressing cases experienced recurrence, but the difference was not significant. HER2-amplification/overexpression is identifiable by immunohistochemistry, occurring infrequently in stage II-III CRC, rising in stage IV and further in KRAS/BRAF WT tumours. The value of HER2-targeted therapy in patients with HER2-amplified CRC must be tested in a clinical trial. © 2015 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Original languageEnglish
Pages (from-to)562-570
Number of pages9
JournalJournal of Pathology
Volume238
Issue number4
Early online date22 Dec 2015
DOIs
Publication statusPublished - Mar 2016

Keywords

  • Antineoplastic Combined Chemotherapy Protocols
  • Clinical Trials as Topic
  • Colorectal Neoplasms
  • DNA Copy Number Variations
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry
  • Male
  • Mutation
  • Neoplasm Recurrence, Local
  • Neoplasm Staging
  • Receptor, ErbB-2
  • Journal Article
  • Research Support, Non-U.S. Gov't

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