title: 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.
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.
authors.affiliation: Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, UK.
authors.forename: Susan D
authors.initials: SD
authors.lastname: Richman
authors.affiliation: Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, UK.
authors.forename: Katie
authors.initials: K
authors.lastname: Southward
authors.affiliation: Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Chambers
authors.affiliation: Histopathology and Molecular Pathology, St James University Hospital, Leeds, UK.
authors.forename: Debra
authors.initials: D
authors.lastname: Cross
authors.affiliation: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Barrett
authors.affiliation: Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, UK.
authors.forename: Gemma
authors.initials: G
authors.lastname: Hemmings
authors.affiliation: Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, UK.
authors.forename: Morag
authors.initials: M
authors.lastname: Taylor
authors.affiliation: Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Wood
authors.affiliation: Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Hutchins
authors.affiliation: Affymetrix UK Ltd, High Wycombe, UK.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Foster
authors.affiliation: Affymetrix UK Ltd, High Wycombe, UK.
authors.forename: Assa
authors.initials: A
authors.lastname: Oumie
authors.affiliation: Affymetrix UK Ltd, High Wycombe, UK.
authors.forename: Karen G
authors.initials: KG
authors.lastname: Spink
authors.affiliation: Clinical Trials Research Unit, University of Leeds, Leeds, UK.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Brown
authors.affiliation: Clinical Trials Research Unit, University of Leeds, Leeds, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: Jones
authors.affiliation: Cancer Medicine, University of Oxford, UK.
authors.forename: David
authors.initials: D
authors.lastname: Kerr
authors.affiliation: Birmingham Clinical Trials Unit, University of Birmingham, UK.
authors.forename: Kelly
authors.initials: K
authors.lastname: Handley
authors.affiliation: Clinical Trials Service Unit and Epidemiology Studies Unit, University of Oxford, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Gray
authors.affiliation: Section of Oncology, Leeds Institute of Cancer and Pathology, University of Leeds, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Seymour
authors.affiliation: Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Quirke
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D009367:Neoplasm Staging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: HER2; amplification; colorectal cancer; overexpression, copy number variation