Epidermal Growth Factor (EGFR) copy number aberrations in esophageal and gastro-esophageal junctional carcinoma

Asa Dahle-Smith, David Stevenson, Doreen Massie, Graeme I Murray, Susan J Dutton, Corran Roberts, David Ferry, Aileen Osborne, Caroline Clark, Russell D Petty, Zofia Miedzybrodzka

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Abstract

Background
Clinical trials of agents targeting epidermal growth factor receptor (EGFR) in esophageal carcinoma (EC) have indicated a minority subgroup responsive to anti-EGFR therapies. Other investigations suggest increases in EGFR copy number are associated with poor prognosis in EC, but have used a variety of different techniques and tested numbers remain small. A validated assay for EGFR copy number in EC is needed, to allow investigation of EGFR copy number gain as a predictive biomarker for the anti-EGFR responsive subgroup of patients. We developed a scoring system in EC based upon established systems for EGFR fluorescence in-situ hybridisation (FISH) in lung cancer, and applied this in a series of 160 UK patients with advanced EC.

Results
Dual colour FISH on formalin fixed paraffin embedded (FFPE) biopsies were scored independently by two operators as: disomy (score = 1), low trisomy (score = 2), high trisomy (score = 3), low polysomy (score = 4), high polysomy (score = 5) and amplification (score = 6). EGFR FISH positive cases (scores 5 and 6) were found in 32/160 (20 %) tumours, with high polysomy in 22 (13.8 %) and amplification in 10 (6.3 %). Two independent operator scores for FISH positivity were 100 % concordant. EGFR FISH positive status was not associated with clinic-pathological features. EGFR amplification was associated with worse survival (HR = 2.64, 95 % CI 1.04 to 6.71, p = 0.03).

Conclusion
Our FISH scoring system for EGFR in advanced EC identifies a significant subgroup (20.0 %) of FISH positive patients. EGFR amplification, which is found in 6.3 %, is associated with poor survival. It is not known if there is a role for EGFR targeted treatment in this subgroup of patients, however we are now utilising this EGFR FISH assay and scoring system in biopsies from clinical trials utilising anti-EGFR targeted therapies.
Original languageEnglish
Article number78
JournalMolecular Cytogenetics
Volume8
DOIs
Publication statusPublished - 17 Oct 2015

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Aberrations
Epidermal Growth Factor
Carcinoma
Fluorescence In Situ Hybridization
Fluorescence
Amplification
Biopsy
Trisomy
Assays
Survival
Biomarkers
Epidermal Growth Factor Receptor
Paraffin
Formaldehyde
Tumors
Lung Neoplasms
Therapeutics
Color
Clinical Trials

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Epidermal Growth Factor (EGFR) copy number aberrations in esophageal and gastro-esophageal junctional carcinoma. / Dahle-Smith, Asa; Stevenson, David; Massie, Doreen; Murray, Graeme I; Dutton, Susan J; Roberts, Corran; Ferry, David; Osborne, Aileen; Clark, Caroline; Petty, Russell D; Miedzybrodzka, Zofia.

In: Molecular Cytogenetics , Vol. 8, 78, 17.10.2015.

Research output: Contribution to journalArticle

Dahle-Smith, Asa ; Stevenson, David ; Massie, Doreen ; Murray, Graeme I ; Dutton, Susan J ; Roberts, Corran ; Ferry, David ; Osborne, Aileen ; Clark, Caroline ; Petty, Russell D ; Miedzybrodzka, Zofia. / Epidermal Growth Factor (EGFR) copy number aberrations in esophageal and gastro-esophageal junctional carcinoma. In: Molecular Cytogenetics . 2015 ; Vol. 8.
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title = "Epidermal Growth Factor (EGFR) copy number aberrations in esophageal and gastro-esophageal junctional carcinoma",
abstract = "BackgroundClinical trials of agents targeting epidermal growth factor receptor (EGFR) in esophageal carcinoma (EC) have indicated a minority subgroup responsive to anti-EGFR therapies. Other investigations suggest increases in EGFR copy number are associated with poor prognosis in EC, but have used a variety of different techniques and tested numbers remain small. A validated assay for EGFR copy number in EC is needed, to allow investigation of EGFR copy number gain as a predictive biomarker for the anti-EGFR responsive subgroup of patients. We developed a scoring system in EC based upon established systems for EGFR fluorescence in-situ hybridisation (FISH) in lung cancer, and applied this in a series of 160 UK patients with advanced EC.ResultsDual colour FISH on formalin fixed paraffin embedded (FFPE) biopsies were scored independently by two operators as: disomy (score = 1), low trisomy (score = 2), high trisomy (score = 3), low polysomy (score = 4), high polysomy (score = 5) and amplification (score = 6). EGFR FISH positive cases (scores 5 and 6) were found in 32/160 (20 {\%}) tumours, with high polysomy in 22 (13.8 {\%}) and amplification in 10 (6.3 {\%}). Two independent operator scores for FISH positivity were 100 {\%} concordant. EGFR FISH positive status was not associated with clinic-pathological features. EGFR amplification was associated with worse survival (HR = 2.64, 95 {\%} CI 1.04 to 6.71, p = 0.03).ConclusionOur FISH scoring system for EGFR in advanced EC identifies a significant subgroup (20.0 {\%}) of FISH positive patients. EGFR amplification, which is found in 6.3 {\%}, is associated with poor survival. It is not known if there is a role for EGFR targeted treatment in this subgroup of patients, however we are now utilising this EGFR FISH assay and scoring system in biopsies from clinical trials utilising anti-EGFR targeted therapies.",
author = "Asa Dahle-Smith and David Stevenson and Doreen Massie and Murray, {Graeme I} and Dutton, {Susan J} and Corran Roberts and David Ferry and Aileen Osborne and Caroline Clark and Petty, {Russell D} and Zofia Miedzybrodzka",
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TY - JOUR

T1 - Epidermal Growth Factor (EGFR) copy number aberrations in esophageal and gastro-esophageal junctional carcinoma

AU - Dahle-Smith, Asa

AU - Stevenson, David

AU - Massie, Doreen

AU - Murray, Graeme I

AU - Dutton, Susan J

AU - Roberts, Corran

AU - Ferry, David

AU - Osborne, Aileen

AU - Clark, Caroline

AU - Petty, Russell D

AU - Miedzybrodzka, Zofia

N1 - Acknowledgements: We thank the NHS Grampian Biorepository (Aberdeen Royal, Infirmary, Aberdeen, UK) for their assistance in sample storage and preparation.

PY - 2015/10/17

Y1 - 2015/10/17

N2 - BackgroundClinical trials of agents targeting epidermal growth factor receptor (EGFR) in esophageal carcinoma (EC) have indicated a minority subgroup responsive to anti-EGFR therapies. Other investigations suggest increases in EGFR copy number are associated with poor prognosis in EC, but have used a variety of different techniques and tested numbers remain small. A validated assay for EGFR copy number in EC is needed, to allow investigation of EGFR copy number gain as a predictive biomarker for the anti-EGFR responsive subgroup of patients. We developed a scoring system in EC based upon established systems for EGFR fluorescence in-situ hybridisation (FISH) in lung cancer, and applied this in a series of 160 UK patients with advanced EC.ResultsDual colour FISH on formalin fixed paraffin embedded (FFPE) biopsies were scored independently by two operators as: disomy (score = 1), low trisomy (score = 2), high trisomy (score = 3), low polysomy (score = 4), high polysomy (score = 5) and amplification (score = 6). EGFR FISH positive cases (scores 5 and 6) were found in 32/160 (20 %) tumours, with high polysomy in 22 (13.8 %) and amplification in 10 (6.3 %). Two independent operator scores for FISH positivity were 100 % concordant. EGFR FISH positive status was not associated with clinic-pathological features. EGFR amplification was associated with worse survival (HR = 2.64, 95 % CI 1.04 to 6.71, p = 0.03).ConclusionOur FISH scoring system for EGFR in advanced EC identifies a significant subgroup (20.0 %) of FISH positive patients. EGFR amplification, which is found in 6.3 %, is associated with poor survival. It is not known if there is a role for EGFR targeted treatment in this subgroup of patients, however we are now utilising this EGFR FISH assay and scoring system in biopsies from clinical trials utilising anti-EGFR targeted therapies.

AB - BackgroundClinical trials of agents targeting epidermal growth factor receptor (EGFR) in esophageal carcinoma (EC) have indicated a minority subgroup responsive to anti-EGFR therapies. Other investigations suggest increases in EGFR copy number are associated with poor prognosis in EC, but have used a variety of different techniques and tested numbers remain small. A validated assay for EGFR copy number in EC is needed, to allow investigation of EGFR copy number gain as a predictive biomarker for the anti-EGFR responsive subgroup of patients. We developed a scoring system in EC based upon established systems for EGFR fluorescence in-situ hybridisation (FISH) in lung cancer, and applied this in a series of 160 UK patients with advanced EC.ResultsDual colour FISH on formalin fixed paraffin embedded (FFPE) biopsies were scored independently by two operators as: disomy (score = 1), low trisomy (score = 2), high trisomy (score = 3), low polysomy (score = 4), high polysomy (score = 5) and amplification (score = 6). EGFR FISH positive cases (scores 5 and 6) were found in 32/160 (20 %) tumours, with high polysomy in 22 (13.8 %) and amplification in 10 (6.3 %). Two independent operator scores for FISH positivity were 100 % concordant. EGFR FISH positive status was not associated with clinic-pathological features. EGFR amplification was associated with worse survival (HR = 2.64, 95 % CI 1.04 to 6.71, p = 0.03).ConclusionOur FISH scoring system for EGFR in advanced EC identifies a significant subgroup (20.0 %) of FISH positive patients. EGFR amplification, which is found in 6.3 %, is associated with poor survival. It is not known if there is a role for EGFR targeted treatment in this subgroup of patients, however we are now utilising this EGFR FISH assay and scoring system in biopsies from clinical trials utilising anti-EGFR targeted therapies.

U2 - 10.1186/s13039-015-0181-0

DO - 10.1186/s13039-015-0181-0

M3 - Article

VL - 8

JO - Molecular Cytogenetics

JF - Molecular Cytogenetics

SN - 1755-8166

M1 - 78

ER -