Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer

Russell D Petty, Asa Dahle-Smith, David A J Stevenson, Aileen Osborne, Doreen Massie, Caroline Clark, Graeme I Murray, Susan J Dutton, Corran Roberts, Irene Y Chong, Wasat Mansoor, Joyce Thompson, Mark Harrison, Anirban Chatterjee, Stephen Falk, Seanmp Elyan, Angel Garcia-Alonso, David Walter Fyfe, Jonathan Wadsley, Ian ChauDavid Ferry, Zosia Miedzybrodzka

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Abstract

Purpose: The cancer esophagus gefitinib (COG) trial demonstrated improved progression free survival with the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI), gefitinib relative to placebo in advanced esophageal cancer patients with disease progression after chemotherapy. Rapid and durable responses were observed in a minority. We hypothesised that
genetic aberration of the EGFR pathway would identify patients benefitting from gefitinib.

Patients and Methods: A pre-specified blinded molecular analysis of COG trial tumours was conducted to compare efficacy of gefitinib to placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF and PIK3CA mutation status. EGFR CNG was determined by fluorescent insitu hybridisation (FISH) using pre-specified criteria and EGFR FISH positive defined as high polysomy or amplification.

Results: Biomarker data were available for 340 patients. In EGFR FISH positive tumours (20.2%) overall survival was improved with gefitinib compared to placebo (hazard ratio [HR] for death, 0.59; 95% confidence interval [CI], 0.35, 1.00 p=0.05). In EGFR FISH negative tumours there was no difference in overall survival with gefitinib compared to placebo (HR for death, 0.90, 95% CI 0.69,
1.18 p=0.46). EGFR amplification (7.2%) patients gained greatest benefit from gefitinib (HR for death, 0.21; 95% CI 0.07-0.64; p=0.006). There was no difference in overall survival for gefitinib versus placebo for patients with EGFR, KRAS, BRAF and PIK3CA mutations, or for any mutation versus none.

Conclusion: EGFR CNG assessed by FISH appears to identify a subgroup of esophageal cancer patients who may benefit from gefitinib as a second line treatment, and suggests that anti-EGFR therapies should be investigated in prospective clinical trials in different settings in EGFR FI SH positive, and in particular EGFR amplified, esophageal cancer.
Original languageEnglish
Pages (from-to)2279-2287
Number of pages9
JournalJournal of Clinical Oncology
Volume35
Issue number20
Early online date24 May 2017
DOIs
Publication statusPublished - Jul 2017

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erbB-1 Genes
Gene Dosage
Esophageal Neoplasms
Epidermal Growth Factor Receptor
Placebos
Confidence Intervals
gefitinib
Mutation
Survival
Neoplasms
Protein-Tyrosine Kinases

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Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer. / Petty, Russell D; Dahle-Smith, Asa; Stevenson, David A J; Osborne, Aileen; Massie, Doreen; Clark, Caroline; Murray, Graeme I; Dutton, Susan J; Roberts, Corran; Chong, Irene Y ; Mansoor, Wasat; Thompson, Joyce; Harrison, Mark; Chatterjee, Anirban; Falk, Stephen; Elyan, Seanmp; Garcia-Alonso, Angel; Fyfe, David Walter; Wadsley, Jonathan ; Chau, Ian; Ferry, David; Miedzybrodzka, Zosia.

In: Journal of Clinical Oncology, Vol. 35, No. 20, 07.2017, p. 2279-2287.

Research output: Contribution to journalArticle

Petty, RD, Dahle-Smith, A, Stevenson, DAJ, Osborne, A, Massie, D, Clark, C, Murray, GI, Dutton, SJ, Roberts, C, Chong, IY, Mansoor, W, Thompson, J, Harrison, M, Chatterjee, A, Falk, S, Elyan, S, Garcia-Alonso, A, Fyfe, DW, Wadsley, J, Chau, I, Ferry, D & Miedzybrodzka, Z 2017, 'Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer', Journal of Clinical Oncology, vol. 35, no. 20, pp. 2279-2287. https://doi.org/10.1200/JCO.2016.70.3934
Petty RD, Dahle-Smith A, Stevenson DAJ, Osborne A, Massie D, Clark C et al. Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer. Journal of Clinical Oncology. 2017 Jul;35(20):2279-2287. https://doi.org/10.1200/JCO.2016.70.3934
Petty, Russell D ; Dahle-Smith, Asa ; Stevenson, David A J ; Osborne, Aileen ; Massie, Doreen ; Clark, Caroline ; Murray, Graeme I ; Dutton, Susan J ; Roberts, Corran ; Chong, Irene Y ; Mansoor, Wasat ; Thompson, Joyce ; Harrison, Mark ; Chatterjee, Anirban ; Falk, Stephen ; Elyan, Seanmp ; Garcia-Alonso, Angel ; Fyfe, David Walter ; Wadsley, Jonathan ; Chau, Ian ; Ferry, David ; Miedzybrodzka, Zosia. / Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer. In: Journal of Clinical Oncology. 2017 ; Vol. 35, No. 20. pp. 2279-2287.
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title = "Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer",
abstract = "Purpose: The cancer esophagus gefitinib (COG) trial demonstrated improved progression free survival with the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI), gefitinib relative to placebo in advanced esophageal cancer patients with disease progression after chemotherapy. Rapid and durable responses were observed in a minority. We hypothesised thatgenetic aberration of the EGFR pathway would identify patients benefitting from gefitinib. Patients and Methods: A pre-specified blinded molecular analysis of COG trial tumours was conducted to compare efficacy of gefitinib to placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF and PIK3CA mutation status. EGFR CNG was determined by fluorescent insitu hybridisation (FISH) using pre-specified criteria and EGFR FISH positive defined as high polysomy or amplification.Results: Biomarker data were available for 340 patients. In EGFR FISH positive tumours (20.2{\%}) overall survival was improved with gefitinib compared to placebo (hazard ratio [HR] for death, 0.59; 95{\%} confidence interval [CI], 0.35, 1.00 p=0.05). In EGFR FISH negative tumours there was no difference in overall survival with gefitinib compared to placebo (HR for death, 0.90, 95{\%} CI 0.69,1.18 p=0.46). EGFR amplification (7.2{\%}) patients gained greatest benefit from gefitinib (HR for death, 0.21; 95{\%} CI 0.07-0.64; p=0.006). There was no difference in overall survival for gefitinib versus placebo for patients with EGFR, KRAS, BRAF and PIK3CA mutations, or for any mutation versus none.Conclusion: EGFR CNG assessed by FISH appears to identify a subgroup of esophageal cancer patients who may benefit from gefitinib as a second line treatment, and suggests that anti-EGFR therapies should be investigated in prospective clinical trials in different settings in EGFR FI SH positive, and in particular EGFR amplified, esophageal cancer.",
author = "Petty, {Russell D} and Asa Dahle-Smith and Stevenson, {David A J} and Aileen Osborne and Doreen Massie and Caroline Clark and Murray, {Graeme I} and Dutton, {Susan J} and Corran Roberts and Chong, {Irene Y} and Wasat Mansoor and Joyce Thompson and Mark Harrison and Anirban Chatterjee and Stephen Falk and Seanmp Elyan and Angel Garcia-Alonso and Fyfe, {David Walter} and Jonathan Wadsley and Ian Chau and David Ferry and Zosia Miedzybrodzka",
note = "We thank the NHS Grampian Biorepository for their assistance with the management of biological specimens. The TRANS-COG study principal investigators are listed in the Data Supplement. http://ascopubs.org/jco/site/misc/open-access.xhtml - Published PDF becomes open on publisher website 12 months after publication.",
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T1 - Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer

AU - Petty, Russell D

AU - Dahle-Smith, Asa

AU - Stevenson, David A J

AU - Osborne, Aileen

AU - Massie, Doreen

AU - Clark, Caroline

AU - Murray, Graeme I

AU - Dutton, Susan J

AU - Roberts, Corran

AU - Chong, Irene Y

AU - Mansoor, Wasat

AU - Thompson, Joyce

AU - Harrison, Mark

AU - Chatterjee, Anirban

AU - Falk, Stephen

AU - Elyan, Seanmp

AU - Garcia-Alonso, Angel

AU - Fyfe, David Walter

AU - Wadsley, Jonathan

AU - Chau, Ian

AU - Ferry, David

AU - Miedzybrodzka, Zosia

N1 - We thank the NHS Grampian Biorepository for their assistance with the management of biological specimens. The TRANS-COG study principal investigators are listed in the Data Supplement. http://ascopubs.org/jco/site/misc/open-access.xhtml - Published PDF becomes open on publisher website 12 months after publication.

PY - 2017/7

Y1 - 2017/7

N2 - Purpose: The cancer esophagus gefitinib (COG) trial demonstrated improved progression free survival with the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI), gefitinib relative to placebo in advanced esophageal cancer patients with disease progression after chemotherapy. Rapid and durable responses were observed in a minority. We hypothesised thatgenetic aberration of the EGFR pathway would identify patients benefitting from gefitinib. Patients and Methods: A pre-specified blinded molecular analysis of COG trial tumours was conducted to compare efficacy of gefitinib to placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF and PIK3CA mutation status. EGFR CNG was determined by fluorescent insitu hybridisation (FISH) using pre-specified criteria and EGFR FISH positive defined as high polysomy or amplification.Results: Biomarker data were available for 340 patients. In EGFR FISH positive tumours (20.2%) overall survival was improved with gefitinib compared to placebo (hazard ratio [HR] for death, 0.59; 95% confidence interval [CI], 0.35, 1.00 p=0.05). In EGFR FISH negative tumours there was no difference in overall survival with gefitinib compared to placebo (HR for death, 0.90, 95% CI 0.69,1.18 p=0.46). EGFR amplification (7.2%) patients gained greatest benefit from gefitinib (HR for death, 0.21; 95% CI 0.07-0.64; p=0.006). There was no difference in overall survival for gefitinib versus placebo for patients with EGFR, KRAS, BRAF and PIK3CA mutations, or for any mutation versus none.Conclusion: EGFR CNG assessed by FISH appears to identify a subgroup of esophageal cancer patients who may benefit from gefitinib as a second line treatment, and suggests that anti-EGFR therapies should be investigated in prospective clinical trials in different settings in EGFR FI SH positive, and in particular EGFR amplified, esophageal cancer.

AB - Purpose: The cancer esophagus gefitinib (COG) trial demonstrated improved progression free survival with the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI), gefitinib relative to placebo in advanced esophageal cancer patients with disease progression after chemotherapy. Rapid and durable responses were observed in a minority. We hypothesised thatgenetic aberration of the EGFR pathway would identify patients benefitting from gefitinib. Patients and Methods: A pre-specified blinded molecular analysis of COG trial tumours was conducted to compare efficacy of gefitinib to placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF and PIK3CA mutation status. EGFR CNG was determined by fluorescent insitu hybridisation (FISH) using pre-specified criteria and EGFR FISH positive defined as high polysomy or amplification.Results: Biomarker data were available for 340 patients. In EGFR FISH positive tumours (20.2%) overall survival was improved with gefitinib compared to placebo (hazard ratio [HR] for death, 0.59; 95% confidence interval [CI], 0.35, 1.00 p=0.05). In EGFR FISH negative tumours there was no difference in overall survival with gefitinib compared to placebo (HR for death, 0.90, 95% CI 0.69,1.18 p=0.46). EGFR amplification (7.2%) patients gained greatest benefit from gefitinib (HR for death, 0.21; 95% CI 0.07-0.64; p=0.006). There was no difference in overall survival for gefitinib versus placebo for patients with EGFR, KRAS, BRAF and PIK3CA mutations, or for any mutation versus none.Conclusion: EGFR CNG assessed by FISH appears to identify a subgroup of esophageal cancer patients who may benefit from gefitinib as a second line treatment, and suggests that anti-EGFR therapies should be investigated in prospective clinical trials in different settings in EGFR FI SH positive, and in particular EGFR amplified, esophageal cancer.

U2 - 10.1200/JCO.2016.70.3934

DO - 10.1200/JCO.2016.70.3934

M3 - Article

C2 - 28537764

VL - 35

SP - 2279

EP - 2287

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 20

ER -