Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer

Russell D. Petty (Lead / Corresponding author), 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 J. Falk, Sean Elyan, Angel Garcia-Alonso, David Walter Fyfe, Jonathan Wadsley, Ian ChauDavid R. 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 in-situ 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 F I 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

    Fingerprint

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

    Cite this

    Petty, R. D., Dahle-Smith, A., Stevenson, D. A. J., Osborne, A., Massie, D., Clark, C., ... Miedzybrodzka, Z. (2017). Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer. Journal of Clinical Oncology, 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 J. ; Elyan, Sean ; Garcia-Alonso, Angel ; Fyfe, David Walter ; Wadsley, Jonathan ; Chau, Ian ; Ferry, David R. ; 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.
    @article{6e643ccee099496a81d8290fb8b0862a,
    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 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 in-situ 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 F I 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 Falk, {Stephen J.} and Sean Elyan and Angel Garcia-Alonso and Fyfe, {David Walter} and Jonathan Wadsley and Ian Chau and Ferry, {David R.} and Zosia Miedzybrodzka",
    note = "This work was funded by the Scottish Government, Chief Scientists Office (grant number ETM/116) and also Grampian Gastro-esophageal Cancer Research Fund.",
    year = "2017",
    month = "7",
    doi = "10.1200/JCO.2016.70.3934",
    language = "English",
    volume = "35",
    pages = "2279--2287",
    journal = "Journal of Clinical Oncology",
    issn = "0732-183X",
    publisher = "American Society of Clinical Oncology",
    number = "20",

    }

    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, SJ, Elyan, S, Garcia-Alonso, A, Fyfe, DW, Wadsley, J, Chau, I, Ferry, DR & 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

    Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer. / Petty, Russell D. (Lead / Corresponding author); 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 J.; Elyan, Sean; Garcia-Alonso, Angel; Fyfe, David Walter; Wadsley, Jonathan; Chau, Ian; Ferry, David R.; Miedzybrodzka, Zosia.

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

    Research output: Contribution to journalArticle

    TY - JOUR

    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 J.

    AU - Elyan, Sean

    AU - Garcia-Alonso, Angel

    AU - Fyfe, David Walter

    AU - Wadsley, Jonathan

    AU - Chau, Ian

    AU - Ferry, David R.

    AU - Miedzybrodzka, Zosia

    N1 - This work was funded by the Scottish Government, Chief Scientists Office (grant number ETM/116) and also Grampian Gastro-esophageal Cancer Research Fund.

    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 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 in-situ 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 F I 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 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 in-situ 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 F I 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 -