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Purpose The Cancer Esophagus Gefitinib trial demonstrated improved progression-free survival with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib relative to placebo in patients with advanced esophageal cancer who had disease progression after chemotherapy. Rapid and durable responses were observed in a minority of patients. We hypothesized that genetic aberration of the EGFR pathway would identify patients benefitting from gefitinib. Methods A prespecified, blinded molecular analysis of Cancer Esophagus Gefitinib trial tumors was conducted to compare efficacy of gefitinib with that of placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF, and PIK3CA mutation status. EGFR CNG was determined by fluorescent in situ hybridization (FISH) using prespecified criteria and EGFR FISH-positive status was defined as high polysomy or amplification. Results Biomarker data were available for 340 patients. In EGFR FISH-positive tumors (20.2%), overall survival was improved with gefitinib compared with placebo (hazard ratio [HR] for death, 0.59; 95% CI, 0.35 to 1.00; P = .05). In EGFR FISH-negative tumors, there was no difference in overall survival with gefitinib compared with placebo (HR for death, 0.90; 95% CI, 0.69 to 1.18; P = .46). Patients with EGFR amplification (7.2%) gained greatest benefit from gefitinib (HR for death, 0.21; 95% CI, 0.07 to 0.64; P = .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 patients with esophageal cancer who may benefit from gefitinib as a second-line treatment. Results of this study suggest that anti-EGFR therapies should be investigated in prospective clinical trials in different settings in EGFR FISH-positive and, in particular, EGFR-amplified esophageal cancer.

Original publication




Journal article


Journal of clinical oncology : official journal of the American Society of Clinical Oncology

Publication Date





2279 - 2287


Russell D. Petty, University of Dundee; Asa Dahle-Smith, Ninewells Hospital and Medical School, Dundee; David A.J. Stevenson, Aileen Osborne, Doreen Massie, Caroline Clark, Zosia Miedzybrodzka, and Graeme I. Murray, University of Aberdeen, Aberdeen; Susan J. Dutton and Corran Roberts, Centre for Statistics in Medicine, University of Oxford, Oxford; Mark Harrison, Mount Vernon Hospital, Northwood; Irene Y. Chong and Ian Chau, Royal Marsden Hospital, London and Surrey; Wasat Mansoor, Christie Hospital, Manchester; Joyce Thompson, Birmingham Heartland Hospital, Heart of England National Health Service Trust, Birmingham; Anirban Chatterjee, Royal Shrewsbury Hospital, Shrewsbury; Stephen J. Falk, Bristol Oncology Centre, Bristol; Sean Elyan, Cheltenham General Hospital, Cheltenham; Angel Garcia-Alonso, Clan Clwyd Hospital, Rhyl; David Walter Fyfe, Furness General Hospital, Furness; Jonathan Wadsley, Weston Park Hospital, Sheffield, United Kingdom; and David R. Ferry, Eli Lilly and Company, Bridgewater, NJ.


Humans, Esophageal Neoplasms, Quinazolines, Proto-Oncogene Proteins B-raf, Receptor, Epidermal Growth Factor, Antineoplastic Agents, In Situ Hybridization, Fluorescence, Survival Rate, Single-Blind Method, DNA Mutational Analysis, Signal Transduction, Gene Amplification, Gene Dosage, Mutation, Genes, erbB-1, Aged, Middle Aged, Female, Male, Proto-Oncogene Proteins p21(ras), Randomized Controlled Trials as Topic, Clinical Trials, Phase III as Topic, Phosphatidylinositol 3-Kinases, Class I Phosphatidylinositol 3-Kinases, Response Evaluation Criteria in Solid Tumors, Biomarkers, Tumor