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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    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
    Issue number20
    Early online date24 May 2017
    Publication statusPublished - Jul 2017


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