Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer

• Published in: Journal of clinical oncology Vol. 35; no. 20; pp. 2279 - 2287
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States 10.07.2017
• Subjects: Aged; Antineoplastic Agents - therapeutic use; Biomarkers, Tumor - genetics; Class I Phosphatidylinositol 3-Kinases; Clinical Trials, Phase III as Topic; DNA Mutational Analysis; ErbB Receptors - genetics; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - genetics; Female; Gefitinib; Gene Amplification; Gene Dosage; Genes, erbB-1; Humans; In Situ Hybridization, Fluorescence; Male; Middle Aged; Mutation; Phosphatidylinositol 3-Kinases - genetics; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins p21(ras) - genetics; Quinazolines - therapeutic use; Randomized Controlled Trials as Topic; Response Evaluation Criteria in Solid Tumors; Signal Transduction - genetics; Single-Blind Method; Survival Rate
• ISSN: 0732-183X; 1527-7755; 1527-7755
• DOI: 10.1200/JCO.2016.70.3934

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.