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Clinical Cancer Research Vol. 11, 5878-5885, August 15, 2005
© 2005 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

Activating Mutations in the Tyrosine Kinase Domain of the Epidermal Growth Factor Receptor Are Associated with Improved Survival in Gefitinib-Treated Chemorefractory Lung Adenocarcinomas

Miguel Taron1, Yukito Ichinose3, Rafael Rosell1, Tony Mok5, Bartomeu Massuti7, Lurdes Zamora1, Jose Luis Mate2, Christian Manegold8, Mayumi Ono4, Cristina Queralt1, Thierry Jahan9, Jose Javier Sanchez10, Maria Sanchez-Ronco10, Victor Hsue6, David Jablons9, Jose Miguel Sanchez1 and Teresa Moran1

Authors' Affiliations: 1 Catalan Institute of Oncology, 2 Pathology Department, Hospital Germans Trias i Pujol, Badalona, Spain; 3 National Kyushu Cancer Center, 4 Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 5 Prince of Wales Hospital, 6 St. Teresa Hospital Cancer Centre, Hong Kong, China; 7 Hospital General de Alicante, Alicante, Spain; 8 Heidelberg University Medical Center, Mannheim, Mannheim, Germany; 9 Comprehensive Cancer Center, University of California, San Francisco, California; and 10 Autonomous University of Madrid, Madrid, Spain

Requests for reprints: Rafael Rosell, Medical Oncology Service, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Ctra Canyet, s/n 08916 Barcelona, Spain. Phone: 34-93-497-8925; Fax: 34-93-497-8950; E-mail: rrosell{at}ns.hugtip.scs.es.

Purpose: Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) confer a strong sensitivity to gefitinib, a selective tyrosine kinase inhibitor of EGFR.

Experimental Design: We examined EGFR mutations at exons 18, 19, and 21 in tumor tissue from 68 gefitinib-treated, chemorefractory, advanced non–small cell lung cancer patients from the United States, Europe, and Asia and in a highly gefitinib-sensitive non–small cell lung cancer cell line and correlated their presence with response and survival. In addition, in a subgroup of 28 patients for whom the remaining tumor tissue was available, we examined the relationship among EGFR mutations, CA repeats in intron 1 of EGFR, EGFR and caveolin-1 mRNA levels, and increased EGFR gene copy numbers.

Results: Seventeen patients had EGFR mutations, all of which were in lung adenocarcinomas. Radiographic response was observed in 16 of 17 (94.1%) patients harboring EGFR mutations, in contrast with 6 of 51 (12.6%) with wild-type EGFR (P < 0.0001). Probability of response increased significantly in never smokers, patients receiving a greater number of prior chemotherapy regimens, Asians, and younger patients. Median survival was not reached for patients with EGFR mutations and was 9.9 months for those with wild-type EGFR (P = 0.001). EGFR mutations tended to be associated with increased numbers of CA repeats and increased EGFR gene copy numbers but not with EGFR and caveolin-1 mRNA overexpression (P = not significant).

Conclusions: The presence of EGFR mutations is a major determinant of gefitinib response, and targeting EGFR should be considered in preference to chemotherapy as first-line treatment in lung adenocarcinomas that have demonstrable EGFR mutations.




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