Mutations in the tyrosine kinase domain of the EGFR gene associated with gefitinib response in non-small-cell lung cancer.
The potential relevance of epidermal growth factor receptor (EGFR) mutations to non-small-cell lung cancer treatment has recently been identified. We have examined the presence of EGFR mutations in Japanese and Spanish gefitinib-treated non-small-cell lung cancer patients. A total of 34 gefitinib-treated patients were screened, 18 from Japan and 16 from Spain. Laser capture microdissection was performed for the accurate procurement of tumor cells. EGFR exons 18, 19 and 21 were amplified from genomic DNA by means of PCR, and the samples were then subjected to bi-directional automatic sequencing. EGFR somatic mutations in the tyrosine kinase domain were found in 8 of 34 patients (23.5%). Gefitinib response was observed in 7 of 8 patients (87.5%) with EGFR mutations and in 3 of 24 (12.5%) with wild-type EGFR (P=0.0003). Five deletion mutations were clustered in the region spanning codons 746 to 750 (ELREA) within exon 19. Three additional tumors had amino acid substitutions within exon 18, at codons 718 and 719. Logistic regression analysis showed that response was primarily linked to the presence of EGFR mutations and secondarily linked to female gender, non-smoker status and a greater number of prior chemotherapy regimens. The presence of EGFR mutations is a major determinant of gefitinib response, and EGFR tyrosine kinase inhibitors should be tested in clinical trials of first-line treatment of lung adenocarcinomas harboring EGFR mutations.
Rosell
Rafael
R
Medical Oncology Service, Institut Catala d'Oncologia, Hospital Germans Trias i Pujol, Ctra Canyet, s/n, 08916 Badalona (Barcelona), Spain. rrosell@ns.hugtip.scs.es
Ichinose
Yukito
Y
Taron
Miquel
M
Sarries
Carme
C
Queralt
Cristina
C
Mendez
Pedro
P
Sanchez
Jose Miguel
JM
Nishiyama
Ken-Ichi
K
Moran
Teresa
T
Cirauqui
Beatriz
B
Mate
Jose Luis
JL
Besse
Benjamin
B
Reguart
Noemi
N
Perez
Maria
M
Sanchez
Jose Javier
JJ
D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology*; D012044:Regression Analysis; D012737:Sex Factors; D012907:Smoking; D016019:Survival Analysis; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib