EGFR mutation conferring primary resistance to gefitinib in non-small-cell lung cancer.

to the editor: Patients with lung cancer who respond to gefitinib have been reported to have somatic mutations consisting of deletions in exon 19 and the L858R mutation in exon 21 of the epidermal growth factor receptor ( EGFR ) gene. 1 In addition, a second mutation (T790M) in exon 20 is also associated with acquired resistance to gefitinib in initially gefitinib-sensitive patients. 2,3 We describe a patient with gefitinib-resistant lung adenocarcinoma harboring both T790M and L858R at diagnosis. A 55-year-old woman who had never smoked presented with blurred vision and slurred speech. Magnetic resonance imaging of the brain disclosed a rim-enhanced mass in the left parietal–occipital area. Computed tomography of the chest showed a mass in the right upper lung with enlarged lymph nodes in the lower neck and mediastinum. Percutaneous transthoracic biopsy guided by ultrasonography revealed lung adenocarcinoma. Gefitinib was started at a dose of 250 mg per day. The patient also underwent whole-brain radiotherapy and stereotactic radiosurgery for control of the brain tumor. One month later, the size of the lung tumor was unchanged, but at nine weeks, chest radiography revealed progression of disease. Gefitinib was stopped, and treatment was changed to chemotherapy with gemcitabine and cisplatin. Screening for mutations of the kinase domain (exons 18 through 21) of EGFR by direct sequencing of DNA isolated from a lung-tumor–biopsy specimen and blood lymphocytes identified a T-to-G mutation at nucleotide 2573 of exon 21, resulting in L858R (Fig. 1A). A C-to-T mutation was identified at nucleotide 2369 of exon 20, resulting in T790M (Fig. 1B). The mutations were detected in both sense and antisense sequences of two independent polymerase chain reactions and were confirmed by subcloning. Lung cancers harboring the EGFR L858R mutation have been reported to be responsive to gefitinib. 1 The studies of cells expressing L858R revealed increased gefitinib sensitivity in vitro. 4 The Figure 1. Sequencing Chromatograms with EGFR Mutations in the TumorBiopsy Specimen at Diagnosis of Lung Adenocarcinoma. In Panel A, sequencing of exon 21 shows a T-to-G (antisense, A-to-C) basepair change (arrows), resulting in a substitution of arginine for leucine at position 858 (L858R) in the tumor, as compared with corresponding lymphocytes. In Panel B, sequencing of exon 20 demonstrates a C-to-T (antisense, G-to-A) base-pair change (arrows), which leads to the substitution of methionine for threonine at position 790 (T790M). The ratio of mutant to wild-type peaks is approximately 1:1; therefore, the nucleotide sequence is read as N. Lymphocyte DNA Sense Antisense