EGFR Mutation Conferring Primary Resistance to Gefitinib in Non–Small-Cell Lung Cancer
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《新英格兰医药杂志》
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 (Figure 1A). A C-to-T mutation was identified at nucleotide 2369 of exon 20, resulting in T790M (Figure 1B). The mutations were detected in both sense and antisense sequences of two independent polymerase chain reactions and were confirmed by subcloning.
Figure 1. Sequencing Chromatograms with EGFR Mutations in the Tumor-Biopsy Specimen at Diagnosis of Lung Adenocarcinoma.
In Panel A, sequencing of exon 21 shows a T-to-G (antisense, A-to-C) base-pair 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.
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 T790M mutation was shown to confer resistance to gefitinib after it was introduced into the sequence of the wild-type EGFR and L858R mutant EGFR in vitro.2,3 The T790M mutation results in steric hindrance of binding of gefitinib to the ATP-kinase–binding pocket. The T790M mutation may cause acquired resistance to gefitinib.2,3 Our patient had concomitant T790M and L858R EGFR mutations in the original lung-biopsy specimen and showed primary resistance to gefitinib — a finding implying that a mutation in the T790M kinase domain can occur during the natural evolution of lung cancer. T790M mutant gefitinib-resistant clones may preexist at levels below the threshold of detection5 in some patients with lung cancer at presentation and then may expand selectively under gefitinib treatment, leading to the failure of gefitinib therapy.
Jin-Yuan Shih, M.D., Ph.D.
Chien-Hung Gow, M.D.
Pan-Chyr Yang, M.D., Ph.D.
National Taiwan University Hospital
Taipei 100, Taiwan
pcyang@ha.mc.ntu.edu.tw
References
Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-2139.
Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786-792.
Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73-e73.
Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004;305:1163-1167.
Marchetti A, Martella C, Felicioni L, et al. EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol 2005;23:857-865.
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 (Figure 1A). A C-to-T mutation was identified at nucleotide 2369 of exon 20, resulting in T790M (Figure 1B). The mutations were detected in both sense and antisense sequences of two independent polymerase chain reactions and were confirmed by subcloning.
Figure 1. Sequencing Chromatograms with EGFR Mutations in the Tumor-Biopsy Specimen at Diagnosis of Lung Adenocarcinoma.
In Panel A, sequencing of exon 21 shows a T-to-G (antisense, A-to-C) base-pair 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.
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 T790M mutation was shown to confer resistance to gefitinib after it was introduced into the sequence of the wild-type EGFR and L858R mutant EGFR in vitro.2,3 The T790M mutation results in steric hindrance of binding of gefitinib to the ATP-kinase–binding pocket. The T790M mutation may cause acquired resistance to gefitinib.2,3 Our patient had concomitant T790M and L858R EGFR mutations in the original lung-biopsy specimen and showed primary resistance to gefitinib — a finding implying that a mutation in the T790M kinase domain can occur during the natural evolution of lung cancer. T790M mutant gefitinib-resistant clones may preexist at levels below the threshold of detection5 in some patients with lung cancer at presentation and then may expand selectively under gefitinib treatment, leading to the failure of gefitinib therapy.
Jin-Yuan Shih, M.D., Ph.D.
Chien-Hung Gow, M.D.
Pan-Chyr Yang, M.D., Ph.D.
National Taiwan University Hospital
Taipei 100, Taiwan
pcyang@ha.mc.ntu.edu.tw
References
Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-2139.
Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786-792.
Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73-e73.
Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004;305:1163-1167.
Marchetti A, Martella C, Felicioni L, et al. EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol 2005;23:857-865.