Correspondence
EGFR Mutation Conferring Primary Resistance to Gefitinib in Non–Small-Cell Lung Cancer
N Engl J Med 2005; 353:207-208July 14, 2005
- Article
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 1AFigure 1
Sequencing Chromatograms with EGFR Mutations in the Tumor-Biopsy Specimen at Diagnosis of Lung Adenocarcinoma.). 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.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.
5 ReferencesJin-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 1
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
Full Text | Web of Science | Medline2
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
Full Text | Web of Science | Medline3
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
CrossRef | Web of Science | Medline4
Sordella R ,Bell DW ,Haber DA ,Settleman J . Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004;305:1163-1167
CrossRef | Web of Science | Medline5
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
CrossRef | Web of Science | Medline
- Citing Articles (27)
Citing Articles
1
Liang Cheng, Riley E Alexander, Gregory T MacLennan, Oscar W Cummings, Rodolfo Montironi, Antonio Lopez-Beltran, Harvey M Cramer, Darrell D Davidson, Shaobo Zhang. (2012) Molecular pathology of lung cancer: key to personalized medicine. Modern Pathology
CrossRef2
Jing Wen, Jianhua Fu, Wei Zhang, Ming Guo. (2011) Genetic and epigenetic changes in lung carcinoma and their clinical implications. Modern Pathology 24:7, 932-943
CrossRef3
Monica Arnedos, Fabrice Andre. (2011) Tumor genotyping for breast cancer: at the front door. Personalized Medicine 8:4, 383-385
CrossRef4
Shahreen Billah, John Stewart, Gregg Staerkel, Su Chen, Yun Gong, Ming Guo. (2011) EGFR and KRAS mutations in lung carcinoma. Cancer Cytopathology 119:2, 111-117
CrossRef5
Liang Cheng, Shaobo Zhang, Riley Alexander, Yongxue Yao, Gregory T MacLennan, Chong-xian Pan, Jiaoti Huang, Mingsheng Wang, Rodolfo Montironi, Antonio Lopez-Beltran. (2011) The landscape of EGFR pathways and personalized management of non-small-cell lung cancer. Future Oncology 7:4, 519-541
CrossRef6
Wendy A Cooper, Sandra OʼToole, Michael Boyer, Lisa Horvath, Annabelle Mahar. (2011) Whatʼs new in non-small cell lung cancer for pathologists: the importance of accurate subtyping, EGFR mutations and ALK rearrangements. Pathology 43:2, 103-115
CrossRef7
Samuel P. Hammar, Sanja Dacic. 2011. Immunohistology of Lung and Pleural Neoplasms. , 369-463.
CrossRef8
Deric L. Wheeler, Emily F. Dunn, Paul M. Harari. (2010) Understanding resistance to EGFR inhibitors—impact on future treatment strategies. Nature Reviews Clinical Oncology 7:9, 493-507
CrossRef9
Lynette M. Sholl, Neal I. Lindeman. (2010) Molecular Diagnostics Testing for Lung Adenocarcinoma. Pathology Case Reviews 15:4, 103-110
CrossRef10
Ulrich Keller, Nikolas Von Bubnoff, Christian Peschel, Justus Duyster. (2010) Oncologist’s/haematologist’s view on the roles of pathologists for molecular targeted cancer therapy. Journal of Cellular and Molecular Medicine 14:4, 805-817
CrossRef11
Nikhil G Thaker, Ian F Pollack. (2009) Molecularly targeted therapies for malignant glioma: rationale for combinatorial strategies. Expert Review of Neurotherapeutics 9:12, 1815-1836
CrossRef12
Hua-Jun Chen, Tony S. Mok, Zhi-Hong Chen, Ai-Lin Guo, Xu-Chao Zhang, Jian Su, Yi-Long Wu. (2009) Clinicopathologic and Molecular Features of Epidermal Growth Factor Receptor T790M Mutation and c-MET Amplification in Tyrosine Kinase Inhibitor-resistant Chinese Non-small Cell Lung Cancer. Pathology & Oncology Research 15:4, 651-658
CrossRef13
H A Burris. (2009) Shortcomings of current therapies for non-small-cell lung cancer: unmet medical needs. Oncogene 28, S4-S13
CrossRef14
Sreenath V. Sharma, Jeffrey Settleman. (2009) ErbBs in lung cancer. Experimental Cell Research 315:4, 557-571
CrossRef15
Chun-Chieh Wu, Hui-Yu Hsu, Hui-Ping Liu, John Wen-Cheng Chang, Ya-Ting Chen, Wen-Yu Hsieh, Jia-Juan Hsieh, Meng-Shu Hsieh, Yi-Rong Chen, Shiu-Feng Huang. (2008) Reversed mutation rates of KRAS and EGFR genes in adenocarcinoma of the lung in Taiwan and their implications. Cancer 113:11, 3199-3208
CrossRef16
Sanja Dacic. (2008) EGFR Assays in Lung Cancer. Advances in Anatomic Pathology 15:4, 241-247
CrossRef17
Chih-Hsin Yang. (2008) EGFR tyrosine kinase inhibitors for the treatment of NSCLC in East Asia: present and future. Lung Cancer 60, S23-S30
CrossRef18
Thomas E. Stinchcombe, David E. Morris, Carrie B. Lee, Dominic T. Moore, D Neil Hayes, Jan S. Halle, M Patricia Rivera, Julian G. Rosenman, Mark A. Socinski. (2008) Induction Chemotherapy with Carboplatin, Irinotecan, and Paclitaxel Followed by High Dose Three-Dimension Conformal Thoracic Radiotherapy (74 Gy) with Concurrent Carboplatin, Paclitaxel, and Gefitinib in Unresectable Stage IIIA and Stage IIIB Non-small Cell Lung Cancer. Journal of Thoracic Oncology 3:3, 250-257
CrossRef19
Tae-You Kim, Sae-Won Han, Yung-Jue Bang. (2007) Chasing targets for EGFR tyrosine kinase inhibitors in non-small-cell lung cancer: Asian perspectives. Expert Review of Molecular Diagnostics 7:6, 821-836
CrossRef20
Christine L. Hann, Julie R. Brahmer. (2007) “Who Should Receive Epidermal Growth Factor Receptor Inhibitors for Non-Small Cell Lung Cancer and When?”. Current Treatment Options in Oncology 8:1, 28-37
CrossRef21
Sreenath V. Sharma, Daphne W. Bell, Jeffrey Settleman, Daniel A. Haber. (2007) Epidermal growth factor receptor mutations in lung cancer. Nature Reviews Cancer 7:3, 169-181
CrossRef22
H Yokoyama, Y Ikehara, Y Kodera, S Ikehara, Y Yatabe, Y Mochizuki, M Koike, M Fujiwara, A Nakao, M Tatematsu, H Nakanishi. (2006) Molecular basis for sensitivity and acquired resistance to gefitinib in HER2-overexpressing human gastric cancer cell lines derived from liver metastasis. British Journal of Cancer 95:11, 1504-1513
CrossRef23
Shinichi Toyooka, Junichi Soh, Hisayuki Shigematsu, Motoi Aoe, Hiroshi Date. (2006) The impact and role of EGFR gene mutation on non-small cell lung cancer. Cancer Chemotherapy and Pharmacology 58:S1, 25-31
CrossRef24
Chih-Hsin Yang, Jin-Yuan Shih, Kun-Chieh Chen, Chong-Jen Yu, Tsung-Ying Yang, Ching-Pei Lin, Wen-Pin Su, Chien-Hung Gow, Chiun Hsu, Gee-Chen Chang, Pan-Chyr Yang. (2006) Survival outcome and predictors of gefitinib antitumor activity in East Asian chemonaive patients with advanced nonsmall cell lung cancer. Cancer 107:8, 1873-1882
CrossRef25
Federica Di Nicolantonio, Alberto Bardelli. (2006) Kinase mutations in cancer: chinks in the enemyʼs armour?. Current Opinion in Oncology 18:1, 69-76
CrossRef26
Hong-Guang Xie, Felix W Frueh. (2005) Pharmacogenomics steps toward personalized medicine. Personalized Medicine 2:4, 325-337
CrossRef27
Giuseppe Giaccone, Jose Antonio Rodriguez. (2005) EGFR inhibitors: what have we learned from the treatment of lung cancer?. Nature Clinical Practice Oncology 2:11, 554-561
CrossRef
