Correspondence
EGFR Mutation and Response of Lung Cancer to Gefitinib
N Engl J Med 2005; 352:2136May 19, 2005
- Article
To the Editor:
Kobayashi et al. (Feb. 24 issue)1 report that a second mutation in the gene encoding the epidermal growth factor receptor (EGFR), one resulting in a threonine-to-methionine substitution at amino acid position 790 (T790M), was associated with acquired resistance to gefitinib in their patient and that this mutant gene had been absent from the primary non–small-cell lung cancer. In a reanalysis of the data from the 397 subjects we have previously described,2,3 we identified two women who had never smoked who had non–small-cell lung cancer and harbored two EGFR mutations — T790M and a leucine-to-arginine substitution at amino acid position 858 (L858R) — in resected tumor specimens before treatment with chemotherapy or radiotherapy. Both patients later had recurrent disease and eventually died — outcomes suggesting that tumors with both the L858R and T790M mutations are very aggressive. One patient was treated with gefitinib and had progression.
These findings indicate the existence of cases with inherent double mutations and provide evidence that the T790M mutant genotype is an important factor conferring resistance to gefitinib in non–small-cell lung cancers containing EGFR sensitivity mutations. In addition, detecting T790M may be useful for predicting pretreatment resistance to EGFR tyrosine kinase inhibitors. Our observation, together with data from recent reports,1,4 may help clarify the role of EGFR mutations in the development of EGFR-related non–small-cell lung cancer and help establish effective strategies against specific subtypes of non–small-cell lung cancer.
4 ReferencesShinichi Toyooka, M.D.
Katsuyuki Kiura, M.D.
Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan
s_toyooka@nigeka2.hospital. okayama-u. ac. jp Tetsuya Mitsudomi, M.D.
Aichi Cancer Center Hospital, Nagoya 464-8681, Japan1
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 | Medline2
Kosaka T ,Yatabe Y ,Endoh H ,Kuwano H ,Takahashi T ,Mitsudomi T . Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res 2004;64:8919-8923
CrossRef | Web of Science | Medline3
Tokumo M ,Toyooka S ,Kiura K , et al. The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. Clin Cancer Res 2005;11:1167-1173
Web of Science | Medline4
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 | Medline
Author/Editor Response
Dr. Toyooka and colleagues describe two patients whose lung tumors harbored a T790M mutation before treatment with chemotherapy or radiotherapy was begun and suggest that this mutation might be a marker of tumor aggressiveness as well as resistance to gefitinib therapy. In the cases we and others1 have described, the T790M mutation was not found in specimens from untreated patients. Nevertheless, the possibilities do exist that this second mutation might be present in some tumors at a low frequency at the time of diagnosis and that tumor cells harboring the mutation might be enriched over time during treatment with gefitinib or erlotinib. By analogy, imatinib-resistant BCR-ABL mutations have, on occasion, been detected in specimens from patients with untreated chronic myeloid leukemia.2,3 We agree that such interesting findings should motivate further research to improve our understanding of the role of EGFR in non–small-cell lung cancers, to encourage the development of alternative EGFR inhibitors able to overcome such resistance mutations, and to incorporate the knowledge gained into clinical treatment.
3 ReferencesSusumu Kobayashi, M.D., Ph.D.
Daniel G. Tenen, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 02115Balázs Halmos, M.D.
Case Western Reserve University, Cleveland, OH 441061
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 | Medline2
Roche-Lestienne C ,Soenen-Cornu V ,Grardel-Duflos N , et al. Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood 2002;100:1014-1018
CrossRef | Web of Science | Medline3
Roche-Lestienne C ,Lai JL ,Darre S ,Facon T ,Preudhomme C . A mutation conferring resistance to imatinib at the time of diagnosis of chronic myelogenous leukemia. N Engl J Med 2003;348:2265-2266
Full Text | Web of Science | Medline
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