To the Editor: Kobayashi et al. (Feb. 24 issue)1 report thata second mutation in the gene encoding the epidermal growthfactor receptor (EGFR), one resulting in a threonine-to-methioninesubstitution at amino acid position 790 (T790M), was associatedwith acquired resistance to gefitinib in their patient and thatthis mutant gene had been absent from the primary non–small-celllung cancer. In a reanalysis of the data from the 397 subjectswe have previously described,2,3 we identified two women whohad never smoked who had non–small-cell lung cancer andharbored two EGFR mutations — T790M and a leucine-to-argininesubstitution at amino acid position 858 (L858R) — in resectedtumor specimens before treatment with chemotherapy or radiotherapy.Both patients later had recurrent disease and eventually died— outcomes suggesting that tumors with both the L858Rand T790M mutations are very aggressive. One patient was treatedwith gefitinib and had progression.
These findings indicate the existence of cases with inherentdouble mutations and provide evidence that the T790M mutantgenotype is an important factor conferring resistance to gefitinibin non–small-cell lung cancers containing EGFR sensitivitymutations. In addition, detecting T790M may be useful for predictingpretreatment resistance to EGFR tyrosine kinase inhibitors.Our observation, together with data from recent reports,1,4may help clarify the role of EGFR mutations in the developmentof EGFR-related non–small-cell lung cancer and help establisheffective strategies against specific subtypes of non–small-celllung cancer.
Shinichi Toyooka, M.D. Katsuyuki Kiura, M.D. Okayama University Graduate School of Medicine and Dentistry Okayama 700-8558, Japan s_toyooka{at}nigeka2.hospital.okayama-u.ac.jp
Tetsuya Mitsudomi, M.D. Aichi Cancer Center Hospital Nagoya 464-8681, Japan
References
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. [Free Full Text]
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. [Free Full Text]
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. [Free Full Text]
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(3):e73.
The authors reply: Dr. Toyooka and colleagues describe two patientswhose lung tumors harbored a T790M mutation before treatmentwith chemotherapy or radiotherapy was begun and suggest thatthis mutation might be a marker of tumor aggressiveness as wellas resistance to gefitinib therapy. In the cases we and others1have described, the T790M mutation was not found in specimensfrom untreated patients. Nevertheless, the possibilities doexist that this second mutation might be present in some tumorsat a low frequency at the time of diagnosis and that tumor cellsharboring the mutation might be enriched over time during treatmentwith gefitinib or erlotinib. By analogy, imatinib-resistantBCR-ABL mutations have, on occasion, been detected in specimensfrom patients with untreated chronic myeloid leukemia.2,3 Weagree that such interesting findings should motivate furtherresearch to improve our understanding of the role of EGFR innon–small-cell lung cancers, to encourage the developmentof alternative EGFR inhibitors able to overcome such resistancemutations, and to incorporate the knowledge gained into clinicaltreatment.
Susumu Kobayashi, M.D., Ph.D. Daniel G. Tenen, M.D. Beth Israel Deaconess Medical Center Boston, MA 02115
Balázs Halmos, M.D. Case Western Reserve University Cleveland, OH 44106
References
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(3):e73.
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. [Free Full Text]
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. [Free Full Text]
Ushiki, A., Koizumi, T., Kobayashi, N., Kanda, S., Yasuo, M., Yamamoto, H., Kubo, K., Aoyagi, D., Nakayama, J.
(2009). Genetic Heterogeneity of EGFR Mutation in Pleomorphic Carcinoma of the Lung: Response to Gefitinib and Clinical Outcome. Jpn J Clin Oncol
39: 267-270
[Abstract][Full Text]
Hodkinson, P. S., MacKinnon, A., Sethi, T.
(2008). Targeting Growth Factors in Lung Cancer. Chest
133: 1209-1216
[Abstract][Full Text]
Toyooka, S., Matsuo, K., Shigematsu, H., Kosaka, T., Tokumo, M., Yatabe, Y., Ichihara, S., Inukai, M., Suehisa, H., Soh, J., Kiura, K., Fong, K. M., Lee, H., Wistuba, I. I., Gazdar, A. F., Mitsudomi, T., Date, H.
(2007). The Impact of Sex and Smoking Status on the Mutational Spectrum of Epidermal Growth Factor Receptor Gene in Non small Cell Lung Cancer. Clin. Cancer Res.
13: 5763-5768
[Abstract][Full Text]
Ogino, A., Kitao, H., Hirano, S., Uchida, A., Ishiai, M., Kozuki, T., Takigawa, N., Takata, M., Kiura, K., Tanimoto, M.
(2007). Emergence of Epidermal Growth Factor Receptor T790M Mutation during Chronic Exposure to Gefitinib in a Non Small Cell Lung Cancer Cell Line. Cancer Res.
67: 7807-7814
[Abstract][Full Text]
Sequist, L. V., Joshi, V. A., Janne, P. A., Muzikansky, A., Fidias, P., Meyerson, M., Haber, D. A., Kucherlapati, R., Johnson, B. E., Lynch, T. J.
(2007). Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing.. The Oncologist
12: 90-98
[Abstract][Full Text]
Helfrich, B. A., Raben, D., Varella-Garcia, M., Gustafson, D., Chan, D. C., Bemis, L., Coldren, C., Baron, A., Zeng, C., Franklin, W. A., Hirsch, F. R., Gazdar, A., Minna, J., Bunn, P. A. Jr.
(2006). Antitumor Activity of the Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor Gefitinib (ZD1839, Iressa) in Non-Small Cell Lung Cancer Cell Lines Correlates with Gene Copy Number and EGFR Mutations but not EGFR Protein Levels. Clin. Cancer Res.
12: 7117-7125
[Abstract][Full Text]
Kosaka, T., Yatabe, Y., Endoh, H., Yoshida, K., Hida, T., Tsuboi, M., Tada, H., Kuwano, H., Mitsudomi, T.
(2006). Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib.. Clin. Cancer Res.
12: 5764-5769
[Abstract][Full Text]
Inukai, M., Toyooka, S., Ito, S., Asano, H., Ichihara, S., Soh, J., Suehisa, H., Ouchida, M., Aoe, K., Aoe, M., Kiura, K., Shimizu, N., Date, H.
(2006). Presence of Epidermal Growth Factor Receptor Gene T790M Mutation as a Minor Clone in Non-Small Cell Lung Cancer. Cancer Res.
66: 7854-7858
[Abstract][Full Text]
Ettinger, D. S.
(2006). Clinical Implications of EGFR Expression in the Development and Progression of Solid Tumors: Focus on Non-Small Cell Lung Cancer.. The Oncologist
11: 358-373
[Abstract][Full Text]
Previous
