Correspondence
EGFR Mutations in Small-Cell Lung Cancers in Patients Who Have Never Smoked
N Engl J Med 2006; 355:213-215July 13, 2006
- Article
To the Editor:
Mutations in the epidermal growth factor receptor gene (EGFR) occur in 10 to 20 percent of non–small-cell lung cancers, specifically adenocarcinomas, and are associated with the response to EGFR tyrosine kinase inhibitors (erlotinib and gefitinib).1 However, the results of screening of small-cell lung cancers for EGFR mutations have been negative.2 Thus, small-cell lung cancers are not routinely tested for EGFR mutations, nor have they been systematically evaluated for responsiveness to EGFR tyrosine kinase inhibitors.
A 45-year-old woman who had never smoked and who had masses in the right lung, pleura, mediastinum, and frontal lobe was given a diagnosis of adenocarcinoma on the basis of transbronchial biopsy and examination of bronchial washes (Figure 1AFigure 1
Small-Cell Lung Cancer.). These specimens were insufficient for mutation analysis. After undergoing stereotactic radiosurgery of the central nervous system, she was given erlotinib (100 mg per day), which led to a partial response on radiographic examination. After 18 months, the mass in the lung had progressed and the patient had a new lesion in the brain. Erlotinib was discontinued, central nervous system radiation was given, and gefitinib (250 mg per day) alone was given for two months, but there was no evidence of a response on radiographic examination. Mitomycin and vinblastine were then added for the next two months, and there was still no evidence of regression on radiographic examination. A second lung biopsy was performed. Examination of the biopsy specimen revealed a synaptophysin-positive small-cell lung cancer (Figure 1B) with an 18-bp deletion in exon 19 of EGFR (Figure 1C) that was detected with the use of a sensitive assay3 and confirmed by sequencing to be L747–P753insQ. During the next six months, the patient continued to take gefitinib. Etoposide was added, owing to the histologic diagnosis of the small-cell lung cancer, but provided no benefit.The patient died four weeks after the discontinuation of all therapy. At autopsy, metastatic small-cell lung cancer was found in multiple organs, without any adenocarcinoma (Figure 1D). Examination of five organ sites of small-cell lung cancer showed the same 18-bp deletion in exon 19 of EGFR that was seen on examination of the second lung-biopsy specimen, and no other mutations were detected in exons 18 through 24 of EGFR or exon 2 of K-RAS.
Small-cell lung cancer is exceedingly rare in patients who have never smoked. Another woman who had never smoked and who had a small-cell lung cancer with a 15-bp deletion in exon 19 of EGFR had a partial response to gefitinib.4,5 In that patient, the initial diagnosis was adenocarcinoma, on the basis of the cytologic features of the sputum, but examination of a bronchoscopic-biopsy specimen obtained three days after the initiation of gefitinib showed small-cell lung cancer. It is unclear whether our patient originally had a combination of non–small-cell lung cancer and small-cell lung cancer or whether the non–small-cell lung cancer transdifferentiated to small-cell lung cancer after prolonged treatment with erlotinib. Nevertheless, the combined data suggest that EGFR mutations are a recurrent alteration in small-cell lung cancer that arises in patients who have never smoked; the prevalence of the mutations warrants further study.
Maureen F. Zakowski, M.D.
Marc Ladanyi, M.D.
Mark G. Kris, M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021
zakowskm@mskcc.org for the Memorial Sloan-Kettering Cancer Center Lung Cancer OncoGenome Group
Supported by grants from the National Cancer Institute (R21 CA115051) and from the Carmel Hill Fund.
Dr. Kris reports having received consulting fees from Genentech.
5 References1
Pao W ,Miller VA . Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol 2005;23:2556-2568
CrossRef | Web of Science | Medline2
Shigematsu H ,Lin L ,Takahashi T , et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005;97:339-346
CrossRef | Web of Science | Medline3
Pan Q ,Pao W ,Ladanyi M . Rapid polymerase chain reaction-based detection of epidermal growth factor receptor gene mutations in lung adenocarcinomas. J Mol Diagn 2005;7:396-403
CrossRef | Web of Science | Medline4
Araki J ,Okamoto I ,Suto R ,Ichikawa Y ,Sasaki J . Efficacy of the tyrosine kinase inhibitor gefitinib in a patient with metastatic small cell lung cancer. Lung Cancer 2005;48:141-144
CrossRef | Web of Science | Medline5
Okamoto I ,Araki J ,Suto R ,Shimada M ,Nakagawa K ,Fukuoka M . EGFR mutation in gefitinib-responsive small-cell lung cancer. Ann Oncol 2006;17:1028-1029
CrossRef | Web of Science | Medline
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Ada T. W. Ma, Wai Kong Chan, Edmond S. K. Ma, Thomas Cheng, Paul N. M. Cheng. (2011) Small cell lung cancer with an epidermal growth factor receptor mutation in primary gefitinib-resistant adenocarcinoma of the lung. Acta Oncologica1-3
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Yu Kurahara, Tomoya Kawaguchi, Kazunobu Tachibana, Shinji Atagi, Seiji Hayashi, Masanori Kitaichi, Sai-Hong I. Ou, Minoru Takada. (2011) Small-Cell Lung Cancer in Never-Smokers: A Case Series With Information on Family History of Cancer and Environmental Tobacco Smoke. Clinical Lung Cancer
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
L. V. Sequist, B. A. Waltman, D. Dias-Santagata, S. Digumarthy, A. B. Turke, P. Fidias, K. Bergethon, A. T. Shaw, S. Gettinger, A. K. Cosper, S. Akhavanfard, R. S. Heist, J. Temel, J. G. Christensen, J. C. Wain, T. J. Lynch, K. Vernovsky, E. J. Mark, M. Lanuti, A. J. Iafrate, M. Mino-Kenudson, J. A. Engelman. (2011) Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors. Science Translational Medicine 3:75, 75ra26-75ra26
CrossRef7
Tsu-Hui Shiao, Yih-Leong Chang, Chong-Jen Yu, Yeun-Chung Chang, Ya-Chieh Hsu, Shih-Han Chang, Jin-Yuan Shih, Pan-Chyr Yang. (2011) Epidermal Growth Factor Receptor Mutations in Small Cell Lung Cancer. Journal of Thoracic Oncology 6:1, 195-198
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Ning Lv, Xiaoming Xie, Qidong Ge, Suxia Lin, Xi Wang, Yanan Kong, Hongliu Shi, Xinhua Xie, Weidong Wei. (2011) Epidermal growth factor receptor in breast carcinoma: association between gene copy number and mutations. Diagnostic Pathology 6:1, 118
CrossRef9
Sodai Narumi, Akira Inoue, Taizo Shibahara, Ryotaro Igusa, Tomohiro Sakakibara, Toshihiro Nukiwa. (2011) A Case of Small-cell Lung Carcinoma with EGFR Gene Mutation. Haigan 51:7, 798-802
CrossRef10
William Pao, Juliann Chmielecki. (2010) Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nature Reviews Cancer 10:11, 760-774
CrossRef11
Naheed Alam, Karen S. Gustafson, Marc Ladanyi, Maureen F. Zakowski, Atul Kapoor, Alexander M. Truskinovsky, Arkadiusz Z. Dudek. (2010) Small-Cell Carcinoma With an Epidermal Growth Factor Receptor Mutation in a Never-Smoker With Gefitinib-Responsive Adenocarcinoma of the Lung. Clinical Lung Cancer 11:5, E1-E4
CrossRef12
George K. Antony, Erin Bertino, Michael Franklin, Gregory A. Otterson, Arkadiusz Z. Dudek. (2010) Small Cell Lung Cancer in Never Smokers. Journal of Thoracic Oncology 5:5, 747-748
CrossRef13
Yasushi Yatabe. (2010) EGFR mutations and the terminal respiratory unit. Cancer and Metastasis Reviews 29:1, 23-36
CrossRef14
Shi-Xu Jiang, Kazuya Yamashita, Michiko Yamamoto, Chun-Ji Piao, Atsuko Umezawa, Makoto Saegusa, Tsutomu Yoshida, Masato Katagiri, Noriyuki Masuda, Kazushige Hayakawa, Isao Okayasu. (2008) EGFR genetic heterogeneity of nonsmall cell lung cancers contributing to acquired gefitinib resistance. International Journal of Cancer 123:11, 2480-2486
CrossRef15
B. Fischer, W. Eberhardt, R. Buhl, M. Thomas. (2008) Hochdosistherapie und molekulare Therapie beim kleinzelligen Lungenkarzinom. Der Onkologe 14:8, 798-805
CrossRef16
Marc Ladanyi, William Pao. (2008) Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond. Modern Pathology 21, S16-S22
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Edurne Arriola, Israel Cañadas, Montse Arumí, Federico Rojo, Ana Rovira, Joan Albanell. (2008) Genetic changes in small cell lung carcinoma. Clinical and Translational Oncology 10:4, 189-197
CrossRef18
T. Sher, G. K. Dy, A. A. Adjei. (2008) Small Cell Lung Cancer. Mayo Clinic Proceedings 83:3, 355-367
CrossRef19
Ryotaro Morinaga, Isamu Okamoto, Kazuyuki Furuta, Yukiko Kawano, Masaru Sekijima, Kensaku Dote, Takao Satou, Kazuto Nishio, Masahiro Fukuoka, Kazuhiko Nakagawa. (2007) Sequential occurrence of non-small cell and small cell lung cancer with the same EGFR mutation. Lung Cancer 58:3, 411-413
CrossRef20
Tomoya Fukui, Koji Tsuta, Koh Furuta, Shun-ichi Watanabe, Hisao Asamura, Yuichiro Ohe, Akiko Miyagi Maeshima, Tatsuhiro Shibata, Noriyuki Masuda, Yoshihiro Matsuno. (2007) Epidermal growth factor receptor mutation status and clinicopathological features of combined small cell carcinoma with adenocarcinoma of the lung. Cancer Science 98:11, 1714-1719
CrossRef21
Marcello Tiseo, Andrea Ardizzoni. (2007) Current Status of Second-Line Treatment and Novel Therapies for Small Cell Lung Cancer. Journal of Thoracic Oncology 2:8, 764-772
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Barbara Fischer, Marin Marinov, Alexandre Arcaro. (2007) Targeting receptor tyrosine kinase signalling in small cell lung cancer (SCLC): What have we learned so far?. Cancer Treatment Reviews 33:4, 391-406
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Vladimir Baltić. (2007) Application of Genomics in Clinical Oncology. Journal of Medical Biochemistry 26:2, 79-93
CrossRef
