EGFR Mutations in Small-Cell Lung Cancers in Patients Who Have Never Smoked
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《新英格兰医药杂志》
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 1A). 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.
Figure 1. Small-Cell Lung Cancer.
Panel A shows a transbronchial-biopsy specimen with well-to-moderately differentiated adenocarcinoma (hematoxylin and eosin); the inset shows a cluster of adenocarcinoma cells from a bronchial wash (Papanicolaou stain). In Panel B, an air-dried smear from a lung specimen, obtained by fine-needle aspiration, shows small-cell lung cancer with characteristic hyperchromatic, crowded cells with "crush" artifact (Diff-Quik stain); the inset shows a specimen immunostained for synaptophysin. Panel C shows the results of capillary electrophoresis of the fluorescently labeled products of a polymerase-chain-reaction assay for short in-frame deletions in exon 19 of EGFR3; an 18-bp deletion was found in the small-cell lung cancer (SCLC) from our patient. The positive control, the H1650 lung-adenocarcinoma cell line, showed a 15-bp deletion. The negative control, normal placental DNA, showed no mutant allele. The numbers refer to base pairs. In Panel D, a section of the lung obtained at autopsy shows small-cell lung cancer (hematoxylin and eosin).
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.
References
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.
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.
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.
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.
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.
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 1A). 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.
Figure 1. Small-Cell Lung Cancer.
Panel A shows a transbronchial-biopsy specimen with well-to-moderately differentiated adenocarcinoma (hematoxylin and eosin); the inset shows a cluster of adenocarcinoma cells from a bronchial wash (Papanicolaou stain). In Panel B, an air-dried smear from a lung specimen, obtained by fine-needle aspiration, shows small-cell lung cancer with characteristic hyperchromatic, crowded cells with "crush" artifact (Diff-Quik stain); the inset shows a specimen immunostained for synaptophysin. Panel C shows the results of capillary electrophoresis of the fluorescently labeled products of a polymerase-chain-reaction assay for short in-frame deletions in exon 19 of EGFR3; an 18-bp deletion was found in the small-cell lung cancer (SCLC) from our patient. The positive control, the H1650 lung-adenocarcinoma cell line, showed a 15-bp deletion. The negative control, normal placental DNA, showed no mutant allele. The numbers refer to base pairs. In Panel D, a section of the lung obtained at autopsy shows small-cell lung cancer (hematoxylin and eosin).
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.
References
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.
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.
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.
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.
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.