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1 Departments of Thoracic Surgery and 2 Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan; 3 Department of Surgery I, Gunma University School of Medicine, Gunma, Japan; and 4 Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Molecular Analysis of Lung Cancer Specimens.
Tumor samples were obtained at the time of surgery, rapidly frozen in liquid nitrogen, and stored at –80°C. Frozen tissue of the tumor specimens were grossly dissected to enrich as much tumor cells as possible by a surgical pathologist (Y. Y.). We isolated total RNA using the RNAeasy kit (Qiagen, Valencia, CA).
The first four exons (exons 18–21) of the seven exons (exons 18–24) that code for TK domain of the EGFR gene that includes all of the mutations reported thus far (8 , 9) were amplified with primers F1 (5'-AGCTTGTGGAGCCTCTTACACC-3') and R1 (5'-TAAAATTGATTCCAATGCCATCC-3'), in a one-step reverse transcription-PCR setup with Qiagen OneStep reverse transcription-PCR kit (Qiagen, Valencia, CA). The cDNA sequence of EGFR gene was obtained from GenBank (accession number NM005228). Reverse transcription-PCR conditions were available after request. Reverse transcription-PCR products were diluted and cycle-sequenced with the Big Dye Terminator v3.1/1.1 cycle sequencing kit (Applied Biosystems, Foster City, CA). Sequencing reactions were electrophoresed on an ABI PRISM 3100 (Applied Biosystems). Both the forward and reverse sequences obtained were analyzed by BLAST and chromatograms by manual review.
KRAS and TP53 Gene Analysis.
We had previously examined the same cohort for KRAS mutations and TP53 mutations (10
, 11)
. Briefly, TP53 gene (exon 4 through 10) and KRAS gene (exons 1 and 2) were amplified and directly sequenced with ABI PRISM 310 Genetic Analyzer (Applied Biosystems).
Statistical Analysis.
For comparisons of proportions, the 
2 test or Fisher’s exact test were used. The Kaplan-Meier method was used to estimate the probability of survival as a function of time, and survival differences were analyzed by the log-rank test. The two-sided significance level was set at P < 0.05. To identify which independent factors jointly had a significant influence on the incidence of EGFR mutations, the logistic regression modeling technique was used. We did all analyses using a StatView (version 5, SAS Institute Inc., Cary, NC) software on a Macintosh computer.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. It is noted that, in all cases, such alterations were in-frame. Forty-six of the 54 point mutations were from a T to a G transversion at the second nucleotide of codon 858 in exon 21 resulting in substitution of leucine with arginine residue. Four of the point mutations occurred at codon 719 in exon 18. We noted that one tumor with a mutation at codon 719 and three tumors with mutations at codon 858 had another mutation occurring at codons 709, 768, 776, and 790, respectively. For rare mutations (all 5 insertions, E709H, T790M, S768I, R776C, V769L), we resequenced and confirmed that these mutations were actually present. In summary, 52 of the 111 (47%) EGFR mutations were deletions around codons 746–750 and 49 (44%) were L858R, altogether accounting for 91% of all of the EGFR mutations found. The four major classes of mutations (i.e., deletions, L858R, mutations at codon 719, duplications/insertions) never occurred simultaneously. Furthermore, it is of note that only mutant sequences were present in chromatograms in 19 of 52 deletions, 13 of 46 in L858R, and 1 of 4 codon 719 mutations.
Relationship between EGFR Mutations and Clinical-Pathologic Features.
EGFR mutations were significantly more frequent in females (59%) than males (26%; P < 0.001), in never-smokers (66%) than ever-smokers (22%; P < 0.001), and in patients with adenocarcinomas (49%) than in those with nonadenocarcinomas (2%; P < 0.001). There was only one patient with an EGFR mutation of 53 nonadenocarcinoma patients. This patient was a 61-year-old male with adenosquamous carcinoma. Because female patients tended to be never-smokers and were likely to have adenocarcinoma, we did logistic regression analysis to determine which of these three variables independently contributed to the EGFR mutations. The result suggested that smoking status and adenocarcinoma histology independently affected EGFR mutations whereas female gender did not (smoking status, odds ratio 3.949, P < 0.001; histologic type, odds ratio 27.486, P = 0.0013; gender odds ratio 0.996, P = 0.9917).
Further Analysis of Patients with Adenocarcinoma.
EGFR mutations were found almost exclusively in adenocarcinomas with only one exception; hence, we did more detailed analysis limited to this subset of patients (Table 1)
. EGFR mutations were also significantly frequent in female, nonsmoking patients. When we divided ever-smokers into 3 categories depending on smoke exposure, there was a trend that the higher the exposure, the lower the incidence of EGFR mutations. EGFR mutations were significantly more frequent in well to moderately differentiated adenocarcinomas (58%) than in poorly differentiated adenocarcinomas (30%; P < 0.001). There were five bronchioloalveolar cell carcinomas (BAC) in our cohort, of which three harbored EGFR mutations (60%), according to the World Health Organization classification of lung cancers (which states that BAC is a true noninvasive cancer without stromal or pleural invasion; ref. 12
). It seemed that EGFR mutations were associated neither with age of the patients nor with stage of diseases. There was no difference in incidence of EGFR mutations between both sexes in patients of age 50 (average age of menopause in Japan) or younger, although the number of patients of this age group was small (2 of 7 males, 2 of 7 females).
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indicated that EGFR mutations did not affect prognosis of the patients (P = 0.9933), although the follow up period was relatively short (median follow up, 788 days)
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shows the relationship among the three mutations by a Venn diagram in 192 patients in whom information about the status of these three genes was available.
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. Of seven mutations either at codon 157, 248, or 273 in which strong and selective adduct formation of benzo(a)pyrene diol epoxide, one of the major tobacco carcinogens, occurs (13)
, six were in tumors without EGFR mutations (Fig. 3)
. Furthermore, of 16 mutations caused by a G to a T transversions characteristic of mutations caused by aromatic polycyclic hydrocarbons (14)
, 15 were in tumors without EGFR mutations (Fig. 3)
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We found that 40% of 277 unselected patients with lung cancer carried mutations in the TK domain of the EGFR gene. More than 90% of the mutations were either deletions around codons 746–750 in exon 19 or L858R in exon 21, which all flank the ATP-binding pocket that is important for TK activity (8 , 9) . We also noted that in about 30% of the cases with EGFR mutations, only bands derived from mutant allele were detected on chromatogram. This is somewhat puzzling considering the heterozygous nature of the EGFR mutations reported thus far (8 , 9) and the presence of stromal cells in resected tumor specimens. This finding may suggest that loss of wild-type alleles or amplification of mutant alleles accompanied with mutations in these cases, as indicated by Minna et al. (16) .
EGFR mutations were almost exclusively present in adenocarcinoma. Mutations were more prevalent in females and nonsmokers, confirming and extending the results of previous reports (8 , 9) . It is noteworthy that these characteristics and Japanese ethnicity are all predictors of gefitinib sensitivity at least by univariate analysis (4 , 5) . Multivariate analysis suggested that nonsmoking status and adenocarcinoma histology independently contributed to EGFR mutations but female gender did not. The fact that premenopausal women did not show higher incidence of EGFR mutations further suggested that apparent difference between female and male was caused by a difference in lifestyle including smoking habit rather than involvement of sexual environment.
Previously described genetic alterations in lung cancer are almost always more frequent in smokers than nonsmokers. For example, mutations of the TP53 gene (17) , KRAS genes (18) , or deletion of the short arm of chromosome 3 (19) are known to be more frequent in smokers, as was the case in the present study for the first two. A plausible explanation for the reason why EGFR mutations are associated with nonsmoking status are not possible at this time, but it is natural to assume that EGFR mutations are caused by carcinogen(s) other than those contained in tobacco smoke. In Taiwan, human papilloma virus type, 16 of 18 infections (20) or cooking oil fume (21) have been investigated as a cause of lung cancer occurring in nonsmoking women. These observations might be relevant with preferential EGFR mutations in nonsmoking women. Nevertheless, EGFR mutations should provide a clue for pathogenesis of adenocarcinoma occurring in nonsmokers and should ultimately lead to discovery of effective prevention.
We were able to confirm higher incidence of EGFR mutations in Japanese patients. Lynch et al. found EGFR mutation in 2 of 25 unselected United States patients (9) , and Paez et al. (8) did so in 1 of 61 United States patients and 15 of 58 Japanese patients. The reason for this marked difference between Japanese and United States patients is not very clear. However, difference in incidence of nonsmoking patients between Japanese and American female patients with lung cancer may partly account for this. In our cohort, 83% of female patients and 10% of male patients were never-smokers. This trend is common in Japan. For example, Toyooka et al. (22) and Minami et al. (23) reported that the proportion of never-smoking women in lung cancer patients is 96% and 75%, respectively. This makes quite a contrast with the fact that only 15% of 706 United States female and 6% of 1,347 male patients with lung cancer are never-smokers (24) .
We found that EGFR mutations and KRAS mutations known to play an important role in pathogenesis of adenocarcinoma of the lung (25) were strictly mutually exclusive, reminding us of a similar exclusionary relationship between retinoblastoma and p16 inactivation in lung cancer (26) . This finding may be explained by the fact that the KRAS-mitogen-activated protein kinase pathway is one of the downstream signaling pathways of EGFR (1) . Because it has been shown that L858R and delL747-P753ins S are activating mutations that result in markedly increased phosphorylation of EGFR when EGF was added (8 , 9) , tumors with KRAS mutations that already have activated further downstream effectors do not need to have EGFR mutations. The high incidence of EGFR mutations in lung adenocarcinomas may explain why KRAS mutations are lower in Japanese than in Caucasian patients. In the present study, KRAS mutations were found in 13% of adenocarcinomas, whereas they were present in 33% of Dutch cases (25) . This may be also at least partially attributable to the difference in smoking status, because KRAS mutations were more frequent in smokers as reported previously (18) . In contrast, the incidence of TP53 mutations was not associated with EGFR mutations, although TP53 mutations also occurred more frequently in smokers (17) . However, TP53 mutations in tumors without EGFR mutations showed characteristics of mutations caused by tobacco carcinogens in terms of sites or base substitution patterns (13 , 14) .
We also noted that well to moderately differentiated adenocarcinomas had a significantly higher incidence of EGFR mutations than poorly differentiated ones. This observation might be relevant to the fact that adenocarcinomas showing BAC feature show higher sensitivity to gefitinib (27) . However, when we used the strict criteria as stated by the World Health Organization Classification of lung tumors (12) , our cohort included only five BAC, of which three had EGFR mutations. Unfortunately, these strict criteria are not applied by many pathologists, leading to considerable confusion between BAC and adenocarcinoma with BAC features in the literature. Alternatively, we proposed terminal respiratory unit type adenocarcinoma that is characterized by morphological resemblance to type II pneumocytes, Clara cells, and/or bronchioles as well as expression of thyroid transcription factor-1 and surfactant proprotein B (refs. 28 , 29 ). In the World Health Organization classification, most nonmucinous bronchioloalveolar, mixed bronchioloalveolar and acinar subtypes, and some papillary subtypes belong to the terminal respiratory unit type adenocarcinoma (28 , 29) . We found that most adenocarcinoma with EGFR mutations were categorized into terminal respiratory unit type adenocarcinoma.6
EGFR mutations were not associated with stage of disease, suggesting that EGFR mutations occurs relatively early in clinical course and are associated with pathogenesis of adenocarcinoma rather than progression.
In conclusion, we found a high incidence of EGFR mutations in Japanese patients with pulmonary adenocarcinoma, especially in those who never smoked. EGFR mutations were never present in tumors with KRAS mutations, indicating possibilities of genotype-oriented approach for pulmonary adenocarcinoma.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: T. Kosaka and Y. Yatabe contributed equally to the present study.
Requests for reprints: Tetsuya Mitsudomi, Department of Thoracic Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. Phone: 81-52-762-6111; Fax: 81-52-764-2963; E-mail: mitsudom{at}aichi-ml.jp
5 T. Mitsudomi, T. Kosaka, H. Endoh, Y. Horio, T. Hida, S. Mori, S. Hatooka, M. Shinoda, T. Takahashi, Y. Yatabe, submitted for publication. 
6 Y. Yatabe, T. Kosaka, T. Takahashi, T. Mitsadomi, submitted for publication.
Received 8/ 5/04. Revised 9/ 8/04. Accepted 10/19/04.
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H. Vikis, M. Sato, M. James, D. Wang, Y. Wang, M. Wang, D. Jia, Y. Liu, J. E. Bailey-Wilson, C. I. Amos, et al. EGFR-T790M Is a Rare Lung Cancer Susceptibility Allele with Enhanced Kinase Activity Cancer Res., May 15, 2007; 67(10): 4665 - 4670. [Abstract] [Full Text] [PDF]
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T. Okabe, I. Okamoto, K. Tamura, M. Terashima, T. Yoshida, T. Satoh, M. Takada, M. Fukuoka, and K. Nakagawa Differential Constitutive Activation of the Epidermal Growth Factor Receptor in Non-Small Cell Lung Cancer Cells Bearing EGFR Gene Mutation and Amplification Cancer Res., March 1, 2007; 67(5): 2046 - 2053. [Abstract] [Full Text] [PDF]
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 X. Zhang and A. Chang Somatic mutations of the epidermal growth factor receptor and non-small-cell lung cancer J. Med. Genet., March 1, 2007; 44(3): 166 - 172. [Abstract] [Full Text] [PDF]
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J. Subramanian and R. Govindan Lung Cancer in Never Smokers: A Review J. Clin. Oncol., February 10, 2007; 25(5): 561 - 570. [Abstract] [Full Text] [PDF]
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L. V. Sequist, D. W. Bell, T. J. Lynch, and D. A. Haber Molecular Predictors of Response to Epidermal Growth Factor Receptor Antagonists in Non-Small-Cell Lung Cancer J. Clin. Oncol., February 10, 2007; 25(5): 587 - 595. [Abstract] [Full Text] [PDF]
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L. Toschi and F. Cappuzzo Understanding the New Genetics of Responsiveness to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Oncologist, February 1, 2007; 12(2): 211 - 220. [Abstract] [Full Text] [PDF]
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 T. Fukazawa, Y. Maeda, M. L. Durbin, T. Nakai, J. Matsuoka, H. Tanaka, Y. Naomoto, and N. Tanaka Pulmonary adenocarcinoma-targeted gene therapy by a cancer- and tissue-specific promoter system Mol. Cancer Ther., January 1, 2007; 6(1): 244 - 252. [Abstract] [Full Text] [PDF]
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 J. Zhang, S. Kalyankrishna, M. Wislez, N. Thilaganathan, B. Saigal, W. Wei, L. Ma, I. I. Wistuba, F. M. Johnson, and J. M. Kurie Src-Family Kinases Are Activated in Non-Small Cell Lung Cancer and Promote the Survival of Epidermal Growth Factor Receptor-Dependent Cell Lines Am. J. Pathol., January 1, 2007; 170(1): 366 - 376. [Abstract] [Full Text] [PDF]
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L. V. Sequist, V. A. Joshi, P. A. Janne, A. Muzikansky, P. Fidias, M. Meyerson, D. A. Haber, R. Kucherlapati, B. E. Johnson, and T. J. Lynch Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. Oncologist, January 1, 2007; 12(1): 90 - 98. [Abstract] [Full Text] [PDF]
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 B. J. Skaggs, M. E. Gorre, A. Ryvkin, M. R. Burgess, Y. Xie, Y. Han, E. Komisopoulou, L. M. Brown, J. A. Loo, E. M. Landaw, et al. Phosphorylation of the ATP-binding loop directs oncogenicity of drug-resistant BCR-ABL mutants PNAS, December 19, 2006; 103(51): 19466 - 19471. [Abstract] [Full Text] [PDF]
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M. Ono and M. Kuwano Molecular Mechanisms of Epidermal Growth Factor Receptor (EGFR) Activation and Response to Gefitinib and Other EGFR-Targeting Drugs Clin. Cancer Res., December 15, 2006; 12(24): 7242 - 7251. [Abstract] [Full Text] [PDF]
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B. A. Helfrich, D. Raben, M. Varella-Garcia, D. Gustafson, D. C. Chan, L. Bemis, C. Coldren, A. Baron, C. Zeng, W. A. Franklin, et al. 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., December 1, 2006; 12(23): 7117 - 7125. [Abstract] [Full Text] [PDF]
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T. Kosaka, Y. Yatabe, H. Endoh, K. Yoshida, T. Hida, M. Tsuboi, H. Tada, H. Kuwano, and T. Mitsudomi Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib. Clin. Cancer Res., October 1, 2006; 12(19): 5764 - 5769. [Abstract] [Full Text] [PDF]
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A. Inoue, T. Suzuki, T. Fukuhara, M. Maemondo, Y. Kimura, N. Morikawa, H. Watanabe, Y. Saijo, and T. Nukiwa Prospective Phase II Study of Gefitinib for Chemotherapy-Naive Patients With Advanced Non-Small-Cell Lung Cancer With Epidermal Growth Factor Receptor Gene Mutations J. Clin. Oncol., July 20, 2006; 24(21): 3340 - 3346. [Abstract] [Full Text] [PDF]
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R. K. Thomas, B. Weir, and M. Meyerson Genomic approaches to lung cancer. Clin. Cancer Res., July 15, 2006; 12(14): 4384s - 4391s. [Abstract] [Full Text] [PDF]
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P. A. Janne and B. E. Johnson Effect of epidermal growth factor receptor tyrosine kinase domain mutations on the outcome of patients with non-small cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors. Clin. Cancer Res., July 15, 2006; 12(14): 4416s - 4420s. [Abstract] [Full Text] [PDF]
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 Y. Yatabe, T. Hida, Y. Horio, T. Kosaka, T. Takahashi, and T. Mitsudomi A Rapid, Sensitive Assay to Detect EGFR Mutation in Small Biopsy Specimens from Lung Cancer J. Mol. Diagn., July 1, 2006; 8(3): 335 - 341. [Abstract] [Full Text] [PDF]
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M. Sonobe, T. Manabe, H. Wada, and F. Tanaka Lung Adenocarcinoma Harboring Mutations in the ERBB2 Kinase Domain J. Mol. Diagn., July 1, 2006; 8(3): 351 - 356. [Abstract] [Full Text] [PDF]
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H. Kimura, K. Kasahara, M. Kawaishi, H. Kunitoh, T. Tamura, B. Holloway, and K. Nishio Detection of Epidermal Growth Factor Receptor Mutations in Serum as a Predictor of the Response to Gefitinib in Patients with Non-Small-Cell Lung Cancer. Clin. Cancer Res., July 1, 2006; 12(13): 3915 - 3921. [Abstract] [Full Text] [PDF]
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K.-H. Lee, S.-W. Han, P. G. Hwang, D.-Y. Oh, D.-W. Kim, D. H. Chung, S.-A. Im, T.-Y. Kim, D. S. Heo, and Y.-J. Bang Epidermal Growth Factor Receptor Mutations and Response to Chemotherapy in Patients with Non-Small-Cell Lung Cancer. Jpn. J. Clin. Oncol., June 1, 2006; 36(6): 344 - 350. [Abstract] [Full Text] [PDF]
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E. Suzuki, H. Sasaki, O. Kawano, K. Endo, H. Haneda, H. Yukiue, Y. Kobayashi, M. Yano, and Y. Fujii Expression and Mutation Statuses of Epidermal Growth Factor Receptor in Thymic Epithelial Tumors Jpn. J. Clin. Oncol., June 1, 2006; 36(6): 351 - 356. [Abstract] [Full Text] [PDF]
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 A. Seow, D. P. Ng, S. Choo, P. Eng, W.-T. Poh, T. Ming, and Y.-T. Wang Joint effect of asthma/atopy and an IL-6 gene polymorphism on lung cancer risk among lifetime non-smoking Chinese women Carcinogenesis, June 1, 2006; 27(6): 1240 - 1244. [Abstract] [Full Text] [PDF]
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J. Baselga Is There a Role for the Irreversible Epidermal Growth Factor Receptor Inhibitor EKB-569 in the Treatment of Cancer? A Mutation-Driven Question J. Clin. Oncol., May 20, 2006; 24(15): 2225 - 2226. [Full Text] [PDF]
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E. Calvo and J. Baselga Ethnic Differences in Response to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors J. Clin. Oncol., May 10, 2006; 24(14): 2158 - 2163. [Abstract] [Full Text] [PDF]
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S.-W. Han, T.-Y. Kim, Y. K. Jeon, P. G. Hwang, S.-A. Im, K.-H. Lee, J. H. Kim, D.-W. Kim, D. S. Heo, N. K. Kim, et al. Optimization of Patient Selection for Gefitinib in Non-Small Cell Lung Cancer by Combined Analysis of Epidermal Growth Factor Receptor Mutation, K-ras Mutation, and Akt Phosphorylation Clin. Cancer Res., April 15, 2006; 12(8): 2538 - 2544. [Abstract] [Full Text] [PDF]
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D. Pham, M. G. Kris, G. J. Riely, I. S. Sarkaria, T. McDonough, S. Chuai, E. S. Venkatraman, V. A. Miller, M. Ladanyi, W. Pao, et al. Use of Cigarette-Smoking History to Estimate the Likelihood of Mutations in Epidermal Growth Factor Receptor Gene Exons 19 and 21 in Lung Adenocarcinomas J. Clin. Oncol., April 10, 2006; 24(11): 1700 - 1704. [Abstract] [Full Text] [PDF]
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T. Takeuchi, S. Tomida, Y. Yatabe, T. Kosaka, H. Osada, K. Yanagisawa, T. Mitsudomi, and T. Takahashi Expression Profile-Defined Classification of Lung Adenocarcinoma Shows Close Relationship With Underlying Major Genetic Changes and Clinicopathologic Behaviors J. Clin. Oncol., April 10, 2006; 24(11): 1679 - 1688. [Abstract] [Full Text] [PDF]
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 S. Shimato, T. Mitsudomi, T. Kosaka, Y. Yatabe, T. Wakabayashi, M. Mizuno, N. Nakahara, H. Hatano, A. Natsume, D. Ishii, et al. EGFR mutations in patients with brain metastases from lung cancer: Association with the efficacy of gefitinib Neuro-oncol, April 1, 2006; 8(2): 137 - 144. [Abstract] [Full Text] [PDF]
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D. S. Ettinger Clinical Implications of EGFR Expression in the Development and Progression of Solid Tumors: Focus on Non-Small Cell Lung Cancer. Oncologist, April 1, 2006; 11(4): 358 - 373. [Abstract] [Full Text] [PDF]
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F. Leone, G. Cavalloni, Y. Pignochino, I. Sarotto, R. Ferraris, W. Piacibello, T. Venesio, L. Capussotti, M. Risio, and M. Aglietta Somatic mutations of epidermal growth factor receptor in bile duct and gallbladder carcinoma. Clin. Cancer Res., March 15, 2006; 12(6): 1680 - 1685. [Abstract] [Full Text] [PDF]
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T. Takano, Y. Ohe, I. Sekine, H. Kunitoh, T. Yoshida, and T. Tamura In Reply: J. Clin. Oncol., March 1, 2006; 24(7): 1221 - 1221. [Full Text] [PDF]
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I. Y. S. Tam, L. P. Chung, W. S. Suen, E. Wang, M. C.M. Wong, K. K. Ho, W. K. Lam, S. W. Chiu, L. Girard, J. D. Minna, et al. Distinct Epidermal Growth Factor Receptor and KRAS Mutation Patterns in Non-Small Cell Lung Cancer Patients with Different Tobacco Exposure and Clinicopathologic Features Clin. Cancer Res., March 1, 2006; 12(5): 1647 - 1653. [Abstract] [Full Text] [PDF]
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S. Toyooka, M. Tokumo, H. Shigematsu, K. Matsuo, H. Asano, K. Tomii, S. Ichihara, M. Suzuki, M. Aoe, H. Date, et al. Mutational and Epigenetic Evidence for Independent Pathways for Lung Adenocarcinomas Arising in Smokers and Never Smokers Cancer Res., February 1, 2006; 66(3): 1371 - 1375. [Abstract] [Full Text] [PDF]
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E. Conde, B. Angulo, M. Tang, M. Morente, J. Torres-Lanzas, A. Lopez-Encuentra, F. Lopez-Rios, and M. Sanchez-Cespedes Molecular Context of the EGFR Mutations: Evidence for the Activation of mTOR/S6K Signaling Clin. Cancer Res., February 1, 2006; 12(3): 710 - 717. [Abstract] [Full Text] [PDF]
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G. J. Riely, W. Pao, D. Pham, A. R. Li, N. Rizvi, E. S. Venkatraman, M. F. Zakowski, M. G. Kris, M. Ladanyi, and V. A. Miller Clinical Course of Patients with Non-Small Cell Lung Cancer and Epidermal Growth Factor Receptor Exon 19 and Exon 21 Mutations Treated with Gefitinib or Erlotinib Clin. Cancer Res., February 1, 2006; 12(3): 839 - 844. [Abstract] [Full Text] [PDF]
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 D. A Frieze and J. S McCune Current Status of Cetuximab for the Treatment of Patients with Solid Tumors Ann. Pharmacother., February 1, 2006; 40(2): 241 - 250. [Abstract] [Full Text] [PDF]
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H. Asano, S. Toyooka, M. Tokumo, K. Ichimura, K. Aoe, S. Ito, K. Tsukuda, M. Ouchida, M. Aoe, H. Katayama, et al. Detection of EGFR Gene Mutation in Lung Cancer by Mutant-Enriched Polymerase Chain Reaction Assay Clin. Cancer Res., January 1, 2006; 12(1): 43 - 48. [Abstract] [Full Text] [PDF]
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J. W. Lee, Y. H. Soung, S. H. Seo, S. Y. Kim, C. H. Park, Y. P. Wang, K. Park, S. W. Nam, W. S. Park, S. H. Kim, et al. Somatic Mutations of ERBB2 Kinase Domain in Gastric, Colorectal, and Breast Carcinomas Clin. Cancer Res., January 1, 2006; 12(1): 57 - 61. [Abstract] [Full Text] [PDF]
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N. Fujimoto, M. Wislez, J. Zhang, K. Iwanaga, J. Dackor, A. E. Hanna, S. Kalyankrishna, D. D. Cody, R. E. Price, M. Sato, et al. High Expression of ErbB Family Members and Their Ligands in Lung Adenocarcinomas That Are Sensitive to Inhibition of Epidermal Growth Factor Receptor Cancer Res., December 15, 2005; 65(24): 11478 - 11485. [Abstract] [Full Text] [PDF]
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E. E.W. Cohen, M. W. Lingen, L. E. Martin, P. L. Harris, B. W. Brannigan, S. M. Haserlat, R. A. Okimoto, D. C. Sgroi, S. Dahiya, B. Muir, et al. Response of Some Head and Neck Cancers to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors May Be Linked to Mutation of ERBB2 rather than EGFR Clin. Cancer Res., November 15, 2005; 11(22): 8105 - 8108. [Abstract] [Full Text] [PDF]
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D. W. Bell, T. J. Lynch, S. M. Haserlat, P. L. Harris, R. A. Okimoto, B. W. Brannigan, D. C. Sgroi, B. Muir, M. J. Riemenschneider, R. B. Iacona, et al. Epidermal Growth Factor Receptor Mutations and Gene Amplification in Non-Small-Cell Lung Cancer: Molecular Analysis of the IDEAL/INTACT Gefitinib Trials J. Clin. Oncol., November 1, 2005; 23(31): 8081 - 8092. [Abstract] [Full Text] [PDF]
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T. Takano, Y. Ohe, H. Sakamoto, K. Tsuta, Y. Matsuno, U. Tateishi, S. Yamamoto, H. Nokihara, N. Yamamoto, I. Sekine, et al. Epidermal Growth Factor Receptor Gene Mutations and Increased Copy Numbers Predict Gefitinib Sensitivity in Patients With Recurrent Non-Small-Cell Lung Cancer J. Clin. Oncol., October 1, 2005; 23(28): 6829 - 6837. [Abstract] [Full Text] [PDF]
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B. E. Johnson and P. A. Janne Selecting Patients for Epidermal Growth Factor Receptor Inhibitor Treatment: A FISH Story or a Tale of Mutations? J. Clin. Oncol., October 1, 2005; 23(28): 6813 - 6816. [Full Text] [PDF]
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Y. Tomizawa, H. Iijima, N. Sunaga, K. Sato, A. Takise, Y. Otani, S. Tanaka, T. Suga, R. Saito, T. Ishizuka, et al. Clinicopathologic Significance of the Mutations of the Epidermal Growth Factor Receptor Gene in Patients with Non-Small Cell Lung Cancer Clin. Cancer Res., October 1, 2005; 11(19): 6816 - 6822. [Abstract] [Full Text] [PDF]
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M. G. Kris How Today's Developments in the Treatment of Non-Small Cell Lung Cancer Will Change Tomorrow's Standards of Care Oncologist, October 1, 2005; 10(suppl_2): 23 - 29. [Abstract] [Full Text] [PDF]
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B. E. Johnson and P. A. Janne Epidermal Growth Factor Receptor Mutations in Patients with Non-Small Cell Lung Cancer Cancer Res., September 1, 2005; 65(17): 7525 - 7529. [Abstract] [Full Text] [PDF]
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X. Tang, H. Shigematsu, B. N. Bekele, J. A. Roth, J. D. Minna, W. K. Hong, A. F. Gazdar, and I. I. Wistuba EGFR Tyrosine Kinase Domain Mutations Are Detected in Histologically Normal Respiratory Epithelium in Lung Cancer Patients Cancer Res., September 1, 2005; 65(17): 7568 - 7572. [Abstract] [Full Text] [PDF]
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T. Shibata, S. Uryu, A. Kokubu, F. Hosoda, M. Ohki, T. Sakiyama, Y. Matsuno, R. Tsuchiya, Y. Kanai, T. Kondo, et al. Genetic Classification of Lung Adenocarcinoma Based on Array-Based Comparative Genomic Hybridization Analysis: Its Association with Clinicopathologic Features Clin. Cancer Res., September 1, 2005; 11(17): 6177 - 6185. [Abstract] [Full Text] [PDF]
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A. P. Dicker and U. Rodeck Predicting the Future From Trials of the Past: Epidermal Growth Factor Receptor Expression and Outcome of Fractionated Radiation Therapy Trials J. Clin. Oncol., August 20, 2005; 23(24): 5437 - 5439. [Full Text] [PDF]
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S. Kobayashi, H. Ji, Y. Yuza, M. Meyerson, K.-K. Wong, D. G. Tenen, and B. Halmos An Alternative Inhibitor Overcomes Resistance Caused by a Mutation of the Epidermal Growth Factor Receptor Cancer Res., August 15, 2005; 65(16): 7096 - 7101. [Abstract] [Full Text] [PDF]
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Y. Nagai, H. Miyazawa, Huqun, T. Tanaka, K. Udagawa, M. Kato, S. Fukuyama, A. Yokote, K. Kobayashi, M. Kanazawa, et al. Genetic Heterogeneity of the Epidermal Growth Factor Receptor in Non-Small Cell Lung Cancer Cell Lines Revealed by a Rapid and Sensitive Detection System, the Peptide Nucleic Acid-Locked Nucleic Acid PCR Clamp Cancer Res., August 15, 2005; 65(16): 7276 - 7282. [Abstract] [Full Text] [PDF]
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M. Taron, Y. Ichinose, R. Rosell, T. Mok, B. Massuti, L. Zamora, J. L. Mate, C. Manegold, M. Ono, C. Queralt, et al. Activating Mutations in the Tyrosine Kinase Domain of the Epidermal Growth Factor Receptor Are Associated with Improved Survival in Gefitinib-Treated Chemorefractory Lung Adenocarcinomas Clin. Cancer Res., August 15, 2005; 11(16): 5878 - 5885. [Abstract] [Full Text] [PDF]
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Q. Pan, W. Pao, and M. Ladanyi Rapid Polymerase Chain Reaction-Based Detection of Epidermal Growth Factor Receptor Gene Mutations in Lung Adenocarcinomas J. Mol. Diagn., August 1, 2005; 7(3): 396 - 403. [Abstract] [Full Text] [PDF]
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R. J. Schilder, M. W. Sill, X. Chen, K. M. Darcy, S. L. Decesare, G. Lewandowski, R. B. Lee, C. A. Arciero, H. Wu, and A. K. Godwin Phase II Study of Gefitinib in Patients with Relapsed or Persistent Ovarian or Primary Peritoneal Carcinoma and Evaluation of Epidermal Growth Factor Receptor Mutations and Immunohistochemical Expression: A Gynecologic Oncology Group Study Clin. Cancer Res., August 1, 2005; 11(15): 5539 - 5548. [Abstract] [Full Text] [PDF]
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R. L. Comis The Current Situation: Erlotinib (Tarceva(R)) and Gefitinib (Iressa(R)) in Non-Small Cell Lung Cancer Oncologist, August 1, 2005; 10(7): 467 - 470. [Full Text] [PDF]
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 M. S. Tsao, A. Sakurada, J.-C. Cutz, C.-Q. Zhu, S. Kamel-Reid, J. Squire, I. Lorimer, T. Zhang, N. Liu, M. Daneshmand, et al. Erlotinib in Lung Cancer -- Molecular and Clinical Predictors of Outcome N. Engl. J. Med., July 14, 2005; 353(2): 133 - 144. [Abstract] [Full Text] [PDF]
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X. L. Mu, L. Y. Li, X. T. Zhang, M. Z. Wang, R. E. Feng, Q. C. Cui, H. S. Zhou, and B. Q. Guo Gefitinib-Sensitive Mutations of the Epidermal Growth Factor Receptor Tyrosine Kinase Domain in Chinese Patients with Non-Small Cell Lung Cancer Clin. Cancer Res., June 15, 2005; 11(12): 4289 - 4294. [Abstract] [Full Text] [PDF]
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S. Toyooka, K. Kiura, T. Mitsudomi, S. Kobayashi, D. G. Tenen, and B. Halmos EGFR Mutation and Response of Lung Cancer to Gefitinib N. Engl. J. Med., May 19, 2005; 352(20): 2136 - 2136. [Full Text] [PDF]
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T.-Y. Chou, C.-H. Chiu, L.-H. Li, C.-Y. Hsiao, C.-Y. Tzen, K.-T. Chang, Y.-M. Chen, R.-P. Perng, S.-F. Tsai, and C.-M. Tsai Mutation in the Tyrosine Kinase Domain of Epidermal Growth Factor Receptor Is a Predictive and Prognostic Factor for Gefitinib Treatment in Patients with Non-Small Cell Lung Cancer Clin. Cancer Res., May 15, 2005; 11(10): 3750 - 3757. [Abstract] [Full Text] [PDF]
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