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Wu et al Medicine Volume 90, Number 3, May 2011 fewer than 100 cigarettes in their lifetime. Date of diagnosis, all chemotherapy received, and responsiveness of chemotherapy were recorded. Lung cancer histology was defined according to the World Health Organization pathology classification.30 Tumor specimens obtained by either surgical or needle biopsy/ aspiration procedures, including primary lung tumors, malig nant effusion cell blocks, and other distant metastases, were sequenced for mutational analysis. Written informed consent for the use of tissue in molecular analysis was acquired from patients when tumor specimens were procured. This study was approved by the institutional review board of the National Taiwan University Hospital. Antitumor Chemotherapy and Evaluation of Effectiveness The timing and order of different chemotherapy regimens depended on the physicians' discretion. Gefitinib was taken orally at a dosage of 250 mg daily. Baseline assessments were usually performed within 2 weeks before treatment. Chest radiography was routinely performed and assessed every 2-3 weeks to eval uate response after the start of treatment. A chest computed to mography (CT) scan (including liver and adrenal glands) was performed every 2-3 months as routine clinical practice and as needed to confirm the response and progression of disease. Treat ment responses were defined as progressive disease, stable disease, partial response, and complete response, according to the criteria of the Response Evaluation Criteria in Solid Tumors (RECIST) group.28 Patients with complete response or partial response were regarded as responders, and the others as nonresponders, to anti tumor therapy. The disease control status included complete re sponse, partial response, and stable disease. Overall survival was measured from the first day of gefitinib treatment until the day of death. Progression-free survival with gefitinib was measured from the first day ofgefitinib treatment until the first obj ective or clinical sign of disease progression. Mutational Analysis for EGFR We retrospectively reviewed the EGFR mutation status of the lung cancer specimens. Tumor specimens, including paraffin blocks or frozen tissues of surgical specimens, fine needle biop sies, and pleural effusions, were procured for mutational analysis. These formalin-fixed and paraffin-embedded blocks were re trieved from the department of pathology, National Taiwan Uni versity Hospital. Patients tested for EGFR mutations were 1) those who underwent fine needle biopsies or thoracentesis for pleural effusions after July 2004, when consecutive recruitment for EGFR mutations was started at the hospital, 2) those whose resected tumors were retrospectively sequenced, or 3) those who were recruited for retrospective NSCLC studies.5,24,34 The above patients underwent EGFR testing, and they were not selected by the clinical or histologic characteristics. Some patients of the study population were reported in previously published papers that focused on specific issues, such as EGFR exon 20 mutations.34 The mutational analysis for EGFR genes has been de scribed previously.24 Briefly, DNA was derived from the tumors embedded in paraffin blocks using a QIAamp DNA Mini kit (Qiagen, Valencia, CA). The TK domain of the EGFR coding sequence, involving exons 18,19, 20, and 21, was amplified, and independent polymerase chain reaction (PCR) amplifications were purified and sequenced in an automatic ABI Prism 3700 DNA Analyzer. The frozen lung cancer tissues were obtained at surgery, immediately snap frozen in liquid nitrogen, and stored until use. Total mRNA was extracted from resected cancer tissue using an RNA extraction kit (RNeasy Mini kit; Qiagen). The 4 exons (exon 18-21) that code for the TK domain of the EGFR gene were amplified with primers and PCR conditions as previously reported.12,34 Reverse transcription (RT)-PCR amplicons were purified and sequenced. All sequencing reactions were performed in both forward and reverse directions, using tracings from at least 2 PCRs. Statistical Analysis All categorical variables were analyzed with chi-square tests, except where a small size (<5) required the use of the Fisher exact test. Otherwise, the Student t test was conducted for continuous variables for means comparisons between the 2 groups. We also constructed the dichotomized response vari able using a logistic regression model. For multivariate analy sis, multiple logistic regression using the stepwise method was implemented to select significant variables, which were defined as 0.05 for both the entering and removing effect in the models. Median overall survival and progression-free survival after gefitinib treatment were estimated by the Kaplan-Meier method to assess the time to death or progression. The log-rank test was used to compare cumulative survival in different groups, such as responder vs. nonresponder. All reported p values were 2-sided, and a p value less than 0.05 was considered statistically signif icant. All statistical analyses were performed using SPSS soft ware (v. 13.0; SPSS Inc. Chicago, IL). RESULTS Patients Receiving Gefitinib for Advanced NSCLC A total of 951 NSCLC patients received gefitinib treatment between January 2004 and August 2008. We excluded 44 951 Patients receiving gefitinib Exclude 44 patients: 3 Previous erlotinib 2 Chemotherapy with gefitinib 39 Follow-up at other hospital 907 Patients in analysis 564 First-line gefitinib (j343 First-line chemotherapy^) 140 Second-line gefitinib (^203 Second-line treatment^) FIGURE 1. Flowchart of treatment algorithm of patients receiving gefitinib for advanced NSCLC. 160 I www.md-journal.com 2011 Lippincott Williams & Wilkins Copyright 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Medicine Volume 90, Number 3, May 2011 Gefitinib Treatment in NSCLC TABLE 1. Clinical Data of Patients Who Received Gefitinib for Advanced NSCLC Variable* Total (n = 907) With EGFR Testing (n = 466) Without EGFR Testing (n = 441) p Age, mean (range), yr Sex (F/M), No. Smoking status (nonsmoker/smoker), No. Cell type (adeno/other), No. Staging (IIIb/IV), No. Performance status (ECOG 0-1/Q2), No. Responders, No. (%) Disease control, No. (%) Gefitinib line, No. 1st line 2nd line 3rd or later line Progression-free durationf, median (range), mo Survival durationf, median (range), mo 65 (25-95) 541/366 646/261 829/78 123/784 551/356 404 (44.5) 566 (62.4) 564 140 203 4.9 (0.5-62.0) 16.2 (0.5-64.8) 64 (25-91) 301/165 359/107 432/34 60/406 305/161 218 (46.8) 302 (64.8) 300 70 96 5.4 (0.5-62.0) 16.7 (0.5-64.8) 65 (29-95) 240/201 287/154 397/44 63/378 246/195 186 (42.2) 264 (59.9) 264 70 107 4.0 (0.5-60.2) 15.3 (0.5-60.2) 0.182 0.001 <0.001 0.150 0.535 0.003 0.163 0.125 0.319 0.689 0.279 Abbreviations: adeno = adenocarcinoma, ECOG = Eastern Cooperative Oncology Group. *See Methods section for definitions. fAfter start of gefitinib. patients: 3 patients who received erlotinib (another TK inhibitor before administration of gefitinib), 2 patients who received other chemotherapy along with gefitinib, and 39 patients who received follow-up at other hospitals after the start of gefitinib treatment in our hospital (Figure 1). Finally, 907 patients who received treatment and follow-up at the National Taiwan University Hospital were included in the analysis of this study. The demo graphic data of these 907 patients are shown in Table 1. In the 907 patients, 564 patients received gefitinib as firstline anticancer treatment, 140 patients as second-line, and 203 patients as third-line or later-line treatment. The first 3 lines of treatment for the 907 patients are listed in Table 2. The cutoff date for data collection was July 31, 2009. Ninety-seven patients (10.7%) were still receiving gefitinib for advanced NSCLC at the cutoff date. Four hundred four patients (44.5%) had an objective clinical response (complete response or partial response) to TABLE 2. First 3 Treatments of Patients Who Received Gefitinib for Advanced NSCLC Gefitinib Line 1st-Line gefitinib (n = 564) 2nd-Line gefitinib (n = 140) 3rd- or Later-line gefitinib (n = 203) 1st-Line Treatment (No.) Gefitinib (564) Cisplatin-containing treatment (102) Gemcitabine (25) Vinorelbine (6) Taxane (7) Cisplatin-containing treatment (161) Gemcitabine (29) Vinorelbine (11) Taxane (2) 2nd-Line Treatment (No.) Cisplatin-containing treatment (121) Erlotinib (85) Gemcitabine (35) Vinorelbine (18) Taxane (8) Pemetrexed (8) Cetuximab-containing treatment (2) No 2nd-line (287) Gefitinib (140) Cisplatin-containing treatment (42) Gemcitabine (29) Vinorelbine (8) Taxane (98) Pemetrexed (26) 3rd-Line Treatment (No.) Cisplatin-containing treatment (27) Erlotinib (5) Gemcitabine (23) Vinorelbine (14) Taxane (44) Pemetrexed (26) Cetuximab-containing treatment (4) No 3rd-line (421) Cisplatin-containing treatment (12) Erlotinib (8) Gemcitabine (10) Vinorelbine (4) Taxane (14) Pemetrexed (12) No 3rd-line (80) Gefitinib (150) Cisplatin-containing treatment (4) Gemcitabine (4) Vinorelbine (8) Taxane (30) Pemetrexed (7) 2011 Lippincott Williams & Wilkins www.md-journal.com I 161 Copyright 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Wu et al Medicine Volume 90, Number 3, May 2011 TABLE 3. Clinical Data of Patients With EGFR Testing Who Received Gefitinib for Advanced NSCLC Variable* Age, mean (range), yr Sex (F/M), No. Smoking status (nonsmoker/smoker), No. Cell type (adeno/other), No. Staging (IIIb/IV), No. Performance status (ECOG 0-1/Q2), No. Responders, No. (%) Disease control, No. (%) Gefitinib line, No. 1st line 2nd line 3rd or later line Progression-free durationf, median (range), mo Survival durationf, median (range), mo Abbreviations: See Table 1. *See Methods section for definitions. fAfter start of gefitinib. Mutant EGFR (n = 272) 65 (28-91) 187/85 224/48 260/12 40/232 169/103 183 (67.3) 228 (83.8) 171 37 64 7.8 (0.5-62.0) 19.4 (1.0-64.8) Wildtype EGFR (n = 194) 64 (25-89) 114/80 135/59 172/22 20/174 136/58 35 (18.0) 74 (38.1) 129 33 32 2.0 (0.5-46.7) 12.4 (0.5-49.9) p 0.363 0.026 0.001 0.005 0.162 0.074 <0.001 <0.001 0.392 <0.001 0.001 gefitinib. In the total 907 patients, the median progression-free survival was 4.9 months, and overall survival after the start of gefitinib was 16.2 months. The 12-month progression-free sur vival rate was 18.5%, and the 12-month survival rate was 50.6%. EGFR Mutations and Treatment Response In the 907 patients who received gefitinib, 466 patients were analyzed for EGFR mutations, and the other 441 patients were not. The demographic data of the patient groups who did or did not undergo EGFR mutation testing are shown in Table 1. The tissues examined for mutations included 102 surgical spec imens, 202 needle biopsies (echo-guided, CT-guided, or bronchoscopic), and 162 cell block preparations of pleural effusion. In the 466 patients who received testing, 272 (58.4%) had EGFR mutations. In the study population, the mutations were more frequent in nonsmokers than smokers (62.4% vs. 44.9%, p = 0.001), in adenocarcinomas than non-adenocarcinomas (60.2% vs. 35.3%, p = 0.005), and in female patients than in males (62.1% vs. 51.5%, p = 0.026) (Table 3). Age and clinical cancer staging were comparable between patients with mutant EGFR and patients with wildtype EGFR. In the 272 patients with EGFR mutations, 106 patients (39.0%) had deletions in exon 19, 114 patients (41.9%) had mutation L858R, 11 patients (4.0%) had mutations in exon 20, and the other 41 patients (15.1%) had other single or complex EGFR mutations. EGFR mutations are associated with objective gefitinib efficacy. The gefitinib response rate and disease control rate were 67.3% and 83.8%, respectively, in patients with EGFR mutations, significantly better than in patients with wildtype EGFR (response rate, 18.0% and disease control rate, 38.1%). The good response rate led to a significantly longer progressionfree survival and overall survival in patients with mutant EGFR (Table 3) (Figure 2 A and B). Female sex, adenocarcinoma cell FIGURE 2. Kaplan-Meier analysis of progression-free survival (A) and overall survival (B) after starting gefitinib in patients with mutant or wildtype EGFR. 162 I www.md-journal.com 2011 Lippincott Williams & Wilkins Copyright 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Medicine Volume 90, Number 3, May 2011 Gefitinib Treatment in NSCLC TABLE 4. Predictive Factors Associated With Clinical Response to Gefitinib in Patients With EGFR Testing Variable Sex Female Male Cell type Adenocarcinoma Other Smoking status Smoker Nonsmoker Age, yr <65 >65 Clinical staging Stage IIIb Stage IV EGFR status Mutant Wildtype *Logistic regression test. fChi-square test. {Fisher exact test. No. of Patients (n = 466) 301 165 432 34 107 359 231 235 60 406 272 194 Responder (No.) 156 62 213 5 33 185 108 110 26 192 183 35 Response Rate (%) 51.8 37.6 49.3 14.7 30.8 51.5 46.8 46.8 43.3 47.3 67.3 18.0 Univariate Analysis, p 0.003f <0.001{ <0.001f 0.990f 0.566f <0.001f Multivariate Analysis, p* 0.550 0.002 0.014 <0.001 type, nonsmoker status, and EGFR mutation were associated with gefitinib objective response in univariate analysis (Table 4). After multivariate analysis by logistic regression, adenocarci noma cell type (p = 0.002), nonsmoker status (p = 0.014), and EGFR mutation (p < 0.001) were independently associated with the clinical response to gefitinib. Patients Not Tested for EGFR Mutations Four hundred forty-one patients did not receive analysis for EGFR mutations, for the following reasons: 128 underwent tissue diagnosis for NSCLC in other hospitals, 276 received tissue diagnosis before consecutive recruitment of tissues for EGFR mutations was started at the hospital, 13 were diagnosed by cytology examination only, and 24 had tissue specimens of inadequate size for EGFR analysis. Sex, smoking status, and Eastern Cooperative Oncology Group performance were different between patients who un derwent testing for EGFR mutation and those who did not (Table 1). Other factors, such as age, histology of cancer, and clinical staging, were similar. The gefitinib response rates of patients who did and did not receive testing for EGFR mutations were not different statistically (46.8% vs. 42.2%, respectively, FIGURE 3. Kaplan-Meier analysis of progression-free survival (A) and overall survival (B) after starting gefitinib in patients with or without testing for EGFR mutations. 2011 Lippincott Williams & Wilkins www.md-journal.com I 163 Copyright 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Wu et al Medicine Volume 90, Number 3, May 2011 p = 0.163). In addition, the progression-tree survival (5.4 mo vs. 4.0 mo, p = 0.660) and overall survival (16.7 mo vs. 15.3 mo, p = 0.295) of the 2 groups were comparable (Figure 3A and B). In patients who were not analyzed for EGFR mutations, female sex, adenocarcinoma cell type, and nonsmoker status tended to predict gefitinib response in univariate analysis (Table 5). After multivariate analysis by logistic regression, nonsmoker status (p < 0.001) was independently associated with clinical response to gefitinib. In the group with all 3 good predictors (female sex, adenocarcinoma cell type, and non smoker status) (n = 209), the progression-free survival was much better than in the group without any good predictors (n = 21) (6.3 mo vs. 1.4 mo, respectively, p < 0.001). Similarly, the overall survival was much longer in the group with all 3 good predictors compared to the group with none (21.8 mo vs. 2.0 mo, p < 0.001). Value of EGFR Mutations Beyond the Clinical and Histologic Characteristics To clarify the additional prediction value that EGFR mu tations added to clinical and histologic characteristics, we further analyzed the subgroup of patients who were female, had ade nocarcinoma cell type, and were nonsmokers in the group of patients who underwent testing for EGFR mutations. In the total 441 patients who underwent EGFR analysis, 276 patients were in this subgroup. In this subgroup, 178 patients had mutant EGFR, and 98 patients had wildtype EGFR. Gefitinib response rate and progression-free survival was better in the 178 patients with mutant EGFR than in the 98 patients with wildtype EGFR, even though all patients had favorable clinical and histologic predictors (response rate, 69.7% vs. 26.5%, and progression-free survival 7.9 mo vs. 2.5 mo, both p < 0.001). Median overall survival was longer in patients with EGFR mutation than in those with wildtype EGFR, but the difference was not statistically significant (21.6 mo vs. 17.5 mo, p = 0.762). Furthermore, in the 441 patients who received EGFR test ing, 99 patients were male and smokers. There were only 12 patients who were male, smoker, and had non-adenocarcinoma cell type; the number is too small for analysis. In the 99 male and smoking patients, 45 patients had EGFR mutations and 54 patients had wildtype EGFR. In this subgroup, gefitinib response rate (57.8% vs. 5.9%, p < 0.001), progression-free survival (6.0 mo vs. 1.5 mo, p < 0.001), and overall survival (16.4 mo vs. 5.4 mo, p = 0.002) were all better in patients with EGFR mutations than patients with wildtype EGFR. We also compared patients who had mutant EGFR (n = 272) with patients who did not undergo testing for EGFR mutations (n = 441). Patients with EGFR mutations had more favorable outcomes after gefitinib treatment than patients who did not undergo testing for EGFR mutations, with better response rate (67.3% vs. 42.2%, p < 0.001), progression-free survival (7.8 mo vs. 4.0 mo, p < 0.001), and overall survival (19.4 mo vs. 15.3 mo, p = 0.019). DISCUSSION In the current study, we present the results of gefitinib treatment in patients with advanced NSCLC in a tertiary medical center in Taiwan (East Asia). Our analysis included a large population and a high proportion of patients who had EGFR mutation testing. The progression-free survival of the total 907 patients was 4.9 months, and the overall survival was 16.2 months. EGFR mutation was strongly associated with ob jective response to gefitinib in the patients who were analyzed for EGFR mutations. In the patients who were not analyzed for EGFR mutations, demographic and histopathologic char acteristics helped to predict a good clinical response to gefitinib treatment. Several studies have revealed obvious differences in EGFR mutation rates in NSCLC between patients of Western and Eastern ethnicities. Patients of Eastern ethnicities have been shown to have higher rates of EGFR mutations. In the study by Shigematsu et al,23 the EGFR mutation rate was only 8% in those ofnon-Asian ethnicities (mainly American and Australian, TABLE 5. Predictive Factors Associated With Clinical Response to Gefitinib in Patients Without EGFR Testing Variable Sex Female Male Cell type Adenocarcinoma Other Smoking status Smoker Nonsmoker Age, yr <65 >65 Clinical staging Stage IIIb Stage IV *Logistic regression test. fChi-square test. {Fisher exact test. No. of Patients (n = 441) 240 201 397 44 154 287 203 238 63 378 Responder (No.) 133 53 174 12 28 158 86 100 29 157 Response Rate (%) 55.4 26.4 43.8 27.3 18.2 55.1 42.4 42.0 46.0 41.5 Univariate Analysis, p <0.001f 0.037{ <0.001f 0.941 ( 0.503f Multivariate Analysis, p {* 0.104 0.222 <0.001 164 I www.md-journal.com 2011 Lippincott Williams & Wilkins Copyright 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Medicine Volume 90, Number 3, May 2011 Gefitinib Treatment in NSCLC n = 158), while 30% of those of Asian ethnicity (mainly Japanese, n = 361) had EGFR mutations. In the study by Cortes-Funes et al,3 including all Spanish patients (n = 83), the EGFR mutation rate was 12%. In contrast, in a study composed of only Thai patients, EGFR mutations were detected in 35 of 61 patients (57.4%).25 In the current study population of Taiwanese patients, a large proportion of patients who took gefitinib for advanced NSCLC were analyzed for EGFR muta tions, and the mutation rate was 58.4% (272/466). The obviously different EGFR mutation rates between Asian and non-Asian populations could be the leading cause of different gefitinib efficacy in treating NSCLC. Before the prevalence of analysis for EGFR mutations was high, large-scale clinical studies disclosed the differences of gefitinib response between those of Asian and non-Asian ethnicities. In the ISEL study,27 the overall survival after gefitinib treatment was 9.5 months in Asian patients (24% of the total study popula tion), while overall survival for the whole study population was 5.6 months. In the INTEREST study9 comparing gefitinib and docetaxel as second- or third-line regimens, in the gefitinib arm Asian patients had a longer survival than non-Asian patients. These differences are now considered to be the result of different EGFR mutation rates between different ethnicities. The current study is representative of general clinical practice compared to other clinical trials in Asian populations. We found that the re sponse rate to gefitinib, progression-free survival, and overall survival were comparable with the results of Asian populations in these other clinical trials comprising patients of different ethnicity. The large-scale clinical trial, IPASS, compared gefitinib and standard chemotherapy as first-line treatment for NSCLC.13 The IPASS trial was composed of only Asian patients (total n = 1196, mainly from China and Japan). Of the 437 patients tested for EGFR mutations, 261 (59.7%) had mutant EGFR. The overall survival rate after first-line gefitinib was 18.6 months. The cur rent study also included a large group of patients; we found a mutation rate of 58.4% (272/466). The patients receiving gefitinib as first-line treatment had a survival rate of 17.3 months (data not shown). From these clinical data, we suggest that Taiwanese patients have NSCLC characteristics and gefitinib treatment results similar to those of patients in the IPASS trial, even though the current study is retrospective and based on general daily practice. Patients with mutant EGFR have much better treatment outcomes than those with wildtype EGFR, as reported in the current study and in others. Because EGFR status greatly influences the treatment outcome of gefitinib for NSCLC, there is a call for universal analysis for EGFR mutations before treating advanced NSCLC. Through such analysis, physicians can select highly active therapies, and personalized medicine can be achieved.4 However, universal analysis for EGFR muta tions is not in place at present due to technical and financial concerns. Not every patient with advanced NSCLC receives testing, and physicians can only judge possible treatment out comes and select therapies based on the demographic and histopathology characteristics of the patients. In the current study, the patients who underwent EGFR mutation testing had a progression-free survival and overall survival comparable to those of patients who did not receive testing. For the patients who did not receive testing, factors including female sex, adenocarcinoma cell type, and nonsmoker status tended to pre dict gefitinib response. In Taiwan, advanced NSCLC patients with these factors can be treated with gefitinib with an expec tation of better responses. Moreover, although clinical factors can predict response, our analysis revealed that EGFR status had a more useful predictive value than clinical and histologic characteristics. For example, patients with unfavorable factors, such as male sex and smoking history, can still have a favorable response to gefitinib if they have EGFR mutations. Besides, our analysis also showed that patients with mutant EGFR can have better outcomes than the whole population who did not undergo testing for EGFR mutations. EGFR testing can be performed to guide treatment for NSCLC. That being said, EGFR mutations do not guarantee good gefitinib efficacy, and about 30% patients with mutant EGFR do not respond to gefitinib. Patients with favorable clinical and histologic factors do not definitely respond to gefitinib, either. On the other hand, some patients with wildtype EGFR do respond to gefitinib. Reasons for these phenomena are still not clear. Some new molecular findings may provide a possible hypothesis for the phenomena, for example MET and EML4-ALK genes. Amplification of MET gene and existence of EML4-ALK oncogene both are associated with poor re sponse to TK inhibitors.21,22 Other mechanisms for the resis tance of TK inhibitors and treatment for the resistance will be the focus of future research, and will no doubt change the course of treatment for NSCLC patients. The current study has some limitations. First, there are limitations related to the study's retrospective design. The use of gefitinib and the sequence of other chemotherapy depended on the clinical decisions of the physicians caring for the patients. Selection of gefitinib can be influenced. More female patients, patients with adenocarcinoma cell type, and nonsmoking patients received gefitinib, because they probably had EGFR mutations. There may have been bias in patient selection, and this study population does not represent the whole population of NSCLC patients. Second, the study was done in a single tertiary care center. To compensate for this limitation, we compared the gefitinib response rate and median survival of patients in hos pitals in other parts of Taiwan. The response rates ranged from 30% to 56%, and median survival ranged from 7.5 months to 16.0 months.2,31 We found that the gefitinib treatment outcomes in our study are comparable to those in other parts of Taiwan. In conclusion, a high proportion of NSCLC patients in Taiwan and other Asian areas have favorable treatment outcomes with gefitinib, which can be taken orally and is well tolerated. In the current study of Taiwanese patients, more than half of the patients with advanced NSCLC received EGFR mutation test ing. In patients with EGFR mutations, gefitinib efficacy was prominent and significant. Therefore, analysis for EGFR muta tions should be advocated. In patients who do not receive EGFR analysis, demographic and histopathology factors can be used to guide the choice of gefitinib treatment. REFERENCES 1. Chan SK, Gullick WJ, Hill ME. Mutations of the epidermal growth factor receptor in non-small cell lung cancer--search and destroy. Eur J Cancer. 2006;42:17-23. 2. Chang JW, Liu HP, Hsieh MH, Fang YF, Hsieh MS, Hsieh JJ, Chiu YT, Tsai HY, Chen YH, Chen YT, Hsu HY, Chen YT, Tsai SF, Chen YR, Hsi BL, Huang SF. Increased epidermal growth factor receptor (EGFR) gene copy number is strongly associated with EGFR mutations and adenocarcinoma in non-small cell lung cancers: a chromogenic in situ hybridization study of 182 patients. Lung Cancer. 2008;61:328-339. 3. 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