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Frequency and Type of Epidermal Growth Factor Receptor Mutations in Moroccan Patients with Lung Adenocarcinoma
ORIGINAL ARTICLE
Frequency and Type of Epidermal Growth Factor Receptor Mutations in Moroccan Patients with Lung Adenocarcinoma Hassan Errihani, MD, PhD,* Hanane Inrhaoun, MD,* Anouar Boukir, MD,* Fouad Kettani, MD, PhD,† Lamia Gamra, MD, PhD,‡ Amina Mestari, MD,§ Lamia Jabri, MD,║ Youssef Bensouda, MD,* Hind Mrabti, MD,* and Ibrahim Elghissassi, MD*
Introduction: Epidermal growth factor receptor (EGFR) mutations in non–small-cell lung cancer predict response to tyrosine kinase inhibitors. The frequency of EGFR mutations is ethnicity-dependent, with a higher proportion in Asian populations than in whites. The prevalence of these mutations among North African patients is unknown.The objective of this study was to report the frequency and spectrum of EGFR mutations in a group of Moroccan patients with lung adenocarcinoma (AC). Methods: Tumor specimens from 137 Moroccan patients with lung AC were selected to determine frequency and spectrum of EGFR mutations. Mutation detection techniques were polymerase chain reaction amplification and sequencing of exons 18, 19, 20, and 21. Results: The overall frequency of the EGFR mutation was 21%. Mutations were mainly detected in the exon 19 (69%), followed by exon 21 (21%) and exon 20 (7%), whereas mutations in the exon 18 were rare (3%). EGFR mutation rate was significantly higher in women and in never smokers. Conclusion: Some one fifth of lung AC tumors in Moroccan patients harbor EGFR mutations. This mutation frequency is higher than that found in whites but lower than in Asian population. Further studies, in larger numbers of patients, are needed to confirm these findings. Key Words: Epidermal growth factor receptor mutation, Morocco, Frequency. (J Thorac Oncol. 2013;8: 1212-1214)
E
pidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that is a member of the protein kinase superfamily. Binding of ligand to the extracellular domain of EGFR leads to receptor dimerization and activation of *Department of Medical Oncology, National Institute of Oncology, Rabat, Morocco; †Department of Pathology, Nations-Unies Pathology Center, Rabat, Morocco; ‡Department of Pathology, Hassan Pathology Center, Rabat, Morocco; §Department of Pathology, Agdal Pathology Center, Rabat, Morocco; and ║Department of Pathology, Casapath Pathology Center, Casablanca, Morocco. Disclosure: The authors declare no conflict of interest. Address for correspondence: Elghissassi Ibrahim, MD, Department of Medical Oncology, National Institute of Oncology, Allal Elfassi Street, Rabat, 62000, Morocco. E-mail: [email protected] Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0809-1212
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signaling pathways associated with cell growth and neoplastic progression.1 EGFR mutations reported in non–small-cell lung cancer (NSCLC) are potential therapeutic targets leading to improved response and survival with tyrosine kinase inhibitors (TKIs) in patients carrying such mutations.2 These mutations are more common in patients with adenocarcinoma (AC), women, and no history of smoking.2,3 The frequency of EGFR mutations is also ethnicity-dependent, with a higher proportion in Asian populations than in whites.4–6 However, such information is still lacking in some other races, such as North African patients. The most common mutations associated with sensitivity to EGFR-TKIs include exon 19 deletions and the L858R point mutation in exon 21. Together, these two mutations account for nearly 90% of all EGFR mutations in NSCLC.7,8 The main goal of this study was to report the frequency and spectrum of EGFR mutations in an unselected group of Moroccan patients with lung AC. In addition, we examined the relationship between the mutations and several parameters, including sex and smoking status.
PATIENTS AND METHODS Data of all lung AC samples were collected from four pathology laboratories in Morocco between November 2010 and August 2012. All of these laboratories outsource EGFR mutation testing to the Molecular Biology Laboratory at Georges Pompidou European Hospital (Paris, France) and perform more than 90% of all tests requested in Morocco. Genomic DNA was isolated from formalin-fixed paraffin-embedded tumor tissues. Genetic analysis of the EGFR gene was performed by TaqMan (Roche Molecular Diagnostics, Basel, Switzerland) polymerase chain reaction assay and direct sequencing of exons 18, 19, 20, and 21. All tumor specimens were biopsy samples. Only Moroccan patients with advanced lung AC were included. All EGFR tests that were outsourced from the pathology labs were considered for this study. The histologic diagnosis of AC was verified using the pathology report provided by participating laboratories. Never smokers were defined as individuals who reported smoking fewer than 100 cigarettes in their lifetime.
Journal of Thoracic Oncology ® • Volume 8, Number 9, September 2013
Journal of Thoracic Oncology ® • Volume 8, Number 9, September 2013
TABLE 1. Demographic Characteristics of the Study Population All Patients (n = 137) No %
Characteristics Age (yr) Median Range Sex Male Female Smoking history Never Ever Histology Adenocarcinoma Stage at diagnosis IV
59 37–87 91 (66%) 46 (44%) 58 (42%) 79 (58%) 137 (100%) 137 (100%)
The potential associations of EGFR mutation with age, sex, and smoking status were analyzed using χ2 statistics. Means of age were compared using the t test. A p value less than 0.05 was considered statistically significant. All analyses were performed using SPSS (version 20; SPSS Inc., Chicago, IL).
RESULTS One hundred thirty-seven lung ACs from Moroccan patients were collected. The study population consisted of 91 men (66%) and 46 women (44%), with a median age of 59 years (range, 37–87 years). The demographic characteristics of the patients are provided in Table 1. A total of 29 EGFR mutations were found in this series of 137 patients (21%). The most frequent EGFR mutation was detected in exon 19 (20 patients; 69%), followed by exon 21 (6 patients; 21%). There were two mutations in exon 18 (7%) and only one in exon 20 (3%). In the population with EGFR mutations, the frequency of women was significantly higher than that found in patients with wild-type EGFR (76% versus 22%; p < 0.0001). The frequency of never smokers in patients with tumors having
Frequency of EGFR Mutations in Moroccan Patients
EGFR mutations was significantly higher than that observed in patients without mutations (83% versus 31%; p < 0.0001). The mean age did not differ between the two groups (Table 2).
DISCUSSION Lung cancer is one of the most common cancers in Morocco and in the world, and is the leading cause of cancer mortality in both men and women.9 EGFR mutations are currently used as predictive markers of clinical response to EGFR-TKIs, with 70% to 80% of patients deriving substantial benefit from these targeted therapies.2 This shows the clinical relevance of EGFR mutational status for therapeutic decision making in patients with advanced NSCLC. In the present series, EGFR mutations were identified in 29 of 137 Moroccan patients (21%). To the best of our knowledge, this study represents the first study to date reporting the EGFR mutation rate in North African and Arab populations. Some previous studies have demonstrated a genetic divergence of EGFR mutation rates according to ethnicity.4–6,10,11 Indeed, the EGFR mutation rate in East-Asian patients (39%–43%) is much higher than that of the white population (11%–13%) whereas some races, such SouthAsian, have an intermediate rate (23%). EGFR mutation frequency in Moroccan patients, as reported in this study, is higher than that found in whites but lower than in Asians. This rate is in the same order of magnitude as that reported in some developing countries, like Bangladesh (Table 3). In ACs, the majority of mutations have been identified in exons 18 to 21, which encode the tyrosine kinase domain. Over 90% of the clinically important EGFR mutations are either a small deletion in exon 19 or a point mutation in exon 21.7,8 Several studies have reported similar distribution of exon 19 mutation (35%–50%) and exon 21 mutation (33%–48%) between Asian and non-Asian patients6–8,12 (Table 4). In our subjects, EGFR mutations were mainly detected in the exon 19 (69%) followed by exon 21 (21%) and exon 20 (7%), whereas mutations in the exon 18 were rare (3%). Therefore, Moroccan patients may have a higher rate of exon 19 mutation and lower frequency of exon 21 mutation than other races. Mutation type status may have clinical relevance because some studies have shown that response to EGFR-TKIs varies
TABLE 2. Patient Characteristics by EGFR Mutation Status Characteristics Mean age at diagnosis (yr) Sex Male Female Smoking history Ever Never
EGFR Mutations
EGFR Wild Type
(n = 29)
(n = 108)
60
60
7 (24%) 22 (76%)
84 (78%) 24 (22%)
<0.0001**
5 (17%) 24 (83%)
74 (69%) 34 (31%)
<0.0001**
p 0.98*
*p value calculated by t test. **p value calculated by χ2 test. EGFR, epidermal growth factor receptor.
Copyright © 2013 by the International Association for the Study of Lung Cancer
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Journal of Thoracic Oncology ® • Volume 8, Number 9, September 2013
Errihani
TABLE 3. Frequency of EGFR Mutation by Race Study Tanaka et al. Choi et al.5 Rahman et al.11 Castro et al.6 Smits et al.10 This study 4
Race
EGFR Mutation (%)
East Asian (Japan) East Asian (Korea) South Asian (Bangladesh) White White North African
104/242 (43%) 203/521 (39%) 14/61 (23%) 29/216 (13%) 66/620 (11%) 29/137 (21%)
ACKNOWLEDGMENT
This work was supported by the Research and Investigation in Medical Oncology Moroccan Group. REFERENCES
EGFR, epidermal growth factor receptor.
TABLE 4. Frequency of EGFR Mutation Types by Race Exon 21 Study
Race
Exon 19 Deletion (%)
L858R Mutation (%)
Huang et al.7 Shigematsu et al.8 Castro et al.6 De Mello et al.12 This study
Asian American White White North African
35 44 39 50 69
48 41 33 45 21
EGFR, epidermal growth factor receptor.
according to the mutation type. Rosell et al.13 have reported an increased response to EGFR-TKIs in patients with exon 19 deletions versus exon 21 L858R mutation (p = 0.001). In addition, Jackman et al.14 found that patients with exon 19 deletions treated with EGFR-TKIs had a median survival of 38 months compared with only 17 months in those with the exon 21 point mutation. Thus, the high rate of exon 19 mutation in Moroccan population may result in a higher frequency of response to treatment. In the present study, the EGFR mutation rate was significantly higher in women and in never smokers. These results are in keeping with those reported by other studies.2,3 However, it is now admitted that the presence of EGFR mutation predicts the likelihood of response to EGFR-TKI treatment more than clinical characteristics such sex and smoking history.2 Thus, only EGFR mutation status may truly underlie sensitivity to treatment. In conclusion, the present study revealed that EGFR mutation rate in Moroccan patients lies between that of Asian and white populations. The high rate of exon 19 mutation in
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this study may result in a higher frequency of response to EGFR-TKIs. Further studies, in larger numbers of patients, are needed to confirm these findings.
1. Ciardiello F, De Vita F, Orditura M, Tortora G. The role of EGFR inhibitors in nonsmall cell lung cancer. Curr Opin Oncol 2004;16:130–135. 2. Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361: 947–957. 3. 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. 4. Tanaka T, Matsuoka M, Sutani A, et al. Frequency of and variables associated with the EGFR mutation and its subtypes. Int J Cancer 2010;126:651–655. 5. Choi YL, Sun JM, Cho J, et al. EGFR mutation testing in patients with advanced non-small cell lung cancer: a comprehensive evaluation of real-world practice in an East Asian tertiary hospital. PLoS One 2013;8:e56011. 6. Castro AS, Parente B, Gonçalves I, et al. Epidermal growth factor receptor mutation study for 5 years, in a population of patients with non-small cell lung cancer. Rev Port Pneumol 2013;19:7–12. 7. Huang SF, Liu HP, Li LH, et al. High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res 2004;10:8195–8203. 8. Shigematsu H, Gazdar AF. Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer 2006;118: 257–262. 9. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin 2009;59:225–249. 10. Smits AJ, Kummer JA, Hinrichs JW, et al. EGFR and KRAS mutations in lung carcinomas in the Dutch population: increased EGFR mutation frequency in malignant pleural effusion of lung adenocarcinoma. Cell Oncol (Dordr) 2012;35:189–196. 11. Rahman S, Kondo N, Yoneda K, et al. Frequency of epidermal growth factor receptor mutations in Bangladeshi patients with adenocarcinoma of the lung. Int J Clin Oncol. 2013 Jan 9. 12. de Mello RA, Pires FS, Marques DS, et al. EGFR exon mutation distribution and outcome in non-small-cell lung cancer: a Portuguese retrospective study. Tumour Biol 2012;33:2061–2068. 13. Rosell R, Moran T, Queralt C, et al.; Spanish Lung Cancer Group. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958–967. 14. Jackman DM, Yeap BY, Sequist LV, et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res 2006;12:3908–3914.
Copyright © 2013 by the International Association for the Study of Lung Cancer
Frequency and Type of Epidermal Growth Factor Receptor Mutations in Moroccan Patients with Lung Adenocarcinoma Hassan Errihani, MD, PhD,* Hanane Inrhaoun, MD,* Anouar Boukir, MD,* Fouad Kettani, MD, PhD,† Lamia Gamra, MD, PhD,‡ Amina Mestari, MD,§ Lamia Jabri, MD,║ Youssef Bensouda, MD,* Hind Mrabti, MD,* and Ibrahim Elghissassi, MD*
Introduction: Epidermal growth factor receptor (EGFR) mutations in non–small-cell lung cancer predict response to tyrosine kinase inhibitors. The frequency of EGFR mutations is ethnicity-dependent, with a higher proportion in Asian populations than in whites. The prevalence of these mutations among North African patients is unknown.The objective of this study was to report the frequency and spectrum of EGFR mutations in a group of Moroccan patients with lung adenocarcinoma (AC). Methods: Tumor specimens from 137 Moroccan patients with lung AC were selected to determine frequency and spectrum of EGFR mutations. Mutation detection techniques were polymerase chain reaction amplification and sequencing of exons 18, 19, 20, and 21. Results: The overall frequency of the EGFR mutation was 21%. Mutations were mainly detected in the exon 19 (69%), followed by exon 21 (21%) and exon 20 (7%), whereas mutations in the exon 18 were rare (3%). EGFR mutation rate was significantly higher in women and in never smokers. Conclusion: Some one fifth of lung AC tumors in Moroccan patients harbor EGFR mutations. This mutation frequency is higher than that found in whites but lower than in Asian population. Further studies, in larger numbers of patients, are needed to confirm these findings. Key Words: Epidermal growth factor receptor mutation, Morocco, Frequency. (J Thorac Oncol. 2013;8: 1212-1214)
E
pidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that is a member of the protein kinase superfamily. Binding of ligand to the extracellular domain of EGFR leads to receptor dimerization and activation of *Department of Medical Oncology, National Institute of Oncology, Rabat, Morocco; †Department of Pathology, Nations-Unies Pathology Center, Rabat, Morocco; ‡Department of Pathology, Hassan Pathology Center, Rabat, Morocco; §Department of Pathology, Agdal Pathology Center, Rabat, Morocco; and ║Department of Pathology, Casapath Pathology Center, Casablanca, Morocco. Disclosure: The authors declare no conflict of interest. Address for correspondence: Elghissassi Ibrahim, MD, Department of Medical Oncology, National Institute of Oncology, Allal Elfassi Street, Rabat, 62000, Morocco. E-mail: [email protected] Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0809-1212
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signaling pathways associated with cell growth and neoplastic progression.1 EGFR mutations reported in non–small-cell lung cancer (NSCLC) are potential therapeutic targets leading to improved response and survival with tyrosine kinase inhibitors (TKIs) in patients carrying such mutations.2 These mutations are more common in patients with adenocarcinoma (AC), women, and no history of smoking.2,3 The frequency of EGFR mutations is also ethnicity-dependent, with a higher proportion in Asian populations than in whites.4–6 However, such information is still lacking in some other races, such as North African patients. The most common mutations associated with sensitivity to EGFR-TKIs include exon 19 deletions and the L858R point mutation in exon 21. Together, these two mutations account for nearly 90% of all EGFR mutations in NSCLC.7,8 The main goal of this study was to report the frequency and spectrum of EGFR mutations in an unselected group of Moroccan patients with lung AC. In addition, we examined the relationship between the mutations and several parameters, including sex and smoking status.
PATIENTS AND METHODS Data of all lung AC samples were collected from four pathology laboratories in Morocco between November 2010 and August 2012. All of these laboratories outsource EGFR mutation testing to the Molecular Biology Laboratory at Georges Pompidou European Hospital (Paris, France) and perform more than 90% of all tests requested in Morocco. Genomic DNA was isolated from formalin-fixed paraffin-embedded tumor tissues. Genetic analysis of the EGFR gene was performed by TaqMan (Roche Molecular Diagnostics, Basel, Switzerland) polymerase chain reaction assay and direct sequencing of exons 18, 19, 20, and 21. All tumor specimens were biopsy samples. Only Moroccan patients with advanced lung AC were included. All EGFR tests that were outsourced from the pathology labs were considered for this study. The histologic diagnosis of AC was verified using the pathology report provided by participating laboratories. Never smokers were defined as individuals who reported smoking fewer than 100 cigarettes in their lifetime.
Journal of Thoracic Oncology ® • Volume 8, Number 9, September 2013
Journal of Thoracic Oncology ® • Volume 8, Number 9, September 2013
TABLE 1. Demographic Characteristics of the Study Population All Patients (n = 137) No %
Characteristics Age (yr) Median Range Sex Male Female Smoking history Never Ever Histology Adenocarcinoma Stage at diagnosis IV
59 37–87 91 (66%) 46 (44%) 58 (42%) 79 (58%) 137 (100%) 137 (100%)
The potential associations of EGFR mutation with age, sex, and smoking status were analyzed using χ2 statistics. Means of age were compared using the t test. A p value less than 0.05 was considered statistically significant. All analyses were performed using SPSS (version 20; SPSS Inc., Chicago, IL).
RESULTS One hundred thirty-seven lung ACs from Moroccan patients were collected. The study population consisted of 91 men (66%) and 46 women (44%), with a median age of 59 years (range, 37–87 years). The demographic characteristics of the patients are provided in Table 1. A total of 29 EGFR mutations were found in this series of 137 patients (21%). The most frequent EGFR mutation was detected in exon 19 (20 patients; 69%), followed by exon 21 (6 patients; 21%). There were two mutations in exon 18 (7%) and only one in exon 20 (3%). In the population with EGFR mutations, the frequency of women was significantly higher than that found in patients with wild-type EGFR (76% versus 22%; p < 0.0001). The frequency of never smokers in patients with tumors having
Frequency of EGFR Mutations in Moroccan Patients
EGFR mutations was significantly higher than that observed in patients without mutations (83% versus 31%; p < 0.0001). The mean age did not differ between the two groups (Table 2).
DISCUSSION Lung cancer is one of the most common cancers in Morocco and in the world, and is the leading cause of cancer mortality in both men and women.9 EGFR mutations are currently used as predictive markers of clinical response to EGFR-TKIs, with 70% to 80% of patients deriving substantial benefit from these targeted therapies.2 This shows the clinical relevance of EGFR mutational status for therapeutic decision making in patients with advanced NSCLC. In the present series, EGFR mutations were identified in 29 of 137 Moroccan patients (21%). To the best of our knowledge, this study represents the first study to date reporting the EGFR mutation rate in North African and Arab populations. Some previous studies have demonstrated a genetic divergence of EGFR mutation rates according to ethnicity.4–6,10,11 Indeed, the EGFR mutation rate in East-Asian patients (39%–43%) is much higher than that of the white population (11%–13%) whereas some races, such SouthAsian, have an intermediate rate (23%). EGFR mutation frequency in Moroccan patients, as reported in this study, is higher than that found in whites but lower than in Asians. This rate is in the same order of magnitude as that reported in some developing countries, like Bangladesh (Table 3). In ACs, the majority of mutations have been identified in exons 18 to 21, which encode the tyrosine kinase domain. Over 90% of the clinically important EGFR mutations are either a small deletion in exon 19 or a point mutation in exon 21.7,8 Several studies have reported similar distribution of exon 19 mutation (35%–50%) and exon 21 mutation (33%–48%) between Asian and non-Asian patients6–8,12 (Table 4). In our subjects, EGFR mutations were mainly detected in the exon 19 (69%) followed by exon 21 (21%) and exon 20 (7%), whereas mutations in the exon 18 were rare (3%). Therefore, Moroccan patients may have a higher rate of exon 19 mutation and lower frequency of exon 21 mutation than other races. Mutation type status may have clinical relevance because some studies have shown that response to EGFR-TKIs varies
TABLE 2. Patient Characteristics by EGFR Mutation Status Characteristics Mean age at diagnosis (yr) Sex Male Female Smoking history Ever Never
EGFR Mutations
EGFR Wild Type
(n = 29)
(n = 108)
60
60
7 (24%) 22 (76%)
84 (78%) 24 (22%)
<0.0001**
5 (17%) 24 (83%)
74 (69%) 34 (31%)
<0.0001**
p 0.98*
*p value calculated by t test. **p value calculated by χ2 test. EGFR, epidermal growth factor receptor.
Copyright © 2013 by the International Association for the Study of Lung Cancer
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Journal of Thoracic Oncology ® • Volume 8, Number 9, September 2013
Errihani
TABLE 3. Frequency of EGFR Mutation by Race Study Tanaka et al. Choi et al.5 Rahman et al.11 Castro et al.6 Smits et al.10 This study 4
Race
EGFR Mutation (%)
East Asian (Japan) East Asian (Korea) South Asian (Bangladesh) White White North African
104/242 (43%) 203/521 (39%) 14/61 (23%) 29/216 (13%) 66/620 (11%) 29/137 (21%)
ACKNOWLEDGMENT
This work was supported by the Research and Investigation in Medical Oncology Moroccan Group. REFERENCES
EGFR, epidermal growth factor receptor.
TABLE 4. Frequency of EGFR Mutation Types by Race Exon 21 Study
Race
Exon 19 Deletion (%)
L858R Mutation (%)
Huang et al.7 Shigematsu et al.8 Castro et al.6 De Mello et al.12 This study
Asian American White White North African
35 44 39 50 69
48 41 33 45 21
EGFR, epidermal growth factor receptor.
according to the mutation type. Rosell et al.13 have reported an increased response to EGFR-TKIs in patients with exon 19 deletions versus exon 21 L858R mutation (p = 0.001). In addition, Jackman et al.14 found that patients with exon 19 deletions treated with EGFR-TKIs had a median survival of 38 months compared with only 17 months in those with the exon 21 point mutation. Thus, the high rate of exon 19 mutation in Moroccan population may result in a higher frequency of response to treatment. In the present study, the EGFR mutation rate was significantly higher in women and in never smokers. These results are in keeping with those reported by other studies.2,3 However, it is now admitted that the presence of EGFR mutation predicts the likelihood of response to EGFR-TKI treatment more than clinical characteristics such sex and smoking history.2 Thus, only EGFR mutation status may truly underlie sensitivity to treatment. In conclusion, the present study revealed that EGFR mutation rate in Moroccan patients lies between that of Asian and white populations. The high rate of exon 19 mutation in
1214
this study may result in a higher frequency of response to EGFR-TKIs. Further studies, in larger numbers of patients, are needed to confirm these findings.
1. Ciardiello F, De Vita F, Orditura M, Tortora G. The role of EGFR inhibitors in nonsmall cell lung cancer. Curr Opin Oncol 2004;16:130–135. 2. Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361: 947–957. 3. 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. 4. Tanaka T, Matsuoka M, Sutani A, et al. Frequency of and variables associated with the EGFR mutation and its subtypes. Int J Cancer 2010;126:651–655. 5. Choi YL, Sun JM, Cho J, et al. EGFR mutation testing in patients with advanced non-small cell lung cancer: a comprehensive evaluation of real-world practice in an East Asian tertiary hospital. PLoS One 2013;8:e56011. 6. Castro AS, Parente B, Gonçalves I, et al. Epidermal growth factor receptor mutation study for 5 years, in a population of patients with non-small cell lung cancer. Rev Port Pneumol 2013;19:7–12. 7. Huang SF, Liu HP, Li LH, et al. High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res 2004;10:8195–8203. 8. Shigematsu H, Gazdar AF. Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer 2006;118: 257–262. 9. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin 2009;59:225–249. 10. Smits AJ, Kummer JA, Hinrichs JW, et al. EGFR and KRAS mutations in lung carcinomas in the Dutch population: increased EGFR mutation frequency in malignant pleural effusion of lung adenocarcinoma. Cell Oncol (Dordr) 2012;35:189–196. 11. Rahman S, Kondo N, Yoneda K, et al. Frequency of epidermal growth factor receptor mutations in Bangladeshi patients with adenocarcinoma of the lung. Int J Clin Oncol. 2013 Jan 9. 12. de Mello RA, Pires FS, Marques DS, et al. EGFR exon mutation distribution and outcome in non-small-cell lung cancer: a Portuguese retrospective study. Tumour Biol 2012;33:2061–2068. 13. Rosell R, Moran T, Queralt C, et al.; Spanish Lung Cancer Group. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958–967. 14. Jackman DM, Yeap BY, Sequist LV, et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res 2006;12:3908–3914.
Copyright © 2013 by the International Association for the Study of Lung Cancer