Letters to the Editor
EGFR Mutation Testing for Squamous Cell Lung Carcinoma To the Editor: The evidence-based clinical practice guideline on molecular testing for the selection of lung cancer patients for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase tyrosine kinase inhibitors by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology recommends that patients with lung adenocarcinoma should not be excluded from testing based on clinical characteristics that include ethnicity, smoking history, and sex.1 We totally agree with this recommendation as our experience and findings also show that sex and smoking history are not sensitive or specific enough to exclude individual patients from testing even though in our patients, EGFR mutations were more frequent in women (52.5%) than in men (27.8%) and more frequent in never smokers (54.8%) than in ever smokers (20.7%).2 EGFR mutations are rare in wellcharacterized, fully excised surgical specimens of squamous cell lung carcinoma lacking any adenocarcinoma component with a reported frequency of less than 5%.1 In the case of limited lung cancer specimens by small biopsies where the possibility of an adenocarcinoma component cannot be completely excluded, the guideline recommends that EGFR mutation testing may be performed in cases showing squamous cell histology with clinical characteristics
Disclosure: The authors declare no conflicts of interest. Address for correspondence: Dr. Chong-Kin Liam, MBBS, MRCP, Department of Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia. E-mail: [email protected] Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0812-e114
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such as young age and a lack of smoking history.1 From our experience with small biopsy specimens taken during flexible bronchoscopy or transcutaneous needle biopsy in patients with advanced-stage non–small-lung cancer, EGFR mutations were detected with the use of real-time polymerase chain reaction based on Scorpion® and Amplification Refractory Mutation System® technologies in 39.4% of adenocarcinoma from 132 patients whereas only one (9.1%) of 11 squamous cell carcinomas was EGFR-mutation positive. The only EGFR-mutation–positive squamous cell carcinoma was from a never smoker whereas the squamous cell carcinomas from all 10 smokers were EGFR-mutation negative.3 Other expert panels4 recommend that apart from nonsquamous NSCLC, EGFR mutation testing should be performed in squamous cell carcinoma patients with clinical features associated with higher prevalence of EGFR mutations such as a lack of smoking history. Furthermore, adenosquamous carcinomas and solid adenocarcinomas, in which EGFR mutations have been reported, can mimic squamous cell carcinoma in small biopsy specimens.5 Chong-Kin Liam, MBBS, MRCP Hwong-Ruey Leow, MBBS, MMed Yong-Kek Pang, MD, MRCP Department of Medicine Faculty of Medicine University of Malaya Kuala Lumpur, Malaysia REFERENCES 1. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol 2013;8:823–859. 2. Liam CK, Wahid MI, Rajadurai P, Cheah YK, Ng TS. Epidermal growth factor receptor mutations in lung adenocarcinoma in Malaysian patients. J Thorac Oncol 2013;8:766–772. 3. Liam CK, Leow HR, How HS, et al. A prospective study on epidermal growth factor receptor mutations in non-small cell lung cancer in Malaysian patients. Respirology 2012; 17 (Suppl. 2), page 92 (Abstract 345).
4. Salto-Tellez M, Tsao MS, Shih JY, et al. Clinical and testing protocols for the analysis of epidermal growth factor receptor mutations in East Asian patients with non-small cell lung cancer: a combined clinical-molecular pathological approach. J Thorac Oncol 2011;6:1663–1669. 5. Paik PK, Varghese AM, Sima CS, et al. Response to erlotinib in patients with EGFR mutant advanced non-small cell lung cancers with a squamous or squamous-like component. Mol Cancer Ther 2012;11:2535–2540.
Spectrum of EGFR Mutation in Lung Adenocarcinoma in Morocco To the Editor: We read with great interest the article published by Errihani et al. on the spectrum of epidermal growth factor receptor (EGFR) mutation in Moroccan patients (n = 137) with lung adenocarcinoma (AC), and we would like to congratulate them for their very important study which in our knowledge represent the first study in Morocco and Arab population. In Morocco, lung cancer represents the first cause of cancer in men1,2 and the ninth cause of cancer in women.2 AC is the second most common histological subtype after squamous-cell carcinoma according to the Casablanca registry, representing 26% of all lung cancers (24.7% in men and 36.9% in women [most common histology in women]).2 The authors showed that the overall frequency of the EGFR mutation was 21%, which is higher than that in white population (11%– 13.7%).3–6 Mutations were mainly detected in the exon 19 (69%), followed by exon 21 (21%) and exon 20 (7%), whereas mutations in the Address for correspondence: Nabil Ismaili, MD, Department of Medical Oncology, Oncology Center, Mohammed VI University Hospital, Marrakech, Morocco. E-mail: ismailinabil@ yahoo.fr Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0812-e114
Journal of Thoracic Oncology ® • Volume 8, Number 12, December 2013
Journal of Thoracic Oncology ® • Volume 8, Number 12, December 2013
exon 18 were rare (3%) in concordance with the majority of published studies.3,4,6 In addition, the authors confirmed the Asian and occidental conclusions that EGFR mutation rate was significantly higher in women and in never smokers.3,4,6 However, the study presents several limitations because of numerous biases, and the result presented here should be interpreted with caution3: - The population analyzed was not representative for the overall Moroccan population; as an example, the frequency of EGFR mutation in female patients included was 34% (46 of 137), largely higher than frequencies showed in Rabat and Casablanca registries (the only 2 registries available in Morocco).1,2 According to Casablanca registry, women with AC represent only 16% of lung AC and men with AC represent 84% of lung AC.1 In fact, in Morocco women, lung cancer was a relatively rare condition representing only 8% to 11.5% of all lung cancers versus 33.4% in developed countries.1,2,7,8 And women with lung cancer in Morocco are not smoker in the vast majority of the case (79%).7 - In another hand, the analysis was performed according to specimen available in private laboratories (Nations-Unies Pathology Center, Hassan Pathology Center, and Agdal Pathology Center, at Rabat, Morocco; and Casapath Pathology Center at Casablanca, Morocco.) excluding the majority of specimen available at the most important institutions in Morocco, such as the University Hospitals (National Institute of Oncology at Rabat, Morocco, and Ibn-Rochd University Hospital at Casablanca, Morocco). We do not agree with the author’s conclusion that EGFR mutation frequency in Moroccan patients is higher than that found in whites, but it is the same than that observed in white population. By using the frequency of EGFR mutation in men (7 of 91 = 7.7%) and the frequency of EGFR mutation in women (22 of 46 = 47.8%) calculated from data of the present
article and by using Moroccan statistics (Casablanca registry), we can estimate the true frequency of EGFR mutation in our population; according to Casablanca registry (the most powerful registry), female patients with lung AC represent 16% of lung AC and male patients with lung AC represent 84% of lung AC, the frequency of EGFR mutation will be approximately (16 × 47.8/100 + 7.7 × 84/100 = 7.6% + 6.45%) = 14%. Therefore, we suggest that the incidence of EGFR mutation in Moroccan patients is equivalent than that observed in white population, and we encourage the Moroccan investigators to conduct a multiinstitutional and large study including consecutive patients with AC diagnosed at the most important Cancer Center in Morocco to confirm this suggestion and to refine the result of the present study.3 Nabil Ismaili, MD Rizlane Belbaraka, MD Department of Medical Oncology Oncology Center Mohammed VI University Hospital Marrakech, Morocco REFERENCES 1. Available at: srvweb.sante.gov.ma/.../Registre %20Cancer%20Grand%20Casablanca%2... 2. Tazi MA, Er-Raki A, Benjaafar N. Cancer incidence in Rabat, Morocco: 2006-2008. Ecancermedicalscience. 2013;7:338. 3. Errihani H, Inrhaoun H, Boukir A, et al. Frequency and type of epidermal growth factor receptor mutations in moroccan patients with lung adenocarcinoma. J Thorac Oncol 2013;8:1212–1214. 4. 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. 5. 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. 6. Bauml J, Mick R, Zhang Y, et al. Frequency of EGFR and KRAS mutations in patients with non small cell lung cancer by racial background: do disparities exist? Lung Cancer 2013;81:347–353. 7. Khouchani M, Selmaji I, Elmorabit B, et al. Female lung cancer in Marrakech. Clin Cancer Investig J 2013;2:128–131 8. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69–90.
Copyright © 2013 by the International Association for the Study of Lung Cancer
Letters to the Editor
Spectrum of EGFR Mutation in Lung Adenocarcinoma in Morocco In Response: On behalf of the author group, we thank Dr. Ismaili for his interest in our article Spectrum of EGFR Mutation in Lung Adenocarcinoma in Morocco1 and his insightful comments. With regard to his comments, we think the following points should be clarified. First, our series was a retrospective study and therefore some potential sources of bias cannot be ruled out. Despite this, our results provide some information about the frequency of epidermal growth factor receptor (EGFR) mutation in lung adenocarcinoma in Morocco, and as indicated in our article, have to be confirmed in larger prospective studies. Second, data analysis was performed according to the availability of specimens in private pathology laboratories because these laboratories perform more than 90% of all tests requested in Morocco, and EGFR mutation testing is not available for specimens that could be found in public institutions. We do not fully agree with suggestion made by Dr. Ismaili that the incidence of EGFR mutation in Moroccan patients would be equivalent than that observed in white population. In our series, the EGFR mutation rate was higher than that found in other studies conducted in whites despite similar sex distribution.2,3 For example, Rosell et al.2, in a large prospective Spanish study, reported EGFR mutation in only 16% of patients with lung cancer including 39% of female patients. In such situation, extrapolation as done by Dr. Ismaili should be avoided, and we believe that the best way to provide an accurate EGFR mutation rate in Moroccan patients is to Address for correspondence: Ibrahim Elghissassi, MD, Medical Oncology Department, 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: 1556-0864/13/0812-e115
e115
EGFR Mutation Testing for Squamous Cell Lung Carcinoma To the Editor: The evidence-based clinical practice guideline on molecular testing for the selection of lung cancer patients for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase tyrosine kinase inhibitors by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology recommends that patients with lung adenocarcinoma should not be excluded from testing based on clinical characteristics that include ethnicity, smoking history, and sex.1 We totally agree with this recommendation as our experience and findings also show that sex and smoking history are not sensitive or specific enough to exclude individual patients from testing even though in our patients, EGFR mutations were more frequent in women (52.5%) than in men (27.8%) and more frequent in never smokers (54.8%) than in ever smokers (20.7%).2 EGFR mutations are rare in wellcharacterized, fully excised surgical specimens of squamous cell lung carcinoma lacking any adenocarcinoma component with a reported frequency of less than 5%.1 In the case of limited lung cancer specimens by small biopsies where the possibility of an adenocarcinoma component cannot be completely excluded, the guideline recommends that EGFR mutation testing may be performed in cases showing squamous cell histology with clinical characteristics
Disclosure: The authors declare no conflicts of interest. Address for correspondence: Dr. Chong-Kin Liam, MBBS, MRCP, Department of Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia. E-mail: [email protected] Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0812-e114
e114
such as young age and a lack of smoking history.1 From our experience with small biopsy specimens taken during flexible bronchoscopy or transcutaneous needle biopsy in patients with advanced-stage non–small-lung cancer, EGFR mutations were detected with the use of real-time polymerase chain reaction based on Scorpion® and Amplification Refractory Mutation System® technologies in 39.4% of adenocarcinoma from 132 patients whereas only one (9.1%) of 11 squamous cell carcinomas was EGFR-mutation positive. The only EGFR-mutation–positive squamous cell carcinoma was from a never smoker whereas the squamous cell carcinomas from all 10 smokers were EGFR-mutation negative.3 Other expert panels4 recommend that apart from nonsquamous NSCLC, EGFR mutation testing should be performed in squamous cell carcinoma patients with clinical features associated with higher prevalence of EGFR mutations such as a lack of smoking history. Furthermore, adenosquamous carcinomas and solid adenocarcinomas, in which EGFR mutations have been reported, can mimic squamous cell carcinoma in small biopsy specimens.5 Chong-Kin Liam, MBBS, MRCP Hwong-Ruey Leow, MBBS, MMed Yong-Kek Pang, MD, MRCP Department of Medicine Faculty of Medicine University of Malaya Kuala Lumpur, Malaysia REFERENCES 1. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol 2013;8:823–859. 2. Liam CK, Wahid MI, Rajadurai P, Cheah YK, Ng TS. Epidermal growth factor receptor mutations in lung adenocarcinoma in Malaysian patients. J Thorac Oncol 2013;8:766–772. 3. Liam CK, Leow HR, How HS, et al. A prospective study on epidermal growth factor receptor mutations in non-small cell lung cancer in Malaysian patients. Respirology 2012; 17 (Suppl. 2), page 92 (Abstract 345).
4. Salto-Tellez M, Tsao MS, Shih JY, et al. Clinical and testing protocols for the analysis of epidermal growth factor receptor mutations in East Asian patients with non-small cell lung cancer: a combined clinical-molecular pathological approach. J Thorac Oncol 2011;6:1663–1669. 5. Paik PK, Varghese AM, Sima CS, et al. Response to erlotinib in patients with EGFR mutant advanced non-small cell lung cancers with a squamous or squamous-like component. Mol Cancer Ther 2012;11:2535–2540.
Spectrum of EGFR Mutation in Lung Adenocarcinoma in Morocco To the Editor: We read with great interest the article published by Errihani et al. on the spectrum of epidermal growth factor receptor (EGFR) mutation in Moroccan patients (n = 137) with lung adenocarcinoma (AC), and we would like to congratulate them for their very important study which in our knowledge represent the first study in Morocco and Arab population. In Morocco, lung cancer represents the first cause of cancer in men1,2 and the ninth cause of cancer in women.2 AC is the second most common histological subtype after squamous-cell carcinoma according to the Casablanca registry, representing 26% of all lung cancers (24.7% in men and 36.9% in women [most common histology in women]).2 The authors showed that the overall frequency of the EGFR mutation was 21%, which is higher than that in white population (11%– 13.7%).3–6 Mutations were mainly detected in the exon 19 (69%), followed by exon 21 (21%) and exon 20 (7%), whereas mutations in the Address for correspondence: Nabil Ismaili, MD, Department of Medical Oncology, Oncology Center, Mohammed VI University Hospital, Marrakech, Morocco. E-mail: ismailinabil@ yahoo.fr Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0812-e114
Journal of Thoracic Oncology ® • Volume 8, Number 12, December 2013
Journal of Thoracic Oncology ® • Volume 8, Number 12, December 2013
exon 18 were rare (3%) in concordance with the majority of published studies.3,4,6 In addition, the authors confirmed the Asian and occidental conclusions that EGFR mutation rate was significantly higher in women and in never smokers.3,4,6 However, the study presents several limitations because of numerous biases, and the result presented here should be interpreted with caution3: - The population analyzed was not representative for the overall Moroccan population; as an example, the frequency of EGFR mutation in female patients included was 34% (46 of 137), largely higher than frequencies showed in Rabat and Casablanca registries (the only 2 registries available in Morocco).1,2 According to Casablanca registry, women with AC represent only 16% of lung AC and men with AC represent 84% of lung AC.1 In fact, in Morocco women, lung cancer was a relatively rare condition representing only 8% to 11.5% of all lung cancers versus 33.4% in developed countries.1,2,7,8 And women with lung cancer in Morocco are not smoker in the vast majority of the case (79%).7 - In another hand, the analysis was performed according to specimen available in private laboratories (Nations-Unies Pathology Center, Hassan Pathology Center, and Agdal Pathology Center, at Rabat, Morocco; and Casapath Pathology Center at Casablanca, Morocco.) excluding the majority of specimen available at the most important institutions in Morocco, such as the University Hospitals (National Institute of Oncology at Rabat, Morocco, and Ibn-Rochd University Hospital at Casablanca, Morocco). We do not agree with the author’s conclusion that EGFR mutation frequency in Moroccan patients is higher than that found in whites, but it is the same than that observed in white population. By using the frequency of EGFR mutation in men (7 of 91 = 7.7%) and the frequency of EGFR mutation in women (22 of 46 = 47.8%) calculated from data of the present
article and by using Moroccan statistics (Casablanca registry), we can estimate the true frequency of EGFR mutation in our population; according to Casablanca registry (the most powerful registry), female patients with lung AC represent 16% of lung AC and male patients with lung AC represent 84% of lung AC, the frequency of EGFR mutation will be approximately (16 × 47.8/100 + 7.7 × 84/100 = 7.6% + 6.45%) = 14%. Therefore, we suggest that the incidence of EGFR mutation in Moroccan patients is equivalent than that observed in white population, and we encourage the Moroccan investigators to conduct a multiinstitutional and large study including consecutive patients with AC diagnosed at the most important Cancer Center in Morocco to confirm this suggestion and to refine the result of the present study.3 Nabil Ismaili, MD Rizlane Belbaraka, MD Department of Medical Oncology Oncology Center Mohammed VI University Hospital Marrakech, Morocco REFERENCES 1. Available at: srvweb.sante.gov.ma/.../Registre %20Cancer%20Grand%20Casablanca%2... 2. Tazi MA, Er-Raki A, Benjaafar N. Cancer incidence in Rabat, Morocco: 2006-2008. Ecancermedicalscience. 2013;7:338. 3. Errihani H, Inrhaoun H, Boukir A, et al. Frequency and type of epidermal growth factor receptor mutations in moroccan patients with lung adenocarcinoma. J Thorac Oncol 2013;8:1212–1214. 4. 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. 5. 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. 6. Bauml J, Mick R, Zhang Y, et al. Frequency of EGFR and KRAS mutations in patients with non small cell lung cancer by racial background: do disparities exist? Lung Cancer 2013;81:347–353. 7. Khouchani M, Selmaji I, Elmorabit B, et al. Female lung cancer in Marrakech. Clin Cancer Investig J 2013;2:128–131 8. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69–90.
Copyright © 2013 by the International Association for the Study of Lung Cancer
Letters to the Editor
Spectrum of EGFR Mutation in Lung Adenocarcinoma in Morocco In Response: On behalf of the author group, we thank Dr. Ismaili for his interest in our article Spectrum of EGFR Mutation in Lung Adenocarcinoma in Morocco1 and his insightful comments. With regard to his comments, we think the following points should be clarified. First, our series was a retrospective study and therefore some potential sources of bias cannot be ruled out. Despite this, our results provide some information about the frequency of epidermal growth factor receptor (EGFR) mutation in lung adenocarcinoma in Morocco, and as indicated in our article, have to be confirmed in larger prospective studies. Second, data analysis was performed according to the availability of specimens in private pathology laboratories because these laboratories perform more than 90% of all tests requested in Morocco, and EGFR mutation testing is not available for specimens that could be found in public institutions. We do not fully agree with suggestion made by Dr. Ismaili that the incidence of EGFR mutation in Moroccan patients would be equivalent than that observed in white population. In our series, the EGFR mutation rate was higher than that found in other studies conducted in whites despite similar sex distribution.2,3 For example, Rosell et al.2, in a large prospective Spanish study, reported EGFR mutation in only 16% of patients with lung cancer including 39% of female patients. In such situation, extrapolation as done by Dr. Ismaili should be avoided, and we believe that the best way to provide an accurate EGFR mutation rate in Moroccan patients is to Address for correspondence: Ibrahim Elghissassi, MD, Medical Oncology Department, 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: 1556-0864/13/0812-e115
e115
