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A study on the rate and some risk factors causing gene EGFR mutation in lung adenocarcinoma was conducted at Bachmai Hospital. Objectives: To determine the rate and risk factors for EGFR gene mutations on 152 patients with lung adenocarcinoma at Bachmai Hospital.
Journal of military pharmaco-medicine No7-2016 STUDY ON RATE AND SOME RISK FACTORS FOR EGFR MUTATION IN 152 PATIENTS WITH LUNG ADENOCARCINOMA AT BACHMAI HOSPITAL Nguyen Thi Lan Anh*; Nguyen Huy Binh* Mai Trong Khoa*; Dong Khac Hung** SUMMARY A study on the rate and some risk factors causing gene EGFR mutation in lung adenocarcinoma was conducted at Bachmai Hospital Objectives: To determine the rate and risk factors for EGFR gene mutations on 152 patients with lung adenocarcinoma at Bachmai Hospital Subjects and methods: 152 patients with lung adenocarcinoma diagnosed by histopathological method; the mutation of EGFR gene was identified by assay Strip methods Results: 60 lung cancer patients (39.5%) were diagnosed adenocarcinoma The rate of mutations was found at exons 18, 19, 20, 21 of the EGFR gene The exon mutations were classified as follows: G719S mutation, G719C (exon 18), LREA deletion (exon 19), T790M (exon 20) and L858R; L861Q (exon 21) were 3.2%, 55.6%, 4.8% and 36.4%, respectively The possibility of EGFR gene mutations in female patients was 2.9 times as high as male patients (95%CI 1.4 to 6.1) and 3.4 fold higher compared to patients with history of smoking with 95%CI: 1.6 to 6.2 Conclusions: Among 152 patients with lung adenocarcinoma who were treated at Bachmai Hospital, we found the rate of EGFR gene mutations was 39.5% The mutations of EGFR gene were more common in women and non-smoking patients * Key words: Lung adenocarcinoma; EGFR gene mutation; Gender; Smoking INTRODUCTION In Vietnam, lung cancer is one of the most common malignant diseases in both men and women and is also the leading cause of death from cancer The prevalence of lung cancer is 30.7/100,000 in men and 6.7/100,000 in women [1] Disease-free survival and overall survival rate of lung cancer patients is still very low, although there have been many advances in diagnosis and treatment [3, 4, 5] Currently, adenocarcinoma is the most common type of lung cancer in Vietnam and many other countries at the rate of 50 - 70% [2] In many recent studies in the world as well as in Vietnam, the effectiveness of treatment for non-small cell lung cancer by using drugs inhibit tyrosine kinase activity (TKI - Tyrosine kinase inhibitors) of epithelial growth factor receptor (EGFR) was confirmed Gefitinib and erlotinib are used as target therapy These studies also show the therapeutic effects of the drugs depends on mutations in exons 18, 19, 20, and 21 of EGFR gene due to the creation of EGFR protein that has high affinity for TKI inhibitors, therefore patients with non-small cell lung cancer bearing EGFR gene mutations usually respond well to target treatment * Bachmai Hospital ** Military Medical University Corresponding author: Dong Khac Hung (hungdk688@gmail.com) 30 Journal of military pharmaco-medicine No7-2016 Thereby, mutations of EGFR gene is an important evidence for indications of the target therapy for patients with lung adenocarcinoma There are now a variety of methods of detecting EGFR gene mutations such as gene sequencing or Scopion ARMS [3] At the Center for Nuclear Medicine and Oncology, Bachmai Hospital, testing of EGFR gene mutation with the assay technique Vienalab Strip (Republic of Austria) has been applied since October 2014 This technique combines PCR with specific mixed probes to detect 16 mutations of the EGFR gene [6] Currently, there are not many studies on the rate of EGFR gene mutation and their risk factors (gender and smoking status) on the patients with adenocarcinoma This study was conducted aiming: To determine the rate and risk factors for EGFR gene mutations on 152 patients with lung adenocarcinoma treated at Bachmai Hospital SUBJECTS AND METHODS Subjects 152 patients with lung adenocarcinoma were diagnosed by histopathology at the Center for Nuclear Medicine and Oncology, Bachmai Hospital Specimens were collected by biopsy of lymph node or pleural, or from tumor tissue after surgery - Samples were analyzed for EGFR gene mutations at Gene Therapy Unit, Centre for Nuclear Medicine and Oncology and the Center for Histopathology, Bachmai Hospital - Research period: from November, 2014 to September, 2015 Methods - This is a prospective, descriptive and cross-sectional study * Gathering information about age, gender, smoking status of patients under a unified form * The process of EGFR gene mutation test includes main stages: - Separation of DNA from tissue processing formalin - buried paraffin (FFPE) by kit QIAamp DNA FFPE Tissue specificity (Qiagen) - Amplification gene segments by PCR according to StripAssay EGFR kit (ViennaLab) - Mixed amplification products with specific probes are distributed on test strip - Analysis of results * Processing data: using SPSS 16.0 software RESULTS Gender, age and smoking status Table 1: Characteristics of the subjects Gender Age (year) Smoking status Total Male Female < 60 ≥ 60 Yes No n 108 44 75 77 85 67 152 % 71.7 28.3 49.3 50.7 55.9 44.1 100.0 31 Journal of military pharmaco-medicine No7-2016 Male/female ratio was 2.46/1 Mean age was 59.6 ± 9.9 The lowest was 32 years old and the highest age was 80 More than 50% of the patients have been smoking (55.9%); the rest gave up smoking (44.1%) Rate of EGFR gene mutation * Proportion of EGFR gene mutations in lung cancer patients with adenocarcinoma (n = 152): Mutation: 60 patients (39,5%); no mutation: 92 patients (60,5%) * Number of exon mutations: 95.0% of cases (57 patients) had mutations in only one exon of the gene EGFR, but there were cases (5.0%), who had mutations in three different exons Table 2: Rate of exon mutations Location Sorts of mutation n % Exon18 G719S; G719C 2/63 3.2 Exon 19 Delete (LREA) 35/63 55.6 Exon 20 T790M 3/63 4.8 Exon 21 L858R; L861Q 23/63 36.4 Because cases had two mutations, the total number of mutations in this study was 63 The deletion Exon 19 mutation was the most common (55.6%), followed by the L858R point mutation in exon 21 (36.4%) Table 3: Relationship between the EGFR gene mutation, gender and smoking status EGFR (+) (n = 60) EGFR (-) (n = 92) p n % n OR (95%CI) % Gender Female (n = 43) 25 58,1 18 41,9 < 0,01 Male (n = 109) 35 32,1 74 67,9 2,9 (1,4 - 6,1) Smoking No (n = 85) 44 51,8 41 48,2 < 0,001 Yes (n = 67) 16 23,9 51 76,1 3,4 (1,6 - 6,2) The possibility of EGFR gene mutations in male patients was 2.9 times as high as it was in female (95%CI: 1.4 to 6.1) and 3.4 times compared to patients with a history of smoking (95%CI: 1.6 to 6.2) 32 Journal of military pharmaco-medicine No7-2016 DISCUSSION The rate of EGFR gene mutations in 152 patients with lung adenocarcinoma The results showed that 60 patients (38.4%) had EGFR gene mutations at exon 18, 19, 20, The proportion of G719S mutations (exon 18), delete paragraph LREA (exon 19), T790M (exon 20) and L858R (exon 21) were 3.2%, 55.6%, 4.8% and 36.4%, respectively The rate of EGFR gene mutation in our study was lower than Pioneer’s (64.2%) [7], but higher than Ha's findings (this rate was 35.7%) [3] This difference may be due to the fact that patients in Pioneer's research were in stage III, IV Moreover, samples in this study were collected from the tissue of primary tumors Our study was conducted on the patients of all stages I, II, III and IV; and they were not only the tissue of primary tumors but also the metastases According to foreign literature, although there are about 40 mutations of EGFR as a role of the pathogenesis and they proved to be an effective target treatment, mutations at exon 19 LREA L858R and exon 21 are the most two common types (accounting for 85 - 90%) EGFR gene mutations related to drug responsiveness of treatment [3] These are two types of mutations that increase the sensitivity of tumors to TKI drugs The other mutations occupying a very small percentage as the mutations at exon 18, exon 19 and exon 21 helps increase sensitivity, but mutations at exon 20 (T790M) makes tumors resistant to target treatment Our results were only at beginning step, but had a very important role in the diagnosis, treatment and prognosis of lung adenocarcinoma in Vietnam * Risk factors for age and smoking addiction for EGFR gene mutations: Many researchers in the world and Vietnam indicate strong relation between EGFR gene mutation status with gender, race and smoking status in patients with lung adenocarcinoma [3, 7] The results of this study (table 2) showed the possibility of EGFR gene mutations in female patients 2.9 times higher than male patients (95%CI: 1.4 to 6.1) and the possibility of mutation EGFR gene in non-smoking patients was 3.4 times higher than patients who have been smoking (95%CI: 1.6 to 6.2) Our findings and other studies’ in Asia (Shigemitsu, 2006 ) pointed out the differences in lung adenocarcinoma in compared to the other regions in the world EGFR gene mutation is more prominent in non-smoking female patients [7, 8] It is also advantageous to help lung cancer patients with adenocarcinoma in Asia and Vietnam be indicated for the target treatment and prolong the survival CONCLUSION Throughout the study on 152 patients with lung adenocarcinoma with EGFR gene mutations at the Center of Nuclear Medicine and Oncology, Bachmai Hospital, we drew some conclusions: - The rate of mutations at exon 18, 19, 20, 21 of the EGFR gene was 39.5% The rates of mutation G719S; G719C (exon 18), LREA deletion (exon 19), T790M (exon 20) and L858R; L861Q (exon 21) were 3.2%, 55.6%, 4.8% and 36.4%, respectively 33 Journal of military pharmaco-medicine No7-2016 - The possibility of EGFR gene mutations in women was 2.9 times higher than men (95%CI: 1.4 to 6.1) and 3.4 times higher than the group of patients with a history of smoking (95%CI: 1.6 to 6.2) REFERENCES Globocan 2012 Cancer Incidence IARC multiethnic Malaysian patient population Asian Pac J Cancer Prev 2014, 15 (1), pp.321-326 Liam CK, Pang YK, Poh ME EGFR mutations in Asian patients with advanced lung adenocarcinoma J Thorac Oncol 2014, (9), pp:e70-71 EGFR StripAssay®www.viennalab.com/ products/cancer/egfr_stripassay Ha Ng M Determine gene EGFR mutations in patients with non-small cell lung cancer Journal of Medical Research Hanoi 2013, 17 (1), pp.34-37 Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, Heeroma K, Itoh Y, Cornelio G, Yang PC A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-celllung cancer of adenocarcinoma histology (PIONEER) J Thorac Oncol 2014, (2), pp.154-162 Liam CK, Leow HR, How SH, Pang YK, Chua KT, Lim BK, Lai NL, Kuan YC, Pailoor J, Rajadurai P Epidermal growth factor receptor mutations in non-small cell lung cancers in a Shigematsu H, Gazdar AF Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers Int J Cancer 2006, 118 (2), pp.257-262 Jemal A, Bray F, Ward E et al Global cancer statistics, CA Cancer J Clin 2011, 61 (2), pp.69-90 34 ... their risk factors (gender and smoking status) on the patients with adenocarcinoma This study was conducted aiming: To determine the rate and risk factors for EGFR gene mutations on 152 patients with. .. cancer patients with adenocarcinoma (n = 152) : Mutation: 60 patients (39,5%); no mutation: 92 patients (60,5%) * Number of exon mutations: 95.0% of cases (57 patients) had mutations in only one exon... treatment and prolong the survival CONCLUSION Throughout the study on 152 patients with lung adenocarcinoma with EGFR gene mutations at the Center of Nuclear Medicine and Oncology, Bachmai Hospital,