Indian Journal of Cancer
Home  ICS  Feedback Subscribe Top cited articles Login 
Users Online :1466
Small font sizeDefault font sizeIncrease font size
Navigate here
  Search
 
  
Resource links
 »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
 »  Article in PDF (344 KB)
 »  Citation Manager
 »  Access Statistics
 »  Reader Comments
 »  Email Alert *
 »  Add to My List *
* Registration required (free)  

 
  In this article
 »  Abstract
 » Introduction
 »  Materials and Me...
 » Results
 » Discussion
 » Conclusions
 » Acknowledgment
 »  References
 »  Article Figures
 »  Article Tables

 Article Access Statistics
    Viewed2902    
    Printed65    
    Emailed0    
    PDF Downloaded616    
    Comments [Add]    
    Cited by others 6    

Recommend this journal

 

  Table of Contents  
LCC-A SYMPOSIUM- ORIGINAL ARTICLE
Year : 2013  |  Volume : 50  |  Issue : 2  |  Page : 87-93
 

Epidermal growth factor receptor mutation in non-small-cell lung carcinomas: A retrospective analysis of 1036 lung cancer specimens from a network of tertiary cancer care centers in India


1 Department of Molecular Pathology, Triesta Reference Laboratory, A unit of HCG Oncology Hospitals, Bangalore, Karnataka, India
2 Department of Molecular Pathology, HCG Oncology Hospitals; Department of Molecular Pathology, HCG Foundation, Bangalore, Karnataka, India
3 Department of Molecular Pathology, HCG Oncology Hospitals, Bangalore, Karnataka, India
4 Department of Molecular Pathology, Triesta Reference Laboratory, A unit of HCG Oncology Hospitals; Department of Molecular Pathology, HCG Oncology Hospitals; Department of Molecular Pathology, HCG Foundation, Bangalore, Karnataka, India

Date of Web Publication27-Aug-2013

Correspondence Address:
V H Veldore
Department of Molecular Pathology, Triesta Reference Laboratory, A unit of HCG Oncology Hospitals, Bangalore, Karnataka
India
Login to access the Email id

Source of Support: HCG Research Foundation., Conflict of Interest: None


DOI: 10.4103/0019-509X.117013

Rights and Permissions

 » Abstract 

Background: Epidermal growth factor receptor (EGFR) mutation plays a vital role in the prognosis of patients with lung cancer. However, there is a dearth of studies on EGFR mutation in Indian population. In this retrospective study conducted at a network of tertiary cancer care centers across India, we evaluated the proportion of EGFR mutation in patients with non-small-cell lung carcinomas (NSCLC). Materials and Methods: A total of 1036 cases of non-small lung cancer were assessed for EGFR mutation status using Scorpion amplified refractory mutation system real time polymerase chain reaction method from fine needle aspiration cytology core biopsy, pleural fluid and cell blocks. For a few cases, macro dissection of tumor from H and E slides was also performed for EGFR analysis. EGFR Status was assessed for the most commonly known driver mutations in Exons 18, 19, 20 and 21, which contributes to a total of 29 somatic mutations including the resistance mutation T790M. Results: Around 39% of the cohort was female and 61% were male. Mutation was positive in 40.3% and negative (wild type) in 59.7%. There was 1.8% mutation in exon 18, 24.6% in exon 19, 1.6% in exon 20 and 12.8% in exon 21. 38.2% had a mutation in a single site and 1.1% had a mutation in two sites. Overall mutation was significant in females (50.5% vs. 33.9%) compared with males (χ2 = 28.3, P < 0.001). Mutation was significant in exon 21 (16.8% vs. 10.3%, χ2 = 9.44, P = 0.002) and exon 19 (30.7% vs. 20.7%, χ2 = 13.2, P < 0.001) in females compared with males. Conclusion: EGFR is expressed differentially/mutated in patients with NSCLC. Further studies to unravel the predictors for acquired genetic alterations of EGFR are needed.


Keywords: Amplified refractory mutation system, epidermal growth factor receptor, fine needle aspiration cytology, peptide-nucleic acid, polymerase chain reaction


How to cite this article:
Veldore V H, Rao R M, Kakara S, Pattanayak S, Tejaswi R, Sahoo R, Venkataswamy E, Prabhudesai S A, Krishnamoorthy N, Tejaswini B N, Hazarika D, Gangoli S A, Rahman S M, Naik R, Diwakar R B, Satheesh C T, Shashidhar S P, Patil SG, Ajai Kumar B S. Epidermal growth factor receptor mutation in non-small-cell lung carcinomas: A retrospective analysis of 1036 lung cancer specimens from a network of tertiary cancer care centers in India. Indian J Cancer 2013;50:87-93

How to cite this URL:
Veldore V H, Rao R M, Kakara S, Pattanayak S, Tejaswi R, Sahoo R, Venkataswamy E, Prabhudesai S A, Krishnamoorthy N, Tejaswini B N, Hazarika D, Gangoli S A, Rahman S M, Naik R, Diwakar R B, Satheesh C T, Shashidhar S P, Patil SG, Ajai Kumar B S. Epidermal growth factor receptor mutation in non-small-cell lung carcinomas: A retrospective analysis of 1036 lung cancer specimens from a network of tertiary cancer care centers in India. Indian J Cancer [serial online] 2013 [cited 2019 Nov 21];50:87-93. Available from: http://www.indianjcancer.com/text.asp?2013/50/2/87/117013



 » Introduction Top


Lung cancer is the 2 nd most common cancer world-wide following the breast in women and prostrate in men (SEER, GLOBOCAN). [1],[2] In Indian population, cancer of the lung in males is listed as the highest in the majority of registries, with a decreasing trend in males and increasing trend in females. [3] The risk of developing lung cancer increases with age, with a marginally higher risk in the higher socio-economic categories for men and in the lower socioeconomic categories for women. Lung cancer incidence increases with the number of bidis (Indian cigarettes) smoked per day, the duration of exposure and the age at which the individual is exposed to the same at the beginning, with the calculated risk not reducing even after cessation. [4] Some of the reports also indicate, a major variation in the proportions of different histopathological types, adenocarcinomas predominating in Mumbai and Trivandrum and squamous cell carcinomas elsewhere. [5]

Non-small-cell lung carcinomas (NSCLC) make up the vast majority of lung cancers. NSCLC could be further classified into three major sub types, adenocarcinoma, squamous cell carcinoma and large cell carcinoma. However, most often there are mixed subtypes in NSCLC, which would incorporate more than one histological pattern of the three subtypes. Epidermal growth factor receptor (EGFR) is found to be over expressed in several carcinomas including lung [6] and more so in NSCLC with over expression ranging from 43% to 89% [7],[8] and mutation varying between 5 and 50% across different populations. Our institutional study, reported earlier has shown prevalence of EGFR mutation of 52% among a subset of 210 NSCLC patients in Indian population with a higher prevalence in females compared with males. [9]

The EGFR (also known as ErbB1or human EGFR HER1) is a receptor tyrosine kinase (TK) that belongs to the Erb family of transmembrane glycoproteins. Alterations in EGFR signaling contribute to a number of processes involving tumor growth and survival, hence making it a promising target for cancer therapy. [10],[11],[12],[13] Few of the hall mark events associated with oncogenesis are increased expression of EGFR, mutations in the kinase domain, mutation and activation of downstream cascade molecule Kristen-Ras (K-Ras), which in turn further trigger the mitogen-activated protein kinases and PIK3CA pathways.

A small molecule inhibitor, Iressa had demonstrated potential clinical benefits in a subgroup of non-small-cell lung cancer patients who harbored mutations in one of the four exons [18],[19],[20],[21] in the TK domain of EGFR. Inhibition of EGFR TK domain by specific blocking agents could induce apoptosis and inhibit cellular proliferation. This has been demonstrated time again by in vivo models as well as from global clinical trials during the evolution of two major antineoplastic drugs tyrosine kinase inhibitors (TKIs) Iressa (Gefitinib, Astra Zeneca) and Tarceva (Erlotinib, Pfizerb), which have demonstrated prolonged response to EGFR TKI therapy, back in 2004. These two studies have shown that EGFR mutation in exons 18, 19, 20 and 21 can delineate responders from non-responders to Gefitinib therapy with EGFR kinase domain mutation predicting better response to Gefitinib. [14],[16] However, the presence of mutation varied significantly among different lung cancer populations across the world. These somatic mutations are more common in women who are non-smokers with adenocarcinoma and of Asian origin, thus, demonstrating the role of histology, sex, lifestyle and ethnicity as variables associated with EGFR mutation. Here, we share our results on the frequency of EGFR mutation and correlating with other clinico-pathological variables, from 1036 lung cancer patients, who visited HCG Hospitals, Bangalore during the period 2009-2012.


 » Materials and Methods Top


Patients and tissues

The tumor specimens used for this study were obtained from 1036 NSCLC patients who visited a tertiary comprehensive cancer care Hospital, in Bangalore during the period 2009-2012. The age of subjects varied from 21 to 92 years. There were 632 men and 404 women in the study group and who presented with Stage IIIB or Stage IV disease. A general Informed consent was obtained from all patients enrolled to carry out the tests. The patient's tissue samples were anonymized before any analysis was carried out. In most of the tumor specimens, the amount of tumor cells equaled or exceeded 40% of the overall sample, confirmed by histopathologic examination as recommended by standard international guidelines. [17],[18],[19]

EGFR gene mutation analysis

Genomic deoxyribonucleic acid (DNA) was extracted from different sources of clinical material such as biopsies formalin fixed paraffin embedded (FFPE) blocks, fine needle aspiration cytology (FNAC) slides, Bronchoalveolar lavage, Pleural fluid and cell block according to standard procedures (QIAGEN DNA mini kit). Mutation analysis of the EGFR gene for the Exons 18-21 was performed by Scorpion amplified refractory mutation system (ARMS) based real time polymerase chain reaction (PCR) technology (THERASCREEN EGFR RGQ PCR Kit from Qiagen Inc). Commonly documented 29 somatic mutations, which are known to be driver mutations were screened in all the samples. The screening also included the secondary resistance mutation T790M in Exon 20.

Statistics data analysis

Data were analyzed using the Statistical Package for Social Sciences version 18 for windows. Distribution of frequencies of various mutations across predictor variables such as age and gender were analyzed using Chi-square test for proportions.


 » Results Top


A total of 1036 lung cancer patients who visited a tertiary comprehensive cancer center during the period 2009-2012 and were diagnosed to have non-small-cell lung cancer were screened for the presence of EGFR mutation in order to predict the response to targeted drugs Gefitinib and Erlotinib. Most of the cases were under the histological classification of NSCLC not otherwise specified. The mean age of the present study cohort was 59 ± 12 years. 39% of the cohort was female and 61% were male. EGFR Mutation was positive in 40.3% and negative (wild type) in 59.7%. There were 1.8% mutations in exon 18, 24.6% in exon 19, 1.6% in exon 20 and 12.8% in exon 21 [Figure 1]. 38.2% of the mutated population had a mutation in a single site and 1.1% had a mutation in two sites [Table 1]. Overall mutation was significant in females (50.5% vs. 33.9%) as compared with males (χ2 = 28.3, P < 0.001). Mutation was significant in exon 21 (16.8% vs. 10.3%, χ2 = 9.44, P = 0.002) and exon 19 (30.7% vs. 20.7%, χ2 = 13.2, P < 0.001) in females compared with males [Table 2]. The mutation rate is less in males than in females, though we don't have statistical significance. Among the mutations screened in Exon 20, there were seven cases with insertions, four cases with T790M, seven cases with S768I for the entire study subset. One case had presented with both Exon 21 (L858R) and T790M concomitantly. The preponderance of mutation also increased with the age of onset as described earlier; though, it was not statistically significant.
Figure 1: Frequency/distribution of epidermal growth factor receptor mutation in 1036 lung cancer patients who visited a tertiary cancer care network of hospitals in India during the period 2009-2012

Click here to view
Table 1: Clinical and mutation status of the study population

Click here to view
Table 2: Gender differences in EGFR mutation status

Click here to view



 » Discussion Top


The results suggest that EGFR mutation was positive in 40.3% of the study population. Overall mutation rate was significant in females compared with males. Mutation rate was significant in exon 21 and exon 19 in females compared with males. Our results show a decrease in prevalence of overall mutation among subjects with NSCLC compared with our earlier study, which reported prevalence of 52%. This could be because the larger sample size could have accounted for a type II error seen with the earlier study with a significantly lesser sample size than this present study. [9] Ever since, the discovery of EGFR mutation by Pao et al., (2004) [15] there has been several clinical trials to evaluate the role of TKIs as one of therapeutic options in either first or second line/maintenance therapy in non-small-cell lung cancer. [20],[21],[22],[23],[24],[25],[26],[27],[28] The incidence of EGFR mutations in non-small-cell lung cancers ranges from ~ 5-20% [29],[30],[31],[32] in Caucasians to ~ 30-50% in East Asians [9],[33],[34],[35],[36],[37],[38],[39] mutations have been found to be highly co-existent with adenocarcinoma histology, women and non-smoker. 90-95% of the total mutations are located on Exon 19 (in-frame deletions) and a missense mutation L858R in Exon 21. This report is an epidemiological survey on EGFR mutation in NSCLC and is a robust analysis as compared with our earlier report published in 2011. [9] Wherein we have analyzed a subset of 210 patients and reported 52% mutation. Mutation frequency in Indian Lung Cancer patients reported earlier, were slightly higher than those reported from Japan (32-41%), [33],[34] 30-50% in Korea, [35],[36] 23% in Bangladesh, [37] 34-37% in China, [38],[39] 39.5% in Malaysia. [40] This could be due to several factors, such as ethnic or loco-regional bias or the small subset of study individuals. Nevertheless, the frequency of mutation reported here (1036 patients) in this study is in par with those studies reported from Japanese, Chinese, Korean and Malaysian population. Furthermore, the correlation with sex with females being more probable to carry the mutation as compared with males is also a finding, which has been commonly documented in all the Asian NSCLC studies including the present study.

One of the largest retrospective analysis of EGFR mutation status has been from Memorial Sloan Kettering Cancer Center on 2142 cases of lung adenocarcinoma (during the period 2002-2009), wherein the subjects were screened for activating mutations in Exons 19 and 21 in the EGFR kinase domain. In this study, women had a higher frequency of mutation as compared with men: 26% versus 19% respectively. Furthermore, this study demonstrated the presence of mutation in current smokers 6%, former smokers (15%) in addition to non-smokers (52%) which constitute the majority. [32]

Mutation reports from Spanish (12%), Portuguese (13%), German (5%), North American population (23%) suggests the low prevalence of these driver signals in Caucasian group. [29],[30],[31],[32]

In an independent study of highly selective individuals, of 110 Asian women with adenocarcinoma lung, the smoking and tobacco status was measured as a variable and function of EGFR mutation. The EGFR mutation frequency was 51% in non-smokers as compared with 10.4% in smokers. [41] Mutation analysis of the kinase domain of the EGFR and potentially other molecular markers such as anaplastic lymphoma kinase, K-Ras are among the most important questions asked in the personalized management of lung cancer. Mutations in the EGFR TK domain defines a molecular subtype of lung carcinoma that would benefit the patient population with high probability of prolonged response to targeted therapy with TKIs Gefitinib and Erlotinib, [20],[21],[22],[23],[24],[25],[26],[27],[28] and is warranted as part of the initial clinical work-up. [42] Among the mutations discovered in the kinase domain that spans Exons 18, 19, 20 and 21, mutations in Exons 19 and 21 are more common than others and are consistently associated with a definitive response as described in several reports. [20],[21],[22],[23],[24],[25],[26],[27],[28]

Although the difference in overall survival (OS) has not been clearly demonstrated, in comparison with standard chemotherapy, starting on EGFR TKI has significantly improved the progression-free survival in all these patients. [20],[21],[22],[23],[24],[25],[26],[27],[28] Hence, screening for EGFR kinase domain mutations has become important in the management of lung cancers.

Our earlier report [9] and also the present study didn't involve any pre-screening of individuals who would be really benefited by TKI therapy as it is a retrospective study. The criteria were all patient tumors, which were classified as NSCLC was included in the study.

EGFR mutation and mechanism of action

Spontaneous somatic mutations in EGFR TK domain have known to alter the function of the kinase by introducing a constitutive activation mechanism downstream of the pathway. Thus, increasing the cellular proliferation, survival, metastases, angiogenesis and activating anti-apoptotic pathways. [43],[44] Blocking of the EGFR kinase domain leads to up-regulation of pro-apoptotic signals and hence programmed cell death. [43],[44],[45],[46]

Clinical implications of EGFR mutation in NSCLC

EGFR Molecular testing on tumor samples is important in prospectively identifying patients who would most likely respond to EGFR TKIs. Therefore, it has become an integral part of initial diagnostic work-up in the standard of care. TKI directed therapy in first/second line/maintenance as a monotherapy or combination therapy against EGFR signaling have shown improved PFS and quality-of-life though there was no significant improvement in OS. [14],[15],[16],[20],[21],[22],[23],[24],[25],[26],[27],[28]

Methods for rapid screening for EGFR mutation in population

Although direct sequencing is considered with be the gold standard in nucleic acid studies, considering the tumor heterogeneity and the presence of somatic mutations, preferential enrichment of mutant copies of the tumor DNA is an important factor responsible for detection of somatic mutation, in particular the low copy number mutants by this technology. Also, any mutant copies below 15% fail to amplify and hence may not be detected by this method, limiting the sensitivity. Direct PCR-Sequencing is most often used when the diagnostic specimens are available with a high proportion of tumor cells.

The common limiting factor associated with any molecular testing in lung cancer is the availability of adequate tumor material after confirming the diagnosis on a FFPE sample. In addition, low abundance mutations, presence of stromal, inflammatory and vascular cells could mask the mutation detection. These limitations prompted for the development of highly sensitive testing methods that incorporates the ability to detect low copy number mutants from a small portion of neoplastic cells with template DNA being most often fragmented. There are several such methods reported in the literature, [47],[48],[49] the most widely used are pyro-sequencing, [50] peptide-nucleic acid (PNA) clamping, [51] and Allele specific PCR. [52] Here again, each method has demonstrated variable sensitivity. Pyro-sequencing requires at least 5% mutant copies, PNA clamping and Allele specific PCR have sensitivity to detect up to 1% mutant. [53] Many commercial kit manufacturers have adopted one or a combination of these methods to improve the mutation detection limit, specificity, robustness, turnaround time of this testing for making it most preferable for molecular diagnostic applications. One such technology is the Scorpion probe based Amplified Refractory Mutation Analysis for screening of specific oncogenic mutations in EGFR (QIAGEN Inc) [54] Like other methods, the Scorpion ARMS method has been demonstrated as one of the rapid and reliable method for the detection of EGFR kinase domain mutations in lung cancer. [9],[55]

Technology and choice of subjects

The principles of testing play a significant role in assessing the status of molecular targets that would affect the treatments down the line. Another important aspect, which has been highlighted in several reports [17],[18],[19] and also in this report is the availability of adequate tumor material. There has always been a challenge in lung malignancies for sampling tumor material from the patients for the initial diagnosis. Procedures such image guided tru-cut biopsy, pleural tap, supraclavicular lymph node biopsy are the most common sources for tumor material. Because of sensitivity and robustness of the Scorpions real-time PCR technology, [9],[54],[55] which is being used for screening in this study, we could successfully demonstrate the presence of mutation in poorly enriched and technically suboptimal volume of samples such as FNAC, pleural fluid, cell block and a few cases wherein, a couple of H and E slides were provided.

Though there has been a pattern demonstrated in the current study as well as by other groups across the globe that women, non-smokers and adenocarcinoma are most likely to harbor activating mutations in EGFR kinase domain, genome wide association studies may predict individuals who are likely to have EGFR mutation in NSCLC population and the biological mechanism associated with the onset of these mutations. The classification of adenocarcinoma, squamous cell carcinoma and other subtypes was not a feasible option as many cases were under the category of NSCLC not otherwise specified. Hence, we limited our observation to NSCLC being a broader subset. Also, smoking status was not available for the entire study subset.


 » Conclusions Top


EGFR TK domain mutational analysis is a novel predictive test for selecting lung adenocarcinoma patients for targeted therapy with EGFR TKIs. Owing to novel therapy strategies in EGFR-mutated patients, molecular analysis of the EGFR and KRAS genes has become crucial for routine diagnostics. Here, we report a frequency of 40.3% EGFR mutation in NSCLC at a tertiary care cancer center in the southern part of India. Our findings are similar to those reported across Asia. The high frequency of EGFR mutation positive cases warrants the need for a common methodology for testing in Asian NSCLC patients that would incorporate high sensitivity and specificity without rejecting specimens with < 10% tumor load; thus providing the therapeutic benefit to patients. However, quantitative PCR/real time PCR techniques used in this study require expertise and are expensive and may not be suitable for field testing on large samples. More robust methods, which incorporate the same/similar technology, also cost-effective are needed in order that most of the patients from all the economic strata could be benefited.


 » Acknowledgment Top


The authors acknowledge the HCG Research Foundation for their support.

 
 » References Top

1.Curado MP, Edwards B, Shin HR, et al. editors. Cancer Incidence in Five Continents. Vol. 9. Lyon: IARC, IARC Scientific Publications No 160; 2007.  Back to cited text no. 1
    
2.Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893-917.  Back to cited text no. 2
[PUBMED]    
3.Agarwal N, Yeole BB, Ram U. Lifetime risk and trends in lung cancer incidence in greater Mumbai. Asian Pac J Cancer Prev 2009;10:75-82.  Back to cited text no. 3
[PUBMED]    
4.Jayalekshmy PA, Akiba S, Nair MK, Gangadharan P, Rajan B, Nair RK, et al. Bidi smoking and lung cancer incidence among males in Karunagappally cohort in Kerala, India. Int J Cancer 2008;123:1390-7.  Back to cited text no. 4
[PUBMED]    
5.Behera D, Balamugesh T. Lung cancer in India. Indian J Chest Dis Allied Sci 2004;46:269-81.  Back to cited text no. 5
[PUBMED]    
6.Levitzki A. EGF receptor as a therapeutic target. Lung Cancer 2003;41 Suppl 1:S9-14.  Back to cited text no. 6
[PUBMED]    
7.Hirsch FR, Scagliotti GV, Langer CJ, Varella-Garcia M, Franklin WA. Epidermal growth factor family of receptors in preneoplasia and lung cancer: Perspectives for targeted therapies. Lung Cancer 2003;41 Suppl 1:S29-42.  Back to cited text no. 7
    
8.Brabender J, Danenberg KD, Metzger R, Schneider PM, Park J, Salonga D, et al. Epidermal growth factor receptor and HER2-neu mRNA expression in non-small cell lung cancer Is correlated with survival. Clin Cancer Res 2001;7:1850-5.  Back to cited text no. 8
[PUBMED]    
9.Sahoo R, Harini VV, Babu VC, Patil Okaly GV, Rao S, Nargund A, et al. Screening for EGFR mutations in lung cancer, a report from India. Lung Cancer 2011;73:316-9.  Back to cited text no. 9
[PUBMED]    
10.Cohen S. Purification of the receptor for epidermal growth factor from A-431 cells: Its function as a tyrosyl kinase. Methods Enzymol 1983;99:379-87.  Back to cited text no. 10
[PUBMED]    
11.Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW. Epidermal growth factor receptor: Mechanisms of activation and signalling. Exp Cell Res 2003;284:31-53.  Back to cited text no. 11
[PUBMED]    
12.Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001;411:355-65.  Back to cited text no. 12
[PUBMED]    
13.Lorimer IA. Mutant epidermal growth factor receptors as targets for cancer therapy. Curr Cancer Drug Targets 2002;2:91-102.  Back to cited text no. 13
[PUBMED]    
14.Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-39.  Back to cited text no. 14
[PUBMED]    
15.Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004;101:13306-11.  Back to cited text no. 15
[PUBMED]    
16.Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 2004;304:1497-500.  Back to cited text no. 16
    
17.Pirker R, Herth FJ, Kerr KM, Filipits M, Taron M, Gandara D, et al. Consensus for EGFR mutation testing in non-small cell lung cancer: Results from a European workshop. J Thorac Oncol 2010;5:1706-13.  Back to cited text no. 17
    
18.Marchetti A, Normanno N, AIOM-SIAPEC-IAP, Pinto C, Taddei GL, Adamo V, et al. Recommendations for mutational analysis of EGFR in lung carcinoma. Pathologica 2010;102:119-26.  Back to cited text no. 18
    
19.Eberhard DA, Giaccone G, Johnson BE, Non-Small-Cell Lung Cancer Working Group. Biomarkers of response to epidermal growth factor receptor inhibitors in non-small-cell lung cancer Working Group: Standardization for use in the clinical trial setting. J Clin Oncol 2008;26:983-94.  Back to cited text no. 19
    
20.Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) corrected. J Clin Oncol 2003;21:2237-46.  Back to cited text no. 20
[PUBMED]    
21.Azzoli CG, Baker S Jr, Temin S, Pao W, Aliff T, Brahmer J, et al. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 2009;27:6251-66.  Back to cited text no. 21
    
22.Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-8.  Back to cited text no. 22
[PUBMED]    
23.Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-8.  Back to cited text no. 23
[PUBMED]    
24.Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57.  Back to cited text no. 24
[PUBMED]    
25.Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239-46.  Back to cited text no. 25
    
26.Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, et al. First-SIGNAL: First-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol 2012;30:1122-8.  Back to cited text no. 26
[PUBMED]    
27.Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735-42.  Back to cited text no. 27
[PUBMED]    
28.Chen X, Liu Y, Røe OD, Qian Y, Guo R, Zhu L, et al. Gefitinib or erlotinib as maintenance therapy in patients with advanced stage non-small cell lung cancer: A systematic review. PLoS One 2013;8:e59314.  Back to cited text no. 28
    
29.Cortes-Funes H, Gomez C, Rosell R, Valero P, Garcia-Giron C, Velasco A, et al. Epidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small-cell lung cancer patients. Ann Oncol 2005;16:1081-6.  Back to cited text no. 29
[PUBMED]    
30.Boch C, Kollmeier J, Roth A, Stephan-Falkenau S, Misch D, Grüning W, et al. The frequency of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC): Routine screening data for central Europe from a cohort study. BMJ Open 2013;3:???.  Back to cited text no. 30
    
31.Castro AS, Parente B, Gonçalves I, Antunes A, Barroso A, Conde S, et al. Epidermal growth factor recetor mutation study for 5 years, in a population of patients with non-small cell lung cancer. Rev Port Pneumol 2013;19:7-12.  Back to cited text no. 31
    
32.D'Angelo SP, Pietanza MC, Johnson ML, Riely GJ, Miller VA, Sima CS, et al. Incidence of EGFR exon 19 deletions and L858R in tumor specimens from men and cigarette smokers with lung adenocarcinomas. J Clin Oncol 2011;29:2066-70.  Back to cited text no. 32
[PUBMED]    
33.Tokumo M, Toyooka S, Kiura K, Shigematsu H, Tomii K, Aoe M, et al. The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. Clin Cancer Res 2005;11:1167-73.  Back to cited text no. 33
[PUBMED]    
34.Yoshida K, Yatabe Y, Park JY, Shimizu J, Horio Y, Matsuo K, et al. Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer. J Thorac Oncol 2007;2:22-8.  Back to cited text no. 34
[PUBMED]    
35.Kim HJ, Oh SY, Kim WS, Kim SJ, Yoo GH, Kim WD, et al. Clinical investigation of EGFR mutation detection by pyrosequencing in lung cancer patients. Oncol Lett 2013;5:271-6.  Back to cited text no. 35
[PUBMED]    
36.Sun PL, Seol H, Lee HJ, Yoo SB, Kim H, Xu X, et al. High incidence of EGFR mutations in Korean men smokers with no intratumoral heterogeneity of lung adenocarcinomas: Correlation with histologic subtypes, EGFR/TTF-1 expressions, and clinical features. J Thorac Oncol 2012;7:323-30.  Back to cited text no. 36
[PUBMED]    
37.Rahman S, Kondo N, Yoneda K, Takuwa T, Hashimoto M, Orui H, et al. Frequency of epidermal growth factor receptor mutations in Bangladeshi patients with adenocarcinoma of the lung. Int J Clin Oncol 2013; January 9. [E-publication ahead of print].  Back to cited text no. 37
    
38.Li M, Zhang Q, Liu L, Liu Z, Zhou L, Wang Z, et al. The different clinical significance of EGFR mutations in exon 19 and 21 in non-small cell lung cancer patients of China. Neoplasma 2011;58:74-81.  Back to cited text no. 38
[PUBMED]    
39.Bai H, Wang Z, Chen K, Zhao J, Lee JJ, Wang S, et al. Influence of chemotherapy on EGFR mutation status among patients with non-small-cell lung cancer. J Clin Oncol 2012;30:3077-83.  Back to cited text no. 39
[PUBMED]    
40.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;8:766-72.  Back to cited text no. 40
[PUBMED]    
41.Mazières J, Rouquette I, Lepage B, Milia J, Brouchet L, Guibert N, et al. Specificities of lung adenocarcinoma in women who have never smoked. J Thorac Oncol 2013;???:???.  Back to cited text no. 41
    
42.Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:244-85.  Back to cited text no. 42
[PUBMED]    
43.Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007;7:169-81.  Back to cited text no. 43
[PUBMED]    
44.Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW. Epidermal growth factor receptor: Mechanisms of activation and signalling. Exp Cell Res 2003;284:31-53.  Back to cited text no. 44
[PUBMED]    
45.Giaccone G. The role of gefitinib in lung cancer treatment. Clin Cancer Res 2004;10:4233s-7.  Back to cited text no. 45
[PUBMED]    
46.Wakeling AE, Guy SP, Woodburn JR, Ashton SE, Curry BJ, Barker AJ, et al. ZD1839 (Iressa): An orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 2002;62:5749-54.  Back to cited text no. 46
[PUBMED]    
47.Kimura H, Fujiwara Y, Sone T, Kunitoh H, Tamura T, Kasahara K, et al. EGFR mutation status in tumour-derived DNA from pleural effusion fluid is a practical basis for predicting the response to gefitinib. Br J Cancer 2006;95:1390-5.  Back to cited text no. 47
[PUBMED]    
48.Oshita F, Matsukuma S, Yoshihara M, Sakuma Y, Ohgane N, Kameda Y, et al. Novel heteroduplex method using small cytology specimens with a remarkably high success rate for analysing EGFR gene mutations with a significant correlation to gefitinib efficacy in non-small-cell lung cancer. Br J Cancer 2006;95:1070-5.  Back to cited text no. 48
[PUBMED]    
49.Molina-Vila MA, Bertran-Alamillo J, Reguart N, Taron M, Castellà E, Llatjós M, et al. A sensitive method for detecting EGFR mutations in non-small cell lung cancer samples with few tumor cells. J Thorac Oncol 2008;3:1224-35.  Back to cited text no. 49
    
50.Dufort S, Richard MJ, Lantuejoul S, de Fraipont F. Pyrosequencing, a method approved to detect the two major EGFR mutations for anti EGFR therapy in NSCLC. J Exp Clin Cancer Res 2011;30:57.  Back to cited text no. 50
[PUBMED]    
51.Han HS, Lim SN, An JY, Lee KM, Choe KH, Lee KH, et al. Detection of EGFR mutation status in lung adenocarcinoma specimens with different proportions of tumor cells using two methods of differential sensitivity. J Thorac Oncol 2012;7:355-64.  Back to cited text no. 51
[PUBMED]    
52.Dahse R, Berndt A, Dahse AK, Kosmehl H. Two allele-specific PCR assays for screening epidermal growth factor receptor gene hotspot mutations in lung adenocarcinoma. Mol Med Rep 2008;1:45-50.  Back to cited text no. 52
[PUBMED]    
53.Ellison G, Zhu G, Moulis A, Dearden S, Speake G, McCormack R. EGFR mutation testing in lung cancer: A review of available methods and their use for analysis of tumour tissue and cytology samples. J Clin Pathol 2013;66:79-8.  Back to cited text no. 53
[PUBMED]    
54.Thelwell N, Millington S, Solinas A, Booth J, Brown T. Mode of action and application of Scorpion primers to mutation detection. Nucleic Acids Res 2000;28:3752-61.  Back to cited text no. 54
[PUBMED]    
55.Ellison G, Donald E, McWalter G, Knight L, Fletcher L, Sherwood J, et al. A comparison of ARMS and DNA sequencing for mutation analysis in clinical biopsy samples. J Exp Clin Cancer Res 2010;29:132.  Back to cited text no. 55
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2]

This article has been cited by
1 Biomarkers in Non-Small Cell Lung Cancers: Indian Consensus Guidelines for Molecular Testing
Kumar Prabhash,Suresh H. Advani,Ullas Batra,Bivas Biswas,Anuradha Chougule,Mithua Ghosh,Vamshi Krishna Muddu,T. P. Sahoo,Ashok K. Vaid
Advances in Therapy. 2019; 36(4): 766
[Pubmed] | [DOI]
2 Clinical profile and outcomes of patients with Stage IV adenocarcinoma of lung: A tertiary cancer center experience
P Paliwal,S Rajappa,A Santa,MVTK Mohan,S Murthy,N Lavanya
Indian Journal of Cancer. 2017; 54(1): 197
[Pubmed] | [DOI]
3 Targeted Therapy Management in NSCLC Patients Using Cytology: Experience from a Tertiary Care Cancer Center
Vidya H. Veldore,Shekar Patil,Shilpa Prabhudesai,C. T. Satheesh,H. P. Shashidhara,Naveen Krishnamoorthy,D. Hazarika,R. Tejaswi,Ankita Prabhudev,Radheshyam Naik,Raghavendra M. Rao,B. S. Ajai Kumar
Molecular Diagnosis & Therapy. 2016; 20(2): 119
[Pubmed] | [DOI]
4 Molecular Spectrum of Somatic EGFR and KRAS Gene Mutations in non Small Cell Lung Carcinoma: Determination of Frequency, Distribution Pattern and Identification of Novel Variations in Indian Patients
Bibhu Ranjan Das,Sangeet Bhaumik,Firoz Ahmad,Aziz Mandsaurwala,Heena Satam
Pathology & Oncology Research. 2015;
[Pubmed] | [DOI]
5 Real-time PCR detection chemistry
E. Navarro,G. Serrano-Heras,M.J. Castaño,J. Solera
Clinica Chimica Acta. 2014;
[Pubmed] | [DOI]
6 Personalized medicine: Lung Cancer leads the way
P Parikh,T Puri
Indian Journal of Cancer. 2013; 50(2): 77
[Pubmed] | [DOI]



 

Top
Print this article  Email this article
 

    

  Site Map | What's new | Copyright and Disclaimer
  Online since 1st April '07
  © 2007 - Indian Journal of Cancer | Published by Wolters Kluwer - Medknow