Distribution of EGFR Mutations Commonly Observed in Primary Lung Adenocarcinomas in Pakistan as Predictors for Targeted Therapy

  • Ahmed, Zeeshan Ansar (Department of Pathology and Microbiology, Medical College, The Aga Khan University) ;
  • Moatter, Tariq (Department of Pathology and Microbiology, Medical College, The Aga Khan University) ;
  • Siddiqui, Areeba (Department of Pathology and Microbiology, Medical College, The Aga Khan University) ;
  • Pervez, Shahid (Department of Pathology and Microbiology, Medical College, The Aga Khan University)
  • Published : 2014.09.15


Background: Acquired genetic alterations and presence of sensitizing mutations in the tyrosine kinase domain of EGFR and other signaling molecules have been found in different subsets of primary lung adenocarcinoma. The commonest EGFR mutations are small in frame deletions of exon 19 and a point mutation (L858R) in exon 21, having a combined occurrence of around 90%. The objective of this study was to determine the frequency and types of EGFR mutations in primary lung adenocarcinomas in Pakistan. Materials and Methods: EGFR mutations in tumor samples were screened by multiplex real time PCR. Briefly, DNA from formalin fixed paraffin-embedded tissue was amplified with primers and probes specific to 43 different EGFR mutations in a Cobas z 480 instrument. The assay detects mutations in four exons (18-21) of the EGFR gene. Results: Out of 94 patients, 65 were males and 29 females with a M:F ratio of 2.2: 1. The median age was 62 years (range, 28 - 85 years). In our biopsy samples 70 (74%) cases were of primary lung adenocarcinoma, whereas 24 (26%) were confirmed metastatic adenocarcinoma of primary lung origin. EGFR mutation was positive in 29% of the patients. The highest frequency of L858R was observed in 48% of these, followed by deletion in exon 19 (44%). In addition, other rare mutations such as compound G718X:S768I and insertions in exon 20 insertion were detected in approximately 4% of the patients. Conclusions: This study showed that Del 19 and L858R are the most frequent mutations in Pakistani lung adenocarcinoma patients and around 29% of the patients were found eligible for erlotinib therapy.


  1. Cohen V, Agulnik JS, Ang C, et al (2010). Epidermal growth factor receptor mutations detected by denaturing high performance liquid chromatography in non-small cell lung cancer: impact on response to therapy with epidermal growth factor receptor-tyrosine kinase inhibitors. Cancer, 116, 4215-432.
  2. Ferlay J, Soerjomataram I, Ervik M, et al (2012). Cancer Incidence and Mortality Worldwide: IARC Cancer Base. GLOBOCAN, 1.0, No. 11
  3. Ferlay J, Shin HR, Bray F, et al (2010). Estimates of world-wide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer, 127, 2893-917.
  4. Hanif M, Zaidi P, Kamal S, Hameed A (2009). Institution-based Cancer Incidence in a Local Population in Pakistan: Nine Year Data Analysis. Asian Pac J Cancer Prev, 10, 227-30.
  5. Han JY, Park K, Kim SW, et al (2012). First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol, 30, 1122-8.
  6. Jemal A, Thun MJ, Ries LA, et al (2008). Annual report to the nation on the status of cancer, 1975-2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst, 100, 1672-94.
  7. Liu H, Li Y, Chen G, et al (2009). Detection and its clinical significance of EGFR gene mutation and gene amplification in 187 patients with non-small cell lung cancer. Zhongguo Fei Ai Za Zhi, 12, 1219-47.
  8. Lindeman NI, Cagle PT, Beasley MB, et al (2013). Lung Cancer Molecular Testing Guidelines. Arch Pathol Lab Med, 137, 828-60.
  9. Lindeman NI, Cagle PT, Beasley MB, et al (2013). 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, 8, 823-59.
  10. Mackay J, Jemal A, Lee NC, et al (2006). The Cancer Atlas. Atlanta: American Cancer Society.
  11. Ma BBY, Hui EP, Mok TSK (2010). Population-based differences in treatment outcome following anticancer drug therapies. Lancet Oncol, 11, 75-84.
  12. Maemondo M, Inoue A, Kobayashi K, et al (2010). Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med, 362, 2380-8.
  13. Mitsudomi T, Morita S, Yatabe Y, et al (2010). Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harboring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomized phase 3 trial. Lancet Oncol, 11, 121-8.
  14. Noronha V, Prabhash K, Thavamani A, et al (2013). EGFR Mutations in Indian Lung Cancer Patients: Clinical Correlation and Outcome to EGFR Targeted Therapy. PLoS ONE, 8, 61561-69
  15. Parkin DM, Bray F, Ferlay J, Pisani P (2005). Global cancer statistics, 2002. CA Cancer J Clin, 55, 74-108.
  16. Rosell R, Carcereny E, Gervais R, et al (2012). Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive nonsmallcell lung cancer (EURTAC): a multicentre, open-label, randomized phase 3 trial. Lancet Oncol, 13, 239-46.
  17. Rossi A, Pasquale R, Esposito C, Normanno N (2013). Should epidermal growth factor receptor tyrosine kinase inhibitors be considered ideal drugs for the treatment of selected advanced non-small cell lung cancer patients? Cancer Treatment Reviews, 5, 489-97.
  18. Ren YW, Yin ZH, Wan Y, et al (2013). P53 Arg72Pro and MDM2 SNP309 polymorphisms cooperate to increase lung adenocarcinoma risk in Chinese female non-smokers: a case control study. Asian Pac J Cancer Prev, 14, 5415-20.
  19. Salto Tellez M, Tsao MS, Shih JY, et al (2011): 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, 6, 1663-9.
  20. Sequist LV, Yang JC, Yamamoto N, et al (2013). Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol, 31, 3327-34.
  21. Wang Y, Liu H, Chen J (2010). The predictive value of EGFR status in non-small cell lung cancer patients treated with EGFR-TKIs. Zhongguo Fei Ai Za Zhi, 13, 375-9.
  22. Xiao H, Ding J, Gao S, Yang S, Huang Y (2011). Never smokers with lung cancer: analysis of genetic variants. Asian Pac J Cancer Prev, 12, 2807-9.
  23. Xu Y, Chen L, Tian Q, et al (2010). Application of epidermal growth factor receptor tyrosine kinase inhibitor as the firstline therapy in patients with advanced non-small cell lung cancer. Zhongguo Fei Ai Za Zhi, 13, 48-53.
  24. Zhou C, Wu YL, Chen G, et al (2011). Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, openlabel, randomised, phase 3 study. Lancet Oncol, 12, 735-42.

Cited by

  1. Frequency of EGFR Mutations in Non-small Cell Lung Cancer Patients: Screening Data from West Siberia vol.16, pp.2, 2015,
  2. Oncogenes: The Passport for Viral Oncolysis through PKR Inhibition vol.8, pp.1179-299X, 2016,