J Pathol Transl Med.  2015 Nov;49(6):481-488. 10.4132/jptm.2015.09.14.

Analysis of Mutations in Epidermal Growth Factor Receptor Gene in Korean Patients with Non-small Cell Lung Cancer: Summary of a Nationwide Survey

• Lee SH
• Kim WS
• Choi YD
• Seo JW
• Han JH
• Kim MJ
• Kim L
• Lee GK
• Lee CH
• Oh MH
• Kim GY
• Sung SH
• Lee KY
• Chang SH
• Rho MS
• Kim HK
• Jung SH
• Jang SJ
• The Cardiopulmonary Pathology Study Group of Korean Society of Pathologists

• KMID: 2381407
• DOI: http://doi.org/10.4132/jptm.2015.09.14

Abstract

BACKGROUND
Analysis of mutations in the epidermal growth factor receptor gene (EGFR) is important for predicting response to EGFR tyrosine kinase inhibitors. The overall rate of EGFR mutations in Korean patients is variable. To obtain comprehensive data on the status of EGFR mutations in Korean patients with lung cancer, the Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists initiated a nationwide survey.
METHODS
We obtained 1,753 reports on EGFR mutations in patients with lung cancer from 15 hospitals between January and December 2009. We compared EGFR mutations with patient age, sex, history of smoking, histologic diagnosis, specimen type, procurement site, tumor cell dissection, and laboratory status.
RESULTS
The overall EGFR mutation rate was 34.3% in patients with non-small cell lung cancer (NSCLC) and 43.3% in patients with adenocarcinoma. EGFR mutation rate was significantly higher in women, never smokers, patients with adenocarcinoma, and patients who had undergone excisional biopsy. EGFR mutation rates did not differ with respect to patient age or procurement site among patients with NSCLC.
CONCLUSIONS
EGFR mutation rates and statuses were similar to those in published data from other East Asian countries.

Keyword

Lung neoplasms; Receptor, epidermal growth factor; Mutation survey

MeSH Terms

Adenocarcinoma
Asian Continental Ancestry Group
Biopsy
Carcinoma, Non-Small-Cell Lung*
Diagnosis
Epidermal Growth Factor*
Female
Humans
Lung Neoplasms
Mutation Rate
Pathology
Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor*
Smoke
Smoking
Epidermal Growth Factor
Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor
Smoke

Figure

• 

  Fig. 1. Geographical distribution of the 15 hospitals in Korea.

• 

  Fig. 2. Specimen types used for EGFR mutation testing. EGFR, epidermal growth factor receptor.

• 

  Fig. 3. Frequency of mutations according to exons: 601 mutations in 1,753 specimens from patients with non-small cell lung cancer.

• 

  Fig. 4. EGFR mutation rates in in-house laboratories. EGFR, epidermal growth factor receptor.

Reference

1. Jung KW, Won YJ, Kong HJ, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2012. Cancer Res Treat. 2015; 47:127–41.

2. Owonikoko TK, Ragin CC, Belani CP, et al. Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database. J Clin Oncol. 2007; 25:5570–7.

3. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009; 361:947–57.

4. Rosell R, Carcereny E, Gervais R, 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.

5. Zhou C, Wu YL, Chen G, 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.

6. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010; 362:2380–8.

7. Mitsudomi T, Morita S, Yatabe Y, 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.

8. Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011; 29:2866–74.

9. Yang JC, Wu YL, Schuler M, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015; 16:141–51.

10. Yatabe Y, Kerr KM, Utomo A, et al. EGFR mutation testing practices within the Asia Pacific region: results of a multicenter diagnostic survey. J Thorac Oncol. 2015; 10:438–45.

11. Yang CH. EGFR tyrosine kinase inhibitors for the treatment of NSCLC in East Asia: present and future. Lung Cancer. 2008; 60 Suppl 2:S23–30.

12. 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; 97:339–46.

13. Skov BG, Høgdall E, Clementsen P, et al. The prevalence of EGFR mutations in non-small cell lung cancer in an unselected Caucasian population. APMIS. 2015; 123:108–15.

14. Gahr S, Stoehr R, Geissinger E, et al. EGFR mutational status in a large series of Caucasian European NSCLC patients: data from daily practice. Br J Cancer. 2013; 109:1821–8.

15. Soung YH, Lee JW, Kim SY, et al. Mutational analysis of EGFR and K-RAS genes in lung adenocarcinomas. Virchows Arch. 2005; 446:483–8.

16. Bae NC, Chae MH, Lee MH, et al. EGFR, ERBB2, and KRAS mutations in Korean non-small cell lung cancer patients. Cancer Genet Cytogenet. 2007; 173:107–13.

17. Park S, Holmes-Tisch AJ, Cho EY, et al. Discordance of molecular biomarkers associated with epidermal growth factor receptor pathway between primary tumors and lymph node metastasis in nonsmall cell lung cancer. J Thorac Oncol. 2009; 4:809–15.

18. Lee YJ, Park IK, Park MS, et al. Activating mutations within the EGFR kinase domain: a molecular predictor of disease-free survival in resected pulmonary adenocarcinoma. J Cancer Res Clin Oncol. 2009; 135:1647–54.

19. Ahn MJ, Park BB, Ahn JS, et al. Are there any ethnic differences in molecular predictors of erlotinib efficacy in advanced non-small cell lung cancer? Clin Cancer Res. 2008; 14:3860–6.

20. Sun PL, Seol H, Lee HJ, 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.

21. Kim YT, Seong YW, Jung YJ, et al. The presence of mutations in epidermal growth factor receptor gene is not a prognostic factor for long-term outcome after surgical resection of non-small-cell lung cancer. J Thorac Oncol. 2013; 8:171–8.

22. 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.

23. Ma BB, Hui EP, Mok TS. Population-based differences in treatment outcome following anticancer drug therapies. Lancet Oncol. 2010; 11:75–84.

24. Chan SK, Gullick WJ, Hill ME. Mutations of the epidermal growth factor receptor in non-small cell lung cancer: search and destroy. Eur J Cancer. 2006; 42:17–23.

25. Shi Y, Au JS, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol. 2014; 9:154–62.

26. Liu J, Zhao R, Zhang J, Zhang J. ARMS for EGFR mutation analysis of cytologic and corresponding lung adenocarcinoma histologic specimens. J Cancer Res Clin Oncol. 2015; 141:221–7.

27. Heymann JJ, Bulman WA, Maxfield RA, et al. Molecular testing guidelines for lung adenocarcinoma: utility of cell blocks and concordance between fine-needle aspiration cytology and histology samples. Cytojournal. 2014; 11:12.

28. Khode R, Larsen DA, Culbreath BC, et al. Comparative study of epidermal growth factor receptor mutation analysis on cytology smears and surgical pathology specimens from primary and metastatic lung carcinomas. Cancer Cytopathol. 2013; 121:361–9.

29. Sun PL, Jin Y, Kim H, Lee CT, Jheon S, Chung JH. High concordance of EGFR mutation status between histologic and corresponding cytologic specimens of lung adenocarcinomas. Cancer Cytopathol. 2013; 121:311–9.

30. Pirker R, Herth FJ, Kerr KM, 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.

31. Pao W, Ladanyi M. Epidermal growth factor receptor mutation testing in lung cancer: searching for the ideal method. Clin Cancer Res. 2007; 13:4954–5.

32. Kim SK, Kim DL, Han HS, et al. Pyrosequencing analysis for detection of a BRAFV600E mutation in an FNAB specimen of thyroid nodules. Diagn Mol Pathol. 2008; 17:118–25.

33. 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.

34. Choi JJ, Cho M, Oh M, Kim H, Kil MS, Park H. PNA-mediated real-time PCR clamping for detection of EGFR mutations. Bull Korean Chem Soc. 2010; 31:3525–9.

35. Lee HJ, Xu X, Kim H, et al. Comparison of direct sequencing, PNA clamping-real time polymerase chain reaction, and pyrosequencing methods for the detection of EGFR mutations in non-small cell lung carcinoma and the correlation with clinical responses to EGFR tyrosine kinase inhibitor treatment. Korean J Pathol. 2013; 47:52–60.

36. Kim HJ, Lee KY, Kim YC, et al. Detection and comparison of peptide nucleic acid-mediated real-time polymerase chain reaction clamping and direct gene sequencing for epidermal growth factor receptor mutations in patients with non-small cell lung cancer. Lung Cancer. 2012; 75:321–5.