Detection of EGFR K-ras Mutations and ELM4-ALK Fusion Gene in Non-small Cell Lung Cancer using Cytological Specimen Materials and Their Clinical Pathology Significance_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

 YINYing-chun ¹ , WANGXin-mei ¹ , LILiang ² , HANHong-mei ¹ , ZHANGBao-hua ¹ , LIANGXiao ³ , HOUZhen-bo ¹ , MENGYun-xiao ⁴

1. Department of Pathology, Central Hospital of Zibo City, Zibo 255036 Shandong, P. R. China;
2. Department of Breast and Thyroid Surgery, Central Hospital of Zibo City, Zibo 255036 Shandong, P. R. China;
3. Department of Thoracic Surgery, Central Hospital of Zibo City, Zibo 255036 Shandong, P. R. China;
4. Department of Pathology, Peking Union Medical College Hospital, Beijing 100730, P. R. China;

Corresponding author：

YINYing-chun, Email: yingchun1126@163.com

Keywords：

Cell block; Epidermal growth factor receptor (EGFR); K-ras; EML4-ALK; Non-small cell lung cancer; Target therapy; Gene mutation

DOI：

10.7507/1007-4848.20150217

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Objective To explore the relationship of the clinicopathological characteristics of non-small cell lung cancer (NSCLC) with the mutations of epidermal growth factor receptor (EGFR), K-ras and EML4-ALK fusion gene in cell blocks of pleural effusion (PLE). Methods A total of 268 cytological specimens of PLE (pleural effusion), from Central Hospital of Zibo city were collected from advanced NSCLC patients between January 2012 year and June 2014 year. There were 165 male and 103 female patients at age of 53.6 (31-76) years. Qualitative diagnosis has been made in the 268 patients using PLE samples with conventional smear. Immunohistochemical staining combined with cell block section were used for further classification. There were 76 patients diagnosed as NSCLC with 39 patients of adenocarcinoma and 37 patients of squamous-cell carcinoma. In the 76 patients of lung biopsy specimens and PLE, EGFR and K-ras mutations, EML4-ALK fusions were tested. Results EGFR mutations rate was 34.21% (26/76). K-ras mutations rate was 6.58% (5/76). EML4-ALK fusions rate was 7.89% (6/76) at the same time. EGFR and K-ras mutations, EML4-ALK fusions were mostly found in young female adenocarcinoma patients who were non-smokers. EGFR and K-ras mutations or EML4-ALK fusions were not found in the same patient. Conclusion Cytological specimens are feasible for detecting EGFR were K-ras mutations and EML4-ALK fusions. This will especially benefit to patients whose histological specimen can not be obtained.

Citation： YINYing-chun, WANGXin-mei, LILiang, HANHong-mei, ZHANGBao-hua, LIANGXiao, HOUZhen-bo, MENGYun-xiao. Detection of EGFR K-ras Mutations and ELM4-ALK Fusion Gene in Non-small Cell Lung Cancer using Cytological Specimen Materials and Their Clinical Pathology Significance. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2015, 22(9): 870-874. doi: 10.7507/1007-4848.20150217 Copy

1.	Cai G, Wong R, Chhieng D, et al. Identification of EGFR mutation, KRAS mutation, and ALK gene rearrangement in cytological specimens of primary and metastatic lung adenocarcinoma. Cancer Cytopathol, 2013, 121(9):500-507.
2.	Malapelle U, Bellevicine C, De Luca C, et al. EGFR mutations detected on cytology samples by a centralized laboratory reliably predict response to gefitinib in non-small cell lung carcinoma patients. Cancer Cytopathol, 2013, 121(10):552-560.
3.	Xue C, Hu Z, Jiang W, et al. National survey of the medical treatment status for non-small cell lung cancer(NSCLC) in China. Lung Cancer, 2012, 77(2):371-375.
4.	Blackhall F, Thatcher N, Booton R, et al. The impact on the muhidiseiplinary team of molecular profiling for personalized therapy in non-small cell lung cancer. Lung Cancer, 2013, 79(2):101-103.
5.	Fathi AT, Brahmer JR. Chemotherapy for advanced stage non-small cell lung cancer. Semin Thorac Cardiovasc Surg, 2008, 20(3):210-216.
6.	De Mello RA, Madureira P, Carvalho LS, et al. EGFR and K-ras mutations, and ALK fusions:current developments and personalized therapies for patients with advanced non-small cell lung cancer. Pharmacogenomies, 2013, 14(14):1765-1777.
7.	Sun PL, Jin Y, Kim H, et al. High concordance of EGFR mutation status between histologic and corresponding of EGFR specimens of lung adenocarcinomas. Cancer Cytopathol, 2013, 121(6):311-319.
8.	Imbrell Hz, Gustafson KS, Huang M, et al. Subelassifieation of nonsmall cell lung cancer by cytological sampling:a logical approach with selective use of immunocytochemistry. Acta Cytol, 2012, 56(4):419-424.
9.	Douillard JY, Ostoros G, Cobo M, et al. First-line gefitinib in caucasian EGFR mutation positive NSCLC patients:a phase-IV, open-label, single-arm study. Br J Cancer, 2014, 110(1):55-62.
10.	王征, 武晓楠, 石远凯, 等. 细胞学标本表皮生长因子受体基因突变检测的规范化流程. 中华肿瘤杂志, 2014, 36(7):516-521.
11.	尹迎春, 王新美, 王新云, 等. 四甲基偶氮唑盐体外药物敏感试验联合多药耐药基因1检测预测非小细胞肺癌的化疗敏感性. 中国胸心血管外科临床杂志, 2012, 19(5):547-550.
12.	Cao C, Lu S, Sowa A, et al. Priming with EGFR tymsine kinase inhibitor and EGF sensitizes ovarian cancer cells to respond to chemotherapeutical drugs. Cancer Let, 2008, 266(2):249-262.
13.	Rosell R, Viteri S, Molina MA, et al. Epidermal growth factor receptor tyrosine kinase inhibitors as first-line treatment in advanced nonsmall cell lung cancer. Curr Opin Oncol, 2010, 22(2):112-120.
14.	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(2):154-162.
15.	Tam IY, Chung LP, Suen WS, et al. Distinct epidermal growth factor receptor and KRAS mumtion patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features. Clin Cancer Res, 2006, 12(5):1647-1653.
16.	Billah S, Stewart J, Staerkel G, et al. EGFR and KRAS mutstions in lung carcinoma:molecular testing by using cytology specimens. Cancer Cytopathol, 2011, 119(2):111-117.
17.	Ulivi P, Romagnoli M, Chiadim E, et al. Assessment of EGFR and K-ras mutations in fixed and fresh specimens from transesophageal ultrasound-guided fine needle aspiration in non-small cell lung cancer patients. Int J Oncol, 2012, 41(1):147-152.
18.	Gainor JF, Varghese AM, Ou SH, et al. ALK rearrangements are mutually exclusive with mutations in EGFRor KRAS:an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res, 2013, 19(15):4273-4281.
19.	Yang JJ, Zhang XC, Su J, et al. Lung cancers with concomitant EGFR mutations and ALK rearrangements:diverse responses to EGFR-TKI and crizotinib in relation to diverse receptors phosphorylation. Clin Cancer Res, 2014, 20(5):1383-1392.
20.	Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer:updated results from a phase l study. Lancet Oncol, 2012, 13(10):1011-1019.
21.	Shaw AT, Kim Dw, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med, 2013, 368(25):2385-2394.
22.	Sasaki T, Rodig SJ, Chiriea LR, et al. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer, 2010, 46(10):1773-1780.
23.	Koivunen JP, Mermel C, Zejnullathu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res, 2008, 14(13):4275-4283.
24.	张绪超, 卢舜, 张力, 等. 中国间变性淋巴瘤激酶(ALK)阳性非小细胞肺癌诊断专家共识(2013版). 中华病理学杂志, 2013, 42(6):402-406.
25.	石远凯. 基于分子靶点的非小细胞肺癌个体化治疗现状和未来.中华肿瘤杂志, 2012, 34(5):398-400.
26.	石远凯, 郏博, 孙燕. 克唑替尼:晚期非小细胞肺癌治疗的新选择. 中华医学杂志, 2013, 93(16):1272-1275.

1. Cai G, Wong R, Chhieng D, et al. Identification of EGFR mutation, KRAS mutation, and ALK gene rearrangement in cytological specimens of primary and metastatic lung adenocarcinoma. Cancer Cytopathol, 2013, 121(9):500-507.
2. Malapelle U, Bellevicine C, De Luca C, et al. EGFR mutations detected on cytology samples by a centralized laboratory reliably predict response to gefitinib in non-small cell lung carcinoma patients. Cancer Cytopathol, 2013, 121(10):552-560.
3. Xue C, Hu Z, Jiang W, et al. National survey of the medical treatment status for non-small cell lung cancer(NSCLC) in China. Lung Cancer, 2012, 77(2):371-375.
4. Blackhall F, Thatcher N, Booton R, et al. The impact on the muhidiseiplinary team of molecular profiling for personalized therapy in non-small cell lung cancer. Lung Cancer, 2013, 79(2):101-103.
5. Fathi AT, Brahmer JR. Chemotherapy for advanced stage non-small cell lung cancer. Semin Thorac Cardiovasc Surg, 2008, 20(3):210-216.
6. De Mello RA, Madureira P, Carvalho LS, et al. EGFR and K-ras mutations, and ALK fusions:current developments and personalized therapies for patients with advanced non-small cell lung cancer. Pharmacogenomies, 2013, 14(14):1765-1777.
7. Sun PL, Jin Y, Kim H, et al. High concordance of EGFR mutation status between histologic and corresponding of EGFR specimens of lung adenocarcinomas. Cancer Cytopathol, 2013, 121(6):311-319.
8. Imbrell Hz, Gustafson KS, Huang M, et al. Subelassifieation of nonsmall cell lung cancer by cytological sampling:a logical approach with selective use of immunocytochemistry. Acta Cytol, 2012, 56(4):419-424.
9. Douillard JY, Ostoros G, Cobo M, et al. First-line gefitinib in caucasian EGFR mutation positive NSCLC patients:a phase-IV, open-label, single-arm study. Br J Cancer, 2014, 110(1):55-62.
10. 王征, 武晓楠, 石远凯, 等. 细胞学标本表皮生长因子受体基因突变检测的规范化流程. 中华肿瘤杂志, 2014, 36(7):516-521.
11. 尹迎春, 王新美, 王新云, 等. 四甲基偶氮唑盐体外药物敏感试验联合多药耐药基因1检测预测非小细胞肺癌的化疗敏感性. 中国胸心血管外科临床杂志, 2012, 19(5):547-550.
12. Cao C, Lu S, Sowa A, et al. Priming with EGFR tymsine kinase inhibitor and EGF sensitizes ovarian cancer cells to respond to chemotherapeutical drugs. Cancer Let, 2008, 266(2):249-262.
13. Rosell R, Viteri S, Molina MA, et al. Epidermal growth factor receptor tyrosine kinase inhibitors as first-line treatment in advanced nonsmall cell lung cancer. Curr Opin Oncol, 2010, 22(2):112-120.
14. 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(2):154-162.
15. Tam IY, Chung LP, Suen WS, et al. Distinct epidermal growth factor receptor and KRAS mumtion patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features. Clin Cancer Res, 2006, 12(5):1647-1653.
16. Billah S, Stewart J, Staerkel G, et al. EGFR and KRAS mutstions in lung carcinoma:molecular testing by using cytology specimens. Cancer Cytopathol, 2011, 119(2):111-117.
17. Ulivi P, Romagnoli M, Chiadim E, et al. Assessment of EGFR and K-ras mutations in fixed and fresh specimens from transesophageal ultrasound-guided fine needle aspiration in non-small cell lung cancer patients. Int J Oncol, 2012, 41(1):147-152.
18. Gainor JF, Varghese AM, Ou SH, et al. ALK rearrangements are mutually exclusive with mutations in EGFRor KRAS:an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res, 2013, 19(15):4273-4281.
19. Yang JJ, Zhang XC, Su J, et al. Lung cancers with concomitant EGFR mutations and ALK rearrangements:diverse responses to EGFR-TKI and crizotinib in relation to diverse receptors phosphorylation. Clin Cancer Res, 2014, 20(5):1383-1392.
20. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer:updated results from a phase l study. Lancet Oncol, 2012, 13(10):1011-1019.
21. Shaw AT, Kim Dw, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med, 2013, 368(25):2385-2394.
22. Sasaki T, Rodig SJ, Chiriea LR, et al. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer, 2010, 46(10):1773-1780.
23. Koivunen JP, Mermel C, Zejnullathu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res, 2008, 14(13):4275-4283.
24. 张绪超, 卢舜, 张力, 等. 中国间变性淋巴瘤激酶(ALK)阳性非小细胞肺癌诊断专家共识(2013版). 中华病理学杂志, 2013, 42(6):402-406.
25. 石远凯. 基于分子靶点的非小细胞肺癌个体化治疗现状和未来.中华肿瘤杂志, 2012, 34(5):398-400.
26. 石远凯, 郏博, 孙燕. 克唑替尼:晚期非小细胞肺癌治疗的新选择. 中华医学杂志, 2013, 93(16):1272-1275.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Detection of EGFR K-ras Mutations and ELM4-ALK Fusion Gene in Non-small Cell Lung Cancer using Cytological Specimen Materials and Their Clinical Pathology Significance

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