바로가기메뉴

본문 바로가기 주메뉴 바로가기

Tuberculosis & Respiratory Diseases

Article Contents

Prev Next
e-Submission

Vol.82 No.1
Citation Share

Factors that Predict Clinical Benefit of EGFR TKI Therapy in Patients with EGFR Wild-Type Lung Adenocarcinoma

Tuberculosis & Respiratory Diseases / Tuberculosis & Respiratory Diseases,
2019, v.82 no.1, pp.62-70







& (2019). Factors that Predict Clinical Benefit of EGFR TKI Therapy in Patients with EGFR Wild-Type Lung Adenocarcinoma. Tuberculosis & Respiratory Diseases, 82(1), 62-70.
  • Downloaded
  • Viewed
PDF Download

Abstract

Background: Epidermal growth factor receptor ( EGFR ) mutations in non-small cell lung cancers have emerged as key predictive biomarkers in EGFR tyrosine kinase inhibitor (TKI) treatment. However, a few patients with wild-type EGFR also respond to EGFR TKIs. This study investigated the factors predicting successful EGFR TKI treatment in lung adenocarcinoma patients with wild-type EGFR . Methods: We examined 66 patients diagnosed with lung adenocarcinoma carrying wide-type EGFR who were treated with EGFR TKIs. The EGFR gene copy number was assessed by silver in situ hybridization (SISH). We evaluated the clinical factors and EGFR gene copy numbers that are associated with a favorable clinical response to EGFR TKIs. Results: The objective response rate was 12.1%, while the disease control rate was 40.9%. EGFR SISH analysis was feasible in 23 cases. Twelve patients tested EGFR SISH–positive, and 11 were EGFR SISH–negative, with no significant difference in tumor response and survival between EGFR SISH–positive and –negative patients. The overall median progression-free survival (PFS) and overall survival (OS) of 66 patients were 2.1 months and 9.7 months, respectively. Female sex and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1 were independent predictors of PFS. ECOG PS 0–1 and a low tumor burden of extrathoracic metastasis were independent predictors of good OS. Conclusion: Factors such as good PS, female sex, and low tumor burden may predict favorable outcomes following EGFR TKI therapy in patients with EGFR wild-type lung adenocarcinoma. However, EGFR gene copy number was not predictive of survival.

keywords
Adenocarcinoma, Receptor, Epidermal Growth Factor, Lung Neoplasms

Reference

1.

1. Torre LA, Siegel RL, Jemal A. Lung cancer statistics. Adv Exp Med Biol 2016; 893:1-19.

2.

2. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346:92-8.

3.

3. Fossella F, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 2003; 21:3016-24.

4.

4. 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.

5.

5. 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.

6.

6. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as firstline 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.

7.

7. Hirsch FR, Bunn PA Jr. EGFR testing in lung cancer is ready for prime time. Lancet Oncol 2009; 10:432-3.

8.

8. Laurie SA, Goss GD. Role of epidermal growth factor receptor inhibitors in epidermal growth factor receptor wild-type nonsmall-cell lung cancer. J Clin Oncol 2013; 31:1061-9.

9.

9. Wang F, Fu S, Shao Q, Zhou YB, Zhang X, Zhang X, et al. High EGFR copy number predicts benefits from tyrosine kinase inhibitor treatment for non-small cell lung cancer patients with wild-type EGFR . J Transl Med 2013; 11:90.

10.

10. Hou MM, Huang SF, Kuo HP, Yang CT, Tsai YH, Yu CT, et al. Erlotinib treatment in patients with advanced lung adenocarcinoma with CISH-positive and CISH-negative EGFR gene alterations. Anticancer Res 2012; 32:1107-12.

11.

11. Hirsch FR, Varella-Garcia M, McCoy J, West H, Xavier AC, Gumerlock P, et al. Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group Study. J Clin Oncol 2005; 23:6838-45.

12.

12. Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 2005; 97:643-55.

13.

13. Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 2000; 19:3159-67.

14.

14. Varella-Garcia M, Diebold J, Eberhard DA, Geenen K, Hirschmann A, Kockx M, et al. EGFR fluorescence in situ hybridisation assay: guidelines for application to non-small-cell lung cancer. J Clin Pathol 2009; 62:970-7.

15.

15. Fritzsche FR, Bode PK, Moch H, Kristiansen G, Varga Z, Bode B. Determination of the Her-2/neu gene amplification status in cytologic breast cancer specimens using automated silverenhanced in-situ hybridization (SISH). Am J Surg Pathol 2010; 34:1180-5.

16.

16. Wulf MA, Bode B, Zimmermann D, Rufibach K, Weder W, Moch H, et al. Silver-enhanced in situ hybridization for determination of EGFR copy number alterations in non-small cell lung cancer. Am J Surg Pathol 2012; 36:1801-8.

17.

17. Gaiser T, Waha A, Moessler F, Bruckner T, Pietsch T, von Deimling A. Comparison of automated silver enhanced in situ hybridization and fluorescence in situ hybridization for evaluation of epidermal growth factor receptor status in human glioblastomas. Mod Pathol 2009; 22:1263-71.

18.

18. Na II, Kang HJ, Cho SY, Koh JS, Lee JK, Lee BC, et al. EGFR mutations and human papillomavirus in squamous cell carcinoma of tongue and tonsil. Eur J Cancer 2007; 43:520-6.

19.

19. Boldrini L, Gisfredi S, Ursino S, Camacci T, Baldini E, Melfi F, et al. Mutational analysis in cytological specimens of advanced lung adenocarcinoma: a sensitive method for molecular diagnosis. J Thorac Oncol 2007; 2:1086-90.

20.

20. Na II, Park JH, Choe du H, Lee JK, Koh JS. Association of epidermal growth factor receptor mutations with metastatic presentations in non-small cell lung cancer. ISRN Oncol 2011; 2011:756265.

21.

21. 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.

22.

22. Chang MH, Ahn HK, Lee J, Jung CK, Choi YL, Park YH, et al. Clinical impact of amphiregulin expression in patients with epidermal growth factor receptor (EGFR ) wild-type nonsmall cell lung cancer treated with EGFR-tyrosine kinase inhibitors. Cancer 2011; 117:143-51.

23.

23. Dahabreh IJ, Linardou H, Kosmidis P, Bafaloukos D, Murray S. EGFR gene copy number as a predictive biomarker for patients receiving tyrosine kinase inhibitor treatment: a systematic review and meta-analysis in non-small-cell lung cancer. Ann Oncol 2011; 22:545-52.

24.

24. Lee Y, Shim HS, Park MS, Kim JH, Ha SJ, Kim SH, et al. High EGFR gene copy number and skin rash as predictive markers for EGFR tyrosine kinase inhibitors in patients with advanced squamous cell lung carcinoma. Clin Cancer Res 2012; 18:1760-8.

25.

25. Li N, Ou W, Yang H, Liu QW, Zhang SL, Wang BX, et al. A randomized phase 2 trial of erlotinib versus pemetrexed as second-line therapy in the treatment of patients with advanced EGFR wild-type and EGFR FISH-positive lung adenocarcinoma. Cancer 2014; 120:1379-86.

26.

26. Ren S, Su C, Wang Z, Li J, Fan L, Li B, et al. Epithelial phenotype as a predictive marker for response to EGFR-TKIs in non-small cell lung cancer patients with wild-type EGFR . Int J Cancer 2014; 135:2962-71.

27.

27. Lai SW, Ho CL, Dai MS, Chen WL, Chang PY, Wu YY, et al. Gefitinib as first-line treatment for patients with epidermal growth factor receptor-mutated advanced lung adenocarcinoma:a single institution experience in Taiwan. J BUON 2014; 19:459-65.

28.

28. Kaneda H, Tamura K, Kurata T, Uejima H, Nakagawa K, Fukuoka M. Retrospective analysis of the predictive factors associated with the response and survival benefit of gefitinib in patients with advanced non-small-cell lung cancer. Lung Cancer 2004; 46:247-54.

29.

29. Yang CH, Shih JY, Chen KC, Yu CJ, Yang TY, Lin CP, et al. Survival outcome and predictors of gefitinib antitumor activity in East Asian chemonaive patients with advanced nonsmall cell lung cancer. Cancer 2006; 107:1873-82.

30.

30. Sanchez de Cos Escuin J, Abal Arca J, Melchor Iniguez R, Miravet Sorribes L, Nunez Ares A, Hernandez Hernandez JR, et al. Tumor, node and metastasis classification of lung cancer:M1a versus M1b: analysis of M descriptors and other prognostic factors. Lung Cancer 2014; 84:182-9.

31.

31. Park S, Kim HJ, Choi CM, Lee DH, Kim SW, Lee JS, et al. Predictive factors for a long-term response duration in nonsquamous cell lung cancer patients treated with pemetrexed. BMC Cancer 2016; 16:417.

32.

32. Park JH, Kim TM, Keam B, Jeon YK, Lee SH, Kim DW, et al. Tumor burden is predictive of survival in patients with nonsmall-cell lung cancer and with activating epidermal growth factor receptor mutations who receive gefitinib. Clin Lung Cancer 2013; 14:383-9.

33.

33. Oh Y, Taylor S, Bekele BN, Debnam JM, Allen PK, Suki D, et al. Number of metastatic sites is a strong predictor of survival in patients with nonsmall cell lung cancer with or without brain metastases. Cancer 2009; 115:2930-8.

Tuberculosis & Respiratory Diseases

e-Submission OA Policy