title: High EGFR copy number predicts benefits from tyrosine kinase inhibitor treatment for non-small cell lung cancer patients with wild-type EGFR.
abstract: BACKGROUND
  This study was designed to determine whether advanced non-small-cell lung cancer (NSCLC) patients with high copy number of epidermal growth factor receptor (EGFR) can benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs).
  
  
  METHODS
  EGFR gene copy number was assessed by fluorescence in situ hybridization (FISH) and EGFR mutations was tested using Luminex xTAG technology in 502 TKI-treated NSCLC patients. The association between both biomarkers and clinical benefit from EGFR-TKI were analyzed.
  
  
  RESULTS
  EGFR FISH+and EGFR mutations were significantly associated with higher response rates (37.2% and 43.7%, respectively), superior progression-free survival (PFS) (FISH+, 11.2 months; hazard ratio [HR], 0.51; 95% CI, 0.42 to 0.62; p<0.001; mutation+, 11.7 months; HR, 0.37; 95% CI, 0.31 to 0.45; p<0.001) and overall survival (OS) (FISH+, 30.2 months; HR, 0.51; 95% CI, 0.40 to 0.65; p<0.001; mutation+, 30.2 months; HR, 0.45; 95% CI, 0.36 to 0.58; p<0.001). In patients with wild-type EGFR, EGFR FISH+correlated with longer PFS than EGFR FISH- status (4.4 months vs. 2.0 months; HR, 0.56; 95% CI, 0.41 to 0.75; p<0.001), so did amplification (5.0 months vs. 2.0 months; HR, 0.43; 95% CI, 0.24 to 0.76; p=0.003). However, FISH+had no association with improved PFS in EGFR-mutated patients (HR, 0.77; 95% CI, 0.57 to 1.03; p=0.076).
  
  
  CONCLUSIONS
  A combined analysis of EGFR FISH and mutation is an effective predictor of EGFR-TKI therapy. Specifically, a high EGFR copy number may predict benefit from TKIs treatment for NSCLC patients with wild-type EGFR.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Sha
authors.initials: S
authors.lastname: Fu
authors.forename: Qiong
authors.initials: Q
authors.lastname: Shao
authors.forename: Yan-Bin
authors.initials: YB
authors.lastname: Zhou
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Cong
authors.initials: C
authors.lastname: Xue
authors.forename: Jian-Guang
authors.initials: JG
authors.lastname: Lin
authors.forename: Li-Xia
authors.initials: LX
authors.lastname: Huang
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Zhang
authors.forename: Jian-Yong
authors.initials: JY
authors.lastname: Shao
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D018628:Gene Dosage; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors
references.citation: EMBO J. 2000 Jul 3;19(13):3159-67
references.pmid: 10880430
references.citation: J Clin Oncol. 2008 Sep 10;26(26):4268-75
references.pmid: 18626007
references.citation: J Clin Oncol. 2010 Feb 10;28(5):744-52
references.pmid: 20038723
references.citation: Clin Cancer Res. 2012 Mar 15;18(6):1760-8
references.pmid: 22271877
references.citation: Lancet Oncol. 2010 Feb;11(2):121-8
references.pmid: 20022809
references.citation: J Clin Oncol. 2008 Jul 10;26(20):3351-7
references.pmid: 18612151
references.citation: Science. 2004 Jun 4;304(5676):1497-500
references.pmid: 15118125
references.citation: Lung Cancer. 2008 Sep;61(3):328-39
references.pmid: 18304690
references.citation: N Engl J Med. 2004 May 20;350(21):2129-39
references.pmid: 15118073
references.citation: N Engl J Med. 2009 Sep 3;361(10):947-57
references.pmid: 19692680
references.citation: N Engl J Med. 2005 Jul 14;353(2):123-32
references.pmid: 16014882
references.citation: EMBO J. 1996 May 15;15(10):2452-67
references.pmid: 8665853
references.citation: Anticancer Res. 2012 Mar;32(3):1107-12
references.pmid: 22399641
references.citation: Cancer. 2007 May 1;109(9):1836-44
references.pmid: 17387741
references.citation: N Engl J Med. 2010 Jun 24;362(25):2380-8
references.pmid: 20573926
references.citation: J Clin Oncol. 2005 Oct 1;23(28):6829-37
references.pmid: 15998907
references.citation: J Clin Oncol. 2006 Nov 1;24(31):5034-42
references.pmid: 17075123
references.citation: J Clin Oncol. 2011 Nov 1;29(31):4113-20
references.pmid: 21969500
references.citation: Lancet Oncol. 2011 Aug;12(8):735-42
references.pmid: 21783417
references.citation: Lung Cancer. 2008 May;60(2):160-5
references.pmid: 18367287
references.citation: Lancet. 2005 Oct 29-Nov 4;366(9496):1527-37
references.pmid: 16257339
references.citation: J Clin Oncol. 2008 Mar 20;26(9):1472-8
references.pmid: 18349398
references.citation: J Clin Oncol. 2005 Oct 1;23(28):6838-45
references.pmid: 15998906
references.citation: J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
references.pmid: 10655437
references.citation: Chest. 2009 Jul;136(1):260-271
references.pmid: 19584208
references.citation: Clin Cancer Res. 2011 Jan 15;17(2):382-90
references.pmid: 20884623
references.citation: Cancer Biomark. 2011-2012;10(2):63-9
references.pmid: 22430133
references.citation: J Clin Oncol. 2009 Apr 1;27(10):1667-74
references.pmid: 19255323
references.citation: Lancet. 2008 Nov 22;372(9652):1809-18
references.pmid: 19027483
references.citation: PLoS One. 2009 Oct 14;4(10):e7464
references.pmid: 19826477
references.citation: J Clin Oncol. 2003 Oct 15;21(20):3798-807
references.pmid: 12953099
references.citation: J Clin Oncol. 2011 Jul 20;29(21):2866-74
references.pmid: 21670455
references.citation: J Natl Cancer Inst. 2005 May 4;97(9):643-55
references.pmid: 15870435