title: Should KRAS mutation still be used as a routine predictor of response to EGFR-TKIs in advanced non-small-cell lung cancer? A revaluation based on meta-analysis.
abstract: OBJECTIVE
  Regarding the controversial investigations characterizing the role of KRAS status for predicting patients' response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small-cell lung cancer (NSCLC), we conducted a meta-analysis in unselected patients and a further subset analysis in EGFR wild-type advanced NSCLC to get a more accurate evaluation.
  
  
  METHODS
  We did systematically searches following the retrieval strategies. The end points were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR).
  
  
  RESULTS
  Twelve prospective intervention trials comprised of 1,859 unselected advanced NSCLC patients were identified. KRAS mutation was associated with shorter OS and PFS [hazard ratio (HR) 2.09, 95 % confidence interval (CI) 1.56-2.80; HR 1.82, 95 % CI 1.50-2.20] and lower ORR (relative ratio 0.25, 95 % CI 0.11-0.59) in unselected advanced NSCLC. After subgroup analysis, the association with survival was strengthened in second- or later-line EGFR-TKIs treatment group, with an HR of 2.45 for OS (95 % CI 1.27-4.74) and 1.86 for PFS (95 % CI 1.51-2.29), while the association with response to EGFR-TKIs became nonsignificant (P = 0.153). Four retrospective studies on the role of KRAS status in EGFR wild-type advanced NSCLC were deemed eligible and presented that KRAS mutation was associated with none of the outcomes in EGFR wild-type patients treated with EGFR-TKIs.
  
  
  CONCLUSIONS
  In unselected advanced NSCLC patients, KRAS mutations could be used as a potential negative predictor of clinical benefit from EGFR-TKIs. However, KRAS testing is of limited value to identify patients for EGFR-TKIs when EGFR status is considered.
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Ying
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Zhu
authors.forename: Kexu
authors.initials: K
authors.lastname: Chen
authors.forename: Zhou
authors.initials: Z
authors.lastname: Sha
authors.forename: Longhua
authors.initials: L
authors.lastname: Chen
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins