title: Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer.
abstract: BACKGROUND
  Somatic mutations of the k-RAS oncogene have been assessed as a mechanism of de-novo resistance to epidermal growth factor receptor (EGFR) tyrosine-kinase inhibition in patients with non-small-cell lung cancer (NSCLC), and to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer (mCRC). The aim of this systematic review and meta-analysis was to assess if k-RAS mutations represent a candidate predictive biomarker for anti-EGFR-targeted therapeutic strategies in mCRC and NSCLC.
  
  
  METHODS
  We systematically identified articles pertaining to k-RAS mutational status in patients with NSCLC treated with tyrosine-kinase inhibitors (TKI), and patients with mCRC treated with any anti-EGFR-based regimens. Eligible studies had to report complete responses (CR) and partial responses (PR), stratified by k-RAS mutational status. Potential between-study heterogeneity was accommodated by use of random-effects models for bivariable meta-analysis of sensitivity and specificity (the primary endpoints). The positive and negative likelihood ratios (+LR and -LR, respectively) of k-RAS mutations for predicting an absence of response were considered as secondary endpoints and were calculated by use of pooled estimates for sensitivity and specificity.
  
  
  RESULTS
  Of 252 retrieved manuscripts, 17 were deemed eligible for the NSCLC meta-analysis (165 of 1008 patients with mutated k-RAS). The presence of k-RAS mutations was significantly associated with an absence of response to TKIs (sensitivity=0.21 [95% CI 0.16-0.28], specificity=0.94 [0.89-0.97]; +LR=3.52; -LR=0.84). Of 68 retrieved manuscripts reporting on anti-EGFR monoclonal-antibody-based treatment of mCRC, eight studies were deemed eligible for the final analysis (306 of 817 patients with mutated k-RAS). The presence of k-RAS mutations was significantly associated with an absence of response to anti-EGFR monoclonal-antibody-based treatments (sensitivity=0.47 [0.43-0.52]; specificity=0.93 [0.83-0.97]; +LR=6.82; -LR=0.57).
  
  
  CONCLUSIONS
  This analysis provides empirical evidence that k-RAS mutations are highly specific negative predictors of response (de-novo resistance) to single-agent EGFR TKIs in advanced NSCLC; and similarly to anti-EGFR monoclonal antibodies alone or in combination with chemotherapy in patients with mCRC. The low sensitivity and relatively high -LR of k-RAS mutations for determining non-responsiveness clearly shows that additional mechanisms of resistance to EGFR inhibitors exist.
authors.affiliation: 1st Department of Medical Oncology, Metropolitan Hospital, Athens, Greece.
authors.forename: Helena
authors.initials: H
authors.lastname: Linardou
authors.forename: Issa J
authors.initials: IJ
authors.lastname: Dahabreh
authors.forename: Dimitra
authors.initials: D
authors.lastname: Kanaloupiti
authors.forename: Fotios
authors.initials: F
authors.lastname: Siannis
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Bafaloukos
authors.forename: Paris
authors.initials: P
authors.lastname: Kosmidis
authors.forename: Christos A
authors.initials: CA
authors.lastname: Papadimitriou
authors.forename: Samuel
authors.initials: S
authors.lastname: Murray
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D011905:Genes, ras; D005819:Genetic Markers; D006801:Humans; D016013:Likelihood Functions; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D005819:Genetic Markers; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors