title: A systematic review and meta-analysis of KRAS status as the determinant of response to anti-EGFR antibodies and the impact of partner chemotherapy in metastatic colorectal cancer.
abstract: BACKGROUND
  In the setting of metastatic colorectal cancer (CRC), anti-EGFR antibodies are not currently recommended for individuals with KRAS mutant tumours. This is based on subgroup analyses of individual clinical trials rather than a formal synthesis of evidence for KRAS status as a predictive biomarker, while newer trials report no benefit for anti-EGFR antibodies irrespective of KRAS status. This study systematically reviewed the evidence for KRAS mutation status as a treatment effect modifier of response to anti-EGFR antibodies and the influence of partner chemotherapy.
  
  
  METHODS
  Medline (1966-2010), EMBASE and American and European oncology meeting abstracts were searched for randomised controlled trials reporting the influence of KRAS status on effectiveness of anti-EGFR antibodies in metastatic CRC. The treatment efficacy was summarised by KRAS status using hazard ratios (HR) for progression-free survival (PFS) and risk differences (RD) for objective response. For each study, a measure of effect modification was calculated, and aggregated using random effects meta-analysis to assess the interaction between KRAS and treatment effect.
  
  
  RESULTS
  Eleven studies (8924 patients) were selected from 198 reports. Two studies assessed anti-EGFR antibodies as monotherapy and nine their use with chemotherapy. KRAS status was reported in 7555 cases. In subgroup analysis, the progression HR for KRAS wild patients assigned to anti-EGFR antibodies was 0.80 (4436 patients 95%CI: 0.64, 0.99) and for mutant cases 1.11 (3119 patients, 95%CI: 0.97, 1.27). A significant treatment effect interaction between KRAS status and addition of anti-EGFR antibodies to standard treatment was found for PFS (ratio of HRs 0.71, 95%CI: 0.57, 0.90 p=0.005) and response rate difference (difference in RDs 15%, 95%CI: 8, 22%, p<0.001). There was no evidence that the extent of effect modification differed between chemotherapeutic partners for both PFS (p=0.3) and response rate (p=0.6).
  
  
  CONCLUSIONS
  KRAS mutation status is a treatment effect modifier for anti-EGFR antibodies in metastatic CRC. Further evidence is needed to determine whether this is true for all chemotherapy partners and all clinical circumstances.
authors.affiliation: Lowy Cancer Centre and Prince of Wales Clinical School, Faculty of Medicine, University of NSW, NSW 2052, Australia.
authors.forename: Barbara-Ann
authors.initials: BA
authors.lastname: Adelstein
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Dobbins
authors.forename: Carole A
authors.initials: CA
authors.lastname: Harris
authors.forename: Ian C
authors.initials: IC
authors.lastname: Marschner
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Ward
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D004252:DNA Mutational Analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000276:immunology*; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D009154:Mutation; D009362:Neoplasm Metastasis; D016032:Randomized Controlled Trials as Topic; D012306:Risk; D016896:Treatment Outcome; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D018631:ras Proteins