title: Prevalence of RAS mutations and individual variation patterns among patients with metastatic colorectal cancer: A pooled analysis of randomised controlled trials.
abstract: BACKGROUND
  The use of epidermal growth factor receptor inhibitors to treat metastatic colorectal cancer (mCRC) patients requires prior confirmation of tumour wild type (WT) RAS mutation status (exons 2/3/4 for KRAS or NRAS). This retrospective pooled analysis aims to robustly estimate RAS mutation prevalence and individual variation patterns in mCRC patients.
  
  
  METHODS
  Individual patient data from five randomised, controlled panitumumab studies (three phase III, one phase II and one phase Ib/II) were pooled for this analysis. The phase III studies included mCRC patients independent of RAS mutation status; the phase II and Ib/II studies included mCRC patients with confirmed WT KRAS exon 2 status. Four studies conducted RAS testing using Sanger sequencing; one study used a combination of next-generation sequencing and Sanger sequencing. In order to assign overall RAS status, the mutation status of all exons 2/3/4 KRAS or NRAS was required to be known.
  
  
  RESULTS
  Data from 3196 mCRC patients from 36 countries were included in the analysis. The overall unadjusted RAS mutation prevalence in mCRC patients was 55.9% (95% confidence interval (CI): [53.9-57.9%]), with the following distribution observed: KRAS exon 2 (prevalence 42.6% [40.7-44.5%]); KRAS exon 3 (3.8% [2.9-4.9%]); KRAS exon 4 (6.2% [5.0-7.6%]); NRAS exon 2 (2.9% [2.1-3.9%]); NRAS exon 3 (4.2% [3.2-5.4%]); NRAS exon 4 (0.3% [0.1-0.7%]). Differences in RAS mutation prevalence estimates were observed by study (p=0.001), gender (p=0.030), and by country (p=0.028).
  
  
  CONCLUSIONS
  This analysis provides robust estimates of overall RAS mutation prevalence and individual variation patterns in mCRC patients.
authors.affiliation: Department of Oncology, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem, Belgium. Electronic address: Marc.Peeters@uza.be.
authors.forename: M
authors.initials: M
authors.lastname: Peeters
authors.affiliation: Center for Observational Research, Amgen Ltd, 1 Uxbridge Business Park, Sanderson Road, Uxbridge UB8 1DH, UK.
authors.forename: G
authors.initials: G
authors.lastname: Kafatos
authors.affiliation: Center for Observational Research, Amgen Ltd, 1 Uxbridge Business Park, Sanderson Road, Uxbridge UB8 1DH, UK.
authors.forename: A
authors.initials: A
authors.lastname: Taylor
authors.affiliation: Center for Observational Research, Amgen Inc, One Amgen Center Drive, Thousand Oaks, CA 91329-1799, USA.
authors.forename: V M
authors.initials: VM
authors.lastname: Gastanaga
authors.affiliation: Medical Sciences, Amgen Inc, One Amgen Center Drive, Thousand Oaks, CA 91329-1799, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Oliner
authors.affiliation: Health Economics, Amgen (Europe) GmbH, Dammstrasse 23, Opus 105, Zug 6301, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Hechmati
authors.affiliation: Medical Development, Amgen (Europe) GmbH, Zählerweg 6, Opus 192, Zug 6301, Switzerland.
authors.forename: J-H
authors.initials: JH
authors.lastname: Terwey
authors.affiliation: Radboud University Nijmegen Medical Center, P.O. Box 9101, 6500 HB Nijmegen (911), The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: van Krieken
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D009362:Neoplasm Metastasis; D000077544:Panitumumab; D018579:Patient Selection; D010641:Phenotype; D057285:Precision Medicine; D011237:Predictive Value of Tests; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D008565:Membrane Proteins; D000077544:Panitumumab; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: BRAF; KRAS; NRAS; Panitumumab; RAS prevalence; mCRC