title: Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group.
abstract: To explore the impact of KRAS, NRAS and BRAF mutations as well as KRAS mutation variants in patients with metastatic colorectal cancer (mCRC) receiving first-line therapy.
  
  
  
  A total of 1239 patients from five randomized trials (FIRE-1, FIRE-3, AIOKRK0207, AIOKRK0604, RO91) were included into the analysis. Outcome was evaluated by the Kaplan-Meier method, log-rank tests and Cox models.
  
  
  
  In 664 tumors, no mutation was detected, 462 tumors were diagnosed with KRAS-, 39 patients with NRAS- and 74 patients with BRAF-mutation. Mutations in KRAS were associated with inferior progression-free survival (PFS) and overall survival (OS) [multivariate hazard ratio (HR) for PFS: 1.20 (1.02-1.42), P = 0.03; multivariate HR for OS: 1.41 (1.17-1.70), P < 0.001]. BRAF mutation was also associated with inferior PFS [multivariate HR: 2.19 (1.59-3.02), P < 0.001] and OS [multivariate HR: 2.99 (2.10-4.25), P < 0.001]. Among specific KRAS mutation variants, the KRAS G12C-variant (n = 28) correlated with inferior OS compared with unmutated tumors [multivariate HR 2.26 (1.25-4.1), P = 0.001]. A similar trend for OS was seen in the KRAS G13D-variant [n = 71, multivariate HR 1.46 (0.96-2.22), P = 0.10]. More frequent KRAS exon 2 variants like G12D [n = 152, multivariate HR 1.17 (0.86-1.6), P = 0.81] and G12V [n = 92, multivariate HR 1.27 (0.87-1.86), P = 0.57] did not have significant impact on OS.
  
  
  
  Mutations in KRAS and BRAF were associated with inferior PFS and OS of mCRC patients compared with patients with non-mutated tumors. KRAS exon 2 mutation variants were associated with heterogeneous outcome compared with unmutated tumors with KRAS G12C and G13D (trend) being associated with rather poor survival.
authors.affiliation: Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg dominik.modest@med.uni-muenchen.de.
authors.forename: D P
authors.initials: DP
authors.lastname: Modest
authors.affiliation: Institute of Medical Informatics, Biometry and Epidemiology, University of Munich, Munich.
authors.forename: I
authors.initials: I
authors.lastname: Ricard
authors.affiliation: Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg.
authors.forename: V
authors.initials: V
authors.lastname: Heinemann
authors.affiliation: HOPE-Practice for Oncology, Hamburg.
authors.forename: S
authors.initials: S
authors.lastname: Hegewisch-Becker
authors.affiliation: Medizinische Klinik, Knappschaftskrankenhaus Ruhr-Universität Bochum, Bochum.
authors.forename: W
authors.initials: W
authors.lastname: Schmiegel
authors.affiliation: Klinik für Innere Medizin, Klinikum Bremen-Ost, Bremen.
authors.forename: R
authors.initials: R
authors.lastname: Porschen
authors.affiliation: Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg.
authors.forename: S
authors.initials: S
authors.lastname: Stintzing
authors.affiliation: Kliniken Maria Hilf GmbH, Department of Hematology, Oncology and Gastroenterology, Mönchengladbach, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Graeven
authors.affiliation: Instituto CUF de Oncologia, Lisboa, Portugal.
authors.forename: D
authors.initials: D
authors.lastname: Arnold
authors.affiliation: Gesundheitszentrum St Marien, Amberg.
authors.forename: L F
authors.initials: LF
authors.lastname: von Weikersthal
authors.affiliation: Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich.
authors.forename: C
authors.initials: C
authors.lastname: Giessen-Jung
authors.affiliation: Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich Institute of Pathology University of Munich, Munich.
authors.forename: A
authors.initials: A
authors.lastname: Stahler
authors.affiliation: Department of Hematology/Oncology, University Hospital Halle, Halle (Saale).
authors.forename: H J
authors.initials: HJ
authors.lastname: Schmoll
authors.affiliation: German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg Institute of Pathology University of Munich, Munich.
authors.forename: A
authors.initials: A
authors.lastname: Jung
authors.affiliation: German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg Institute of Pathology University of Munich, Munich.
authors.forename: T
authors.initials: T
authors.lastname: Kirchner
authors.affiliation: Institute for Pathology, Ruhr-University Bochum, Bochum.
authors.forename: A
authors.initials: A
authors.lastname: Tannapfel
authors.affiliation: Department of Hematology, Oncology and Palliative Care, St Josef-Hospital, Ruhr University Bochum, Bochum, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Reinacher-Schick
mesh_terms: D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D009362:Neoplasm Metastasis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
chemical_list: C117307:KRAS protein, human; D008565:Membrane Proteins; 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; RAS; colorectal cancer; mutation; prognostic factor