title: RAS mutations and cetuximab in locally advanced rectal cancer: results of the EXPERT-C trial.
abstract: BACKGROUND
  RAS mutations predict resistance to anti-epidermal growthfactor receptor (EGFR) monoclonal antibodies in metastatic colorectal cancer. We analysed RAS mutations in 30 non-metastatic rectal cancer patients treated with or without cetuximab within the 31 EXPERT-C trial.
  
  
  METHODS
  Ninety of 149 patients with tumours available for analysis were KRAS/BRAF wild-type, and randomly assigned to capecitabine plus oxaliplatin (CAPOX) followed by chemoradiotherapy, surgery and adjuvant CAPOX or the same regimen plus cetuximab (CAPOX-C). Of these, four had a mutation of NRAS exon 3, and 84 were retrospectively analysed for additional KRAS (exon 4) and NRAS (exons 2/4) mutations by using bi-directional Sanger sequencing. The effect of cetuximab on study end-points in the RAS wild-type population was analysed.
  
  
  RESULTS
  Eleven (13%) of 84 patients initially classified as KRAS/BRAF wild-type were found to have a mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, 78/149 (52%) assessable patients were RAS wild-type (CAPOX, n=40; CAPOX-C, n=38). In this population, after a median follow-up of 63.8months, in line with the initial analysis, the addition of cetuximab was associated with numerically higher, but not statistically significant, rates of complete response (15.8% versus 7.5%, p=0.31), 5-year progression-free survival (75.5% versus 67.5%, hazard ratio (HR) 0.61, p=0.25) and 5-year overall survival (83.8% versus 70%, HR 0.54, p=0.20).
  
  
  CONCLUSIONS
  RAS mutations beyond KRAS exon 2 and 3 were identified in 17% of locally advanced rectal cancer patients. Given the small sample size, no definitive conclusions on the effect of additional RAS mutations on cetuximab treatment in this setting can be drawn and further investigation of RAS in larger studies is warranted.
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: F
authors.initials: F
authors.lastname: Sclafani
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: D
authors.initials: D
authors.lastname: Gonzalez
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom. Electronic address: david.cunningham@rmh.nhs.uk.
authors.forename: D
authors.initials: D
authors.lastname: Cunningham
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Hulkki Wilson
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: C
authors.initials: C
authors.lastname: Peckitt
authors.affiliation: Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Giralt
authors.affiliation: Akademiska Sjukhuset Uppsala, Uppsala, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Glimelius
authors.affiliation: Institute of Health Research Hospital Clinic of Valencia, University of Valencia, Valencia, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Roselló Keränen
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Wotherspoon
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: G
authors.initials: G
authors.lastname: Brown
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: D
authors.initials: D
authors.lastname: Tait
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: J
authors.initials: J
authors.lastname: Oates
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
authors.forename: I
authors.initials: I
authors.lastname: Chau
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D000069287:Capecitabine; D000068818:Cetuximab; D059248:Chemoradiotherapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069287:Capecitabine; D018631:ras Proteins; D000068818:Cetuximab; D005472:Fluorouracil
keywords: BRAF; Cetuximab; KRAS; NRAS; Neoadjuvant chemotherapy; RAS; Rectal cancer