title: Prognostic role of the LCS6 KRAS variant in locally advanced rectal cancer: results of the EXPERT-C trial.
abstract: BACKGROUND
  Lethal-7 (let-7) is a tumour suppressor miRNA which acts by down-regulating several oncogenes including KRAS. A single-nucleotide polymorphism (rs61764370, T > G base substitution) in the let-7 complementary site 6 (LCS-6) of KRAS mRNA has been shown to predict prognosis in early-stage colorectal cancer (CRC) and benefit from anti-epidermal growth factor receptor monoclonal antibodies in metastatic CRC.
  
  
  METHODS
  We analysed rs61764370 in EXPERT-C, a randomised phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX plus or minus cetuximab in locally advanced rectal cancer. DNA was isolated from formalin-fixed paraffin-embedded tumour tissue and genotyped using a PCR-based commercially available assay. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms.
  
  
  RESULTS
  A total of 155/164 (94.5%) patients were successfully analysed, of whom 123 (79.4%) and 32 (20.6%) had the LCS-6 TT and LCS-6 TG genotype, respectively. Carriers of the G allele were found to have a statistically significantly higher rate of complete response (CR) after neoadjuvant therapy (28.1% versus 10.6%; P = 0.020) and a trend for better 5-year progression-free survival (PFS) [77.4% versus 64.5%: hazard ratio (HR) 0.56; P = 0.152] and overall survival (OS) rates (80.3% versus 71.9%: HR 0.59; P = 0.234). Both CR and survival outcomes were independent of the use of cetuximab. The negative prognostic effect associated with KRAS mutation appeared to be stronger in patients with the LCS-6 TT genotype (HR PFS 1.70, P = 0.078; HR OS 1.79, P = 0.082) compared with those with the LCS-6 TG genotype (HR PFS 1.33, P = 0.713; HR OS 1.01, P = 0.995).
  
  
  CONCLUSIONS
  This analysis suggests that rs61764370 may be a biomarker of response to neoadjuvant treatment and an indicator of favourable outcome in locally advanced rectal cancer possibly by mitigating the poor prognosis of KRAS mutation. In this setting, however, this polymorphism does not appear to predict cetuximab benefit.
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey.
authors.forename: F
authors.initials: F
authors.lastname: Sclafani
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey.
authors.forename: I
authors.initials: I
authors.lastname: Chau
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey.
authors.forename: D
authors.initials: D
authors.lastname: Cunningham
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey.
authors.forename: C
authors.initials: C
authors.lastname: Peckitt
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton.
authors.forename: A
authors.initials: A
authors.lastname: Lampis
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton.
authors.forename: J C
authors.initials: JC
authors.lastname: Hahne
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey; Division of Cancer Therapeutics, The Institute of Cancer Research, London and Sutton, UK.
authors.forename: C
authors.initials: C
authors.lastname: Braconi
authors.affiliation: Department of Medical Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Department of Immunology, Genetics and Pathology, University of Uppsala, Uppsala, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Glimelius
authors.affiliation: Department of Hematology and Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Cervantes
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey.
authors.forename: R
authors.initials: R
authors.lastname: Begum
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey.
authors.forename: D
authors.initials: D
authors.lastname: Gonzalez De Castro
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey.
authors.forename: S
authors.initials: S
authors.lastname: Hulkki Wilson
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey.
authors.forename: Z
authors.initials: Z
authors.lastname: Eltahir
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey.
authors.forename: A
authors.initials: A
authors.lastname: Wotherspoon
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey.
authors.forename: D
authors.initials: D
authors.lastname: Tait
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey.
authors.forename: G
authors.initials: G
authors.lastname: Brown
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey.
authors.forename: J
authors.initials: J
authors.lastname: Oates
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey; Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton. Electronic address: nicola.valeri@icr.ac.uk.
authors.forename: N
authors.initials: N
authors.lastname: Valeri
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D000069287:Capecitabine / Q000627:therapeutic use; D000068818:Cetuximab / Q000627:therapeutic use; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012004:Rectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000628:therapy*
chemical_list: D014408:Biomarkers, Tumor; D005819:Genetic Markers; C117307:KRAS protein, human; D035683:MicroRNAs; D009944:Organoplatinum Compounds; C487931:mirnlet7 microRNA, human; D000077150:Oxaliplatin; D000069287:Capecitabine; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab
keywords: KRAS; LCS-6 KRAS variant; cetuximab; let-7; rectal cancer; single-nucleotide polymorphism