title: Derived neutrophil to lymphocyte ratio as a prognostic factor in patients with advanced colorectal cancer according to RAS and BRAF status: a post-hoc analysis of the MRC COIN study.
abstract: The phase III Continuous or Intermittent (COIN) trial failed to show a benefit in overall survival (OS) of cetuximab in combination with chemotherapy for patients with metastatic colorectal cancer. High derived neutrophil to lymphocyte ratio (dNLR) has been shown to be prognostic in patients with metastatic colorectal cancer. The aim of this analysis is to evaluate dNLR as a predictive biomarker of the survival according to RAS and BRAF mutations status within the COIN trial. A post-hoc exploratory analysis of the COIN trial arms A and B was carried out. All patients with available white blood cell and neutrophil data were analysed. The dNLR was calculated using a formula that has previously shown predictive power in cancer patients: dNLR=ANC/(WBC-ANC). A high dNLR was defined as a value of 2.2 or more. dNLR was correlated with clinical outcomes using Kaplan-Meier and Cox regression analysis. A total of 1603 patients were assigned to the oxaliplatin-based chemotherapy (arm A, N=815) or oxaliplatin-based chemotherapy plus cetuximab (arm B, N=815) arms. There was a strong association between dNLR level and overall survival (OS) using Kaplan-Meier analysis. In all mutation groups, dNLR less than 2.2 was associated with better OS compared to dNLR of 2.2 or more. The median OS in patients with wild-type disease (dNLR<2.2 vs. dNLR≥2.2) was 22.8 versus 13.1 months [hazard ratio (HR)=1.33]; 16.9 versus 11.8 months (HR=1.36) in patients with RAS mutant tumours; and 12.6 versus 6.8 months (HR=1.67) in patients with BRAF mutant tumours. In patients with dNLR less than 2.2, the median OS was 19.2 months in arm A compared to 18.0 months in arm B (HR=1.11). Among patients with dNLR greater than or equal to 2.2, the median OS was 13.0 months in arm A compared with 13.1 months in arm B (HR=0.96). dNLR is strongly prognostic for survival in all mutation groups. dNLR does not predict for benefit from the addition of cetuximab.
authors.affiliation: aDepartment of Oncology, University College London Hospital bCancer Research UK & UCL Cancer Trials Centre cMRC Clinical Trials Unit at UCL dUCL Cancer Institute, London, UK eInstitute of Cancer & Genetics, Cardiff University School of Medicine, Velindre Hospital, Cardiff fCRUK/MRC Oxford Institute for Radiation, Oxford, UK gOncology Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Georgina
authors.initials: G
authors.lastname: Wood
authors.forename: Tal
authors.initials: T
authors.lastname: Grenader
authors.forename: Stephen
authors.initials: S
authors.lastname: Nash
authors.forename: Richard
authors.initials: R
authors.lastname: Adams
authors.forename: Richard
authors.initials: R
authors.lastname: Kaplan
authors.forename: David
authors.initials: D
authors.lastname: Fisher
authors.forename: Tim
authors.initials: T
authors.lastname: Maughan
authors.forename: John
authors.initials: J
authors.lastname: Bridgewater
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000069287:Capecitabine / Q000008:administration & dosage; D000068818:Cetuximab / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008214:Lymphocytes / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009504:Neutrophils / Q000473:pathology*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000069287:Capecitabine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins; D000068818:Cetuximab; D005472:Fluorouracil