title: Genome Wide Association Study for Predictors of Progression Free Survival in Patients on Capecitabine, Oxaliplatin, Bevacizumab and Cetuximab in First-Line Therapy of Metastatic Colorectal Cancer.
abstract: OBJECTIVE
  Despite expanding options for systemic treatment, survival for metastatic colorectal cancer (mCRC) remains limited and individual response is difficult to predict. In search of pre-treatment predictors, pharmacogenetic research has mainly used a candidate gene approach. Genome wide association (GWA) studies offer the benefit of simultaneously analyzing a large number of SNPs, in both known and still unidentified functional regions. Using a GWA approach, we searched for genetic markers affecting progression free survival (PFS) in mCRC patients treated with first-line capecitabine, oxaliplatin and bevacizumab (CAPOX-B), with or without cetuximab.
  
  
  METHODS
  755 patients were included in the CAIRO2-trial, a multicenter phase III trial, randomizing between first-line treatment with CAPOX-B versus CAPOX-B plus cetuximab. Germline DNA and complete clinical information was available from 553 patients and genome wide genotyping was performed, using Illumina's OmniExpress beadchip arrays, with 647,550 markers passing all quality checks. Another 2,202,473 markers were imputated by using HapMap2. Association with PFS was analysed using a Cox proportional hazards model.
  
  
  RESULTS
  One marker, rs885036, associated significantly with PFS (P = 2.17x10(-8)) showing opposite effects on PFS depending on treatment arm. The minor allele was associated with increased PFS in patients receiving cetuximab. A cluster of markers located on chromosome 8 associated with PFS, irrespective of treatment arm (P-values of 2.30x10(-7) to 1.04x10(-6)).
  
  
  CONCLUSIONS
  This is the first GWA study to find SNPs affecting PFS in mCRC patients treated with CAPOX-B, either with or without cetuximab. Rs885036 is a potential predictive marker for cetuximab efficacy. These markers need to be validated in independent treatment cohorts.
authors.affiliation: Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, The Netherlands; PO box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Pander
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, The Netherlands; PO box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Lieke
authors.initials: L
authors.lastname: van Huis-Tanja
authors.affiliation: Department of Biostatistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Böhringer
authors.affiliation: Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, The Netherlands; PO box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Tahar
authors.initials: T
authors.lastname: van der Straaten
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, The Netherlands; PO box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.affiliation: Department of Medical Oncology, Academic Medical Center Amsterdam, The Netherlands; PO Box 22660, 1100 DD Amsterdam, The Netherlands.
authors.forename: Cornelis
authors.initials: C
authors.lastname: Punt
authors.affiliation: Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, The Netherlands; PO box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D000068258:Bevacizumab / Q000008:administration & dosage; D000069287:Capecitabine / Q000008:administration & dosage; D000068818:Cetuximab / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D020641:Polymorphism, Single Nucleotide; D015996:Survival Rate
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000068258:Bevacizumab; D000069287:Capecitabine; D000068818:Cetuximab