title: Gene expression signature and response to the use of leucovorin, fluorouracil and oxaliplatin in colorectal cancer patients.
abstract: OBJECTIVE
  FOLFOX (a combination of leucovorin, fluorouracil and oxaliplatin) has achieved substantial success in the treatment of colorectal cancer (CRC) patients. However, about half of all patients show resistance to this regimen and some develop adverse symptoms such as neurotoxicity. In order to select patients who would benefit most from this therapy, we aimed to build a predictor for the response to FOLFOX using microarray gene expression profiles of primary CRC samples.
  
  
  METHODS
  Forty patients who underwent surgery for primary lesions were examined. All patients had metastatic or recurrent CRC and received modified FOLFOX6. Responders and nonresponders were determined according to the best observed response at the end of the first-line treatment. Gene-expression profiles of primary CRC were determined using Human Genome GeneChip arrays U133. We identified discriminating genes whose expression differed significantly between responders and nonresponders and then carried out supervised class prediction using the k-nearest-neighbour method.
  
  
  RESULTS
  We identified 27 probes that were differentially expressed between responders and nonresponders at significant levels. Based on the expression of these genes, we constructed a FOLFOX response predictor with an overall accuracy of 92.5%. The sensitivity, specificity, positive and negative predictive values were 78.6%, 100%, 100% and 89.7%, respectively.
  
  
  CONCLUSIONS
  The present model suggests the possibility of selecting patients who would benefit from FOLFOX therapy both in the metastatic and the adjuvant setting. To our knowledge, this is the first study to establish a prediction model for the response to FOLFOX chemotherapy based on gene expression by microarray analysis.
authors.affiliation: Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan. toshwatanabe@yahoo.co.jp
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobunai
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Keiji
authors.initials: K
authors.lastname: Matsuda
authors.forename: Soichiro
authors.initials: S
authors.lastname: Ishihara
authors.forename: Keijiro
authors.initials: K
authors.lastname: Nozawa
authors.forename: Hisae
authors.initials: H
authors.lastname: Iinuma
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Konishi
authors.forename: Hisanaga
authors.initials: H
authors.lastname: Horie
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ikeuchi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Eshima
authors.forename: Tetsuichiro
authors.initials: T
authors.lastname: Muto
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D020869:Gene Expression Profiling; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil