title: ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy.
abstract: OBJECTIVE
  To test the hypotheses of whether the relative mRNA expression of the thymidylate synthase (TS) gene and the excision cross-complementing (ERCC1) gene are associated with response to and survival of fluorouracil (5-FU)/oxaliplatin chemotherapy in metastatic colorectal cancer.
  
  
  METHODS
  Patients had progressive stage IV disease after unsuccessful 5-FU and irinotecan chemotherapy. All patients were evaluated for eligibility for a compassionate 5-FU/oxaliplatin protocol. cDNA was derived from paraffin-embedded tumor specimens to determine TS and ERCC1 mRNA expression relative to the internal reference gene beta-actin using fluorescence-based, real-time reverse transcriptase polymerase chain reaction.
  
  
  RESULTS
  The median TS gene expression level from 50 metastasized tumors was 3.4 x 10(-3) (minimum expression, 0.18 x 10(-3);maximum expression, 11.5 x 10(-3)), and the median ERCC1 gene expression level was 2.53 x 10(-3) (minimum, 0.0; maximum, 14.61 x 10(-3)). The gene expression cutoff values for chemotherapy nonresponse were 7.5 x 10(-3) for TS and 4.9 x 10(-3) for ERCC1. The median survival time for patients with TS <or= 7.5 x 10(-3) (43 of 50 patients) was 10.2 months, compared with 1.5 months for patients with TS greater than 7.5 x 10(-3) (P < .001). Patients with ERCC1 expression <or= 4.9 x 10(-3) (40 of 50 patients) had a median survival time of 10.2 months, compared with 1.9 months for patients with ERCC1 expression greater than 4.9 x 10(-3) (P < .001). A TS of 7.5 x 10(-3) segregated significantly into response, stable disease, and progression (P = .02), whereas the association between ERCC1 and response did not reach statistical significance (P = .29).
  
  
  CONCLUSIONS
  These data suggest that intratumoral ERCC1 mRNA and TS mRNA expression levels are independent predictive markers of survival for 5-FU and oxaliplatin combination chemotherapy in 5-FU-resistant metastatic colorectal cancer. Precise definition of the best TS cut point will require further analysis in a large, prospective study.
authors.affiliation: University of Southern California/Norris Comprehensive Cancer Center and Response Genetics Inc, Los Angeles, CA 90033, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Shirota
authors.forename: J
authors.initials: J
authors.lastname: Stoehlmacher
authors.forename: J
authors.initials: J
authors.lastname: Brabender
authors.forename: Y P
authors.initials: YP
authors.lastname: Xiong
authors.forename: H
authors.initials: H
authors.lastname: Uetake
authors.forename: K D
authors.initials: KD
authors.lastname: Danenberg
authors.forename: S
authors.initials: S
authors.lastname: Groshen
authors.forename: D D
authors.initials: DD
authors.lastname: Tsao-Wei
authors.forename: P V
authors.initials: PV
authors.lastname: Danenberg
authors.forename: H J
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002140:California; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D017931:DNA Primers; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011379:Prognosis; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D013940:Thymidylate Synthase / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D009944:Organoplatinum Compounds; D011506:Proteins; D012333:RNA, Messenger; D000077150:Oxaliplatin; D013940:Thymidylate Synthase; C071447:ERCC1 protein, human; D004720:Endonucleases; D005472:Fluorouracil