title: DNA Topoisomerase I Gene Copy Number and mRNA Expression Assessed as Predictive Biomarkers for Adjuvant Irinotecan in Stage II/III Colon Cancer.
abstract: OBJECTIVE
  Prospective-retrospective assessment of the TOP1 gene copy number and TOP1 mRNA expression as predictive biomarkers for adjuvant irinotecan in stage II/III colon cancer.
  
  
  METHODS
  Formalin-fixed, paraffin-embedded tissue microarrays were obtained from an adjuvant colon cancer trial (PETACC3) where patients were randomized to 5-fluorouracil/folinic acid with or without additional irinotecan. TOP1 copy number status was analyzed by fluorescence in situ hybridization (FISH) using a TOP1/CEN20 dual-probe combination. TOP1 mRNA data were available from previous analyses.
  
  
  RESULTS
  TOP1 FISH and follow-up data were obtained from 534 patients. TOP1 gain was identified in 27% using a single-probe enumeration strategy (≥4 TOP1 signals per cell) and in 31% when defined by a TOP1/CEN20 ratio ≥ 1.5. The effect of additional irinotecan was not dependent on TOP1 FISH status.TOP1 mRNA data were available from 580 patients with stage III disease. Benefit of irinotecan was restricted to patients characterized by TOP1 mRNA expression ≥ third quartile (RFS: HRadjusted, 0.59;P= 0.09; OS: HRadjusted, 0.44;P= 0.03). The treatment by TOP1 mRNA interaction was not statistically significant, but in exploratory multivariable fractional polynomial interaction analysis, increasing TOP1 mRNA values appeared to be associated with increasing benefit of irinotecan.
  
  
  CONCLUSIONS
  In contrast to the TOP1 copy number, a trend was demonstrated for a predictive property of TOP1 mRNA expression. On the basis of TOP1 mRNA, it might be possible to identify a subgroup of patients where an irinotecan doublet is a clinically relevant option in the adjuvant setting of colon cancer.
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark.
authors.forename: Sune Boris
authors.initials: SB
authors.lastname: Nygård
authors.affiliation: Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Ben
authors.initials: B
authors.lastname: Vainer
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark.
authors.forename: Signe Lykke
authors.initials: SL
authors.lastname: Nielsen
authors.affiliation: University of Lausanne, University Institute of Pathology, Lausanne, Switzerland.
authors.forename: Fred
authors.initials: F
authors.lastname: Bosman
authors.affiliation: Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.affiliation: Oncosurgery Unit, University Hospital of Geneva, Geneva, Switzerland.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Roth
authors.affiliation: SIB Swiss Institute of Bioinformatics, Bioinformatics Core Facility, Lausanne, Switzerland. University of Lausanne, Ludwig Center for Cancer Research, Lausanne, Switzerland. Oncology Department, University of Lausanne, Lausanne, Switzerland.
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark. nbr@sund.ku.dk.
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
authors.affiliation: Masaryk University, Institute of Biostatistics and Analyses, Brno, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Budinska
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D015415:Biomarkers; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D004264:DNA Topoisomerases, Type I / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D008297:Male; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics*; D059004:Topoisomerase I Inhibitors / Q000627:therapeutic use
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D015415:Biomarkers; D012333:RNA, Messenger; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin