title: Topoisomerase I copy number alterations as biomarker for irinotecan efficacy in metastatic colorectal cancer.
abstract: No biomarker exists to guide the optimal choice of chemotherapy for patients with metastatic colorectal cancer. We examined the copy numbers (CN) of topoisomerase I (TOP1) as well as the ratios of TOP1/CEN-20 and TOP1/CEN-2 as biomarkers for irinotecan efficacy in patients with metastatic colorectal cancer.
  
  
  
  From a national cohort, we identified 163 patients treated every third week with irinotecan 350 mg/m2as second-line therapy. Among these 108 were eligible for analyses and thus entered the study. Primary tumors samples were collected and tissue microarray (TMA) blocks were produced. FISH analysis was performed using two probe-mixes: TOP1/CEN-20 and TOP1/CEN-2. Only samples harboring all three signals (TOP1, CEN-20 and CEN-2) using FISH were included in the analyses.
  
  
  
  In the TOP1/CEN-20 probe-mix the median TOP1- and CEN-20 CN were 4.46 (range: 1.5-9.5) and 2.00 (range: 0.55-4.55), respectively. The median TOP1- and CEN-2 CN in the TOP1/CEN-2 probe-mix, were 4.57 (range: 1.82-10.43) and 1.98 (range: 1.22-6.14), respectively. The median TOP1/CEN-20 ratio and TOP1/CEN-2 ratio were 1.25 (range: 0.92-2.90) and 2.05 (range: 1.00-6.00), respectively. None of the markers TOP1 CN, TOP1/CEN-20-ratio or TOP1/CEN-2-ratio were associated with progression free survival, overall survival or baseline characteristics. Yet, we observed a borderline association for a stepwise increase of the TOP1 CN in relation to objective response as hazard ratio were 1.35 (95% CI 0.96-1.90; p = 0.081).
  
  
  
  We verified a borderline significant association between increasing TOP1 CN and objective response as previously reported. Applying the probes representing CEN-20 and CEN-2, in order to investigate the ratios of TOP1/CEN-20 and TOP1/CEN-2 provided no further information in search of a biomarker driven patient stratification. Other biomarkers to be paired with TOP1 CN are therefore highly warranted.
authors.affiliation: Department of Oncology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730, Herlev, Denmark. jesper.andreas.palshof@regionh.dk.
authors.forename: Jesper Andreas
authors.initials: JA
authors.lastname: Palshof
authors.affiliation: Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730, Herlev, Denmark.
authors.forename: Estrid Vilma Solyom
authors.initials: EV
authors.lastname: Høgdall
authors.affiliation: Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730, Herlev, Denmark.
authors.forename: Tim Svenstrup
authors.initials: TS
authors.lastname: Poulsen
authors.affiliation: Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730, Herlev, Denmark.
authors.forename: Dorte
authors.initials: D
authors.lastname: Linnemann
authors.affiliation: Department of Oncology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730, Herlev, Denmark.
authors.forename: Benny Vittrup
authors.initials: BV
authors.lastname: Jensen
authors.affiliation: Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Pfeiffer
authors.affiliation: Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark.
authors.forename: Line Schmidt
authors.initials: LS
authors.lastname: Tarpgaard
authors.affiliation: Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Section for Molecular Disease Biology and Sino-Danish Breast Cancer Research Centre, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
authors.affiliation: Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Section for Molecular Disease Biology and Sino-Danish Breast Cancer Research Centre, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Stenvang
authors.affiliation: Department of Oncology, Aalborg University Hospital, Hobrovej 18-22, 9100, Aalborg, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Yilmaz
authors.affiliation: Department of Oncology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730, Herlev, Denmark.
authors.forename: Dorte Lisbet
authors.initials: DL
authors.lastname: Nielsen
mesh_terms: D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004264:DNA Topoisomerases, Type I / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D018628:Gene Dosage; D006801:Humans; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D002166:Camptothecin
keywords: Biomarker; Colorectal cancer; FISH; Gene copy number; Irinotecan; Topoisomerase I