title: A phase II study of weekly irinotecan in patients with locally advanced or metastatic HER2- negative breast cancer and increased copy numbers of the topoisomerase 1 (TOP1) gene: a study protocol.
abstract: BACKGROUND
  About 20% of patients with primary breast cancer develop metastatic disease during the course of the disease. At this point the disease is considered incurable and thus treatment is aimed at palliation and life prolongation. As many patients will have received both an anthracycline and a taxane in the adjuvant setting, treatment options for metastatic breast cancer are limited. Furthermore response rates for the most commonly used drugs range from around 30% to 12% . Thus new treatment options are needed and preferably coupled to biomarkers predictive of response. Irinotecan is a topoisomerase 1 inhibitor used for decades for the treatment of colorectal cancer. Four studies have investigated the efficacy of irinotecan monotherapy in breast cancer and all have included non-biomarker selected patients. In these studies response rates for irinotecan ranged from 5%-23% and are thus comparable to response rates obtained with drugs commonly used in the metastatic setting. If a predictive biomarker could be identified for irinotecan, response rates might be even higher.
  
  
  METHODS
  This multi-centre phase II single arm trial was designed to investigate if patients with metastatic breast cancer and increased expression of the topoisomerase 1 gene have a high likelihood of obtaining a clinical benefit from treatment with irinotecan. Trial recruitment is two-staged as 19 patients are planned to participate in the first part. If less than 7 patients have clinical benefit the trial stops, if more than 7 patients have clinical benefit a total of 40 patients will be included.
  
  
  CONCLUSIONS
  This ongoing trial is the first to prospectively test copy number of the topoisomerase I gene as a predictive biomarker of response to irinotecan.
  
  
  BACKGROUND
  EudraCT number 2012-002348-26 .
authors.affiliation: Department of Oncology, Herlev University Hospital, Copenhagen, Denmark. iben.kumler@regionh.dk.
authors.forename: Iben
authors.initials: I
authors.lastname: Kümler
authors.affiliation: Department of Pathology, Herlev University Hospital, Copenhagen, Denmark. eva.balslev@regionh.dk.
authors.forename: Eva
authors.initials: E
authors.lastname: Balslev
authors.affiliation: Department of Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark. stenvang@sund.ku.dk.
authors.forename: Jan
authors.initials: J
authors.lastname: Stenvang
authors.affiliation: Department of Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark. nbr@sund.ku.dk.
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
authors.affiliation: Department of Oncology, Herlev University Hospital, Copenhagen, Denmark. Dorte.Nielsen.01@regionh.dk.
authors.forename: Dorte
authors.initials: D
authors.lastname: Nielsen
mesh_terms: D005260:Female; D006801:Humans; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D017322:Clinical Trials, Phase II as Topic; D004264:DNA Topoisomerases, Type I / Q000235:genetics; D004334:Drug Administration Schedule; D018628:Gene Dosage; D005819:Genetic Markers / Q000235:genetics; D000077146:Irinotecan; D009362:Neoplasm Metastasis; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D016896:Treatment Outcome; D015337:Multicenter Studies as Topic
chemical_list: D002166:Camptothecin; D004264:DNA Topoisomerases, Type I; D005819:Genetic Markers; D000077146:Irinotecan; D018719:Erb-b2 Receptor Tyrosine Kinases; D059004:Topoisomerase I Inhibitors; C508053:ERBB2 protein, human; C528909:TOP1 protein, human