title: A phase II study of Epirubicin in oxaliplatin-resistant patients with metastatic colorectal cancer and TOP2A gene amplification.
abstract: The overall purpose of this study is to provide proof of concept for introducing the anthracycline epirubicin as an effective, biomarker-guided treatment for metastatic colorectal cancer (mCRC) patients who are refractory to treatment with oxaliplatin-based chemotherapy and have TOP2A gene amplification in their tumor cells.
  
  
  BACKGROUND
  Epirubicin is an anthracycline that targets DNA topoisomerase 2-α enzyme encoded by the TOP2A gene. It is used for treatment of several malignancies, but currently not in CRC. TOP2A gene amplifications predict improved efficacy of epirubicin in patients with breast cancer and thus could be an alternative option for patients with CRC and amplified TOP2A gene. We have previously analysed the frequency of TOP2A gene aberrations in CRC and found that 46.6% of these tumors had TOP2A copy gain and 2.0% had loss of TOP2A when compared to adjacent normal tissue. The TOP2A gene is located on chromosome 17 and when the TOP2A/CEN-17 ratio was applied to identify tumors with gene loss or amplifications, 10.5% had a ratio ≥ 1.5 consistent with gene amplification and 2.6% had a ratio ≤ 0.8 suggesting gene deletions. Based on these observations and the knowledge gained from treatment of breast cancer patients, we have initiated a prospective clinical, phase II protocol using epirubicin (90 mg/m2 iv q 3 weeks) in mCRC patients, who are refractory to treatment with oxaliplatin.
  
  
  METHODS
  The study is an open label, single arm, phase II study, investigating the efficacy of epirubicin in patients with oxaliplatin refractory mCRC and with a cancer cell TOP2A/CEN-17 ratio ≥ 1.5. TOP2A gene amplification measured by fluorescence in situ hybridization. A total of 25 evaluable patients (15 + 10 in two steps) will be included (Simon's two-stage minimax design). Every nine weeks, response is measured by computed tomography imaging and evaluated according to RECIST 1.1. The primary end-point of the study is progression-free survival.
  
  
  BACKGROUND
  Eudract no. 2013-001648-79.
authors: Department of Oncology, Odense University Hospital, Odense, Denmark. line.tarpgaard@rsyd.dk.
authors: Line S
authors: LS
authors: Tarpgaard
authors: Department of Oncology, Odense University Hospital, Odense, Denmark. camilla.qvortrup@rsyd.dk.
authors: Camilla
authors: C
authors: Qvortrup
authors: Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark. Sune.Boris.Nygaard@regionh.dk.|Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Sune.Boris.Nygaard@regionh.dk.
authors: Sune B
authors: SB
authors: Nygård
authors: Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark. siln@sund.ku.dk.
authors: Signe L
authors: SL
authors: Nielsen
authors: Department of Oncology, Odense University Hospital, Odense, Denmark. diana.riise.andersen@rsyd.dk.
authors: Diana R
authors: DR
authors: Andersen
authors: Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark. tfm434@alumni.ku.dk.
authors: Niels Frank
authors: NF
authors: Jensen
authors: Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark. stenvang@sund.ku.dk.
authors: Jan
authors: J
authors: Stenvang
authors: Department of Pathology, Odense University Hospital, Odense, Denmark. sonke.detlefsen@rsyd.dk.
authors: Sönke
authors: S
authors: Detlefsen
authors: Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark. nbr@sund.ku.dk.
authors: Nils
authors: N
authors: Brünner
authors: Department of Oncology, Odense University Hospital, Odense, Denmark. per.pfeiffer@rsyd.dk.
authors: Per
authors: P
authors: Pfeiffer
mesh_terms: D000328:Adult; D000951:Antigens, Neoplasm / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D018572:Disease-Free Survival; D015251:Epirubicin / Q000008:administration & dosage*; D005260:Female; D005784:Gene Amplification / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D000075223:Poly-ADP-Ribose Binding Proteins; D011379:Prognosis
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D009944:Organoplatinum Compounds; D000075223:Poly-ADP-Ribose Binding Proteins; D000077150:Oxaliplatin; D015251:Epirubicin; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human