title: A Uridine Glucuronosyltransferase 2B7 Polymorphism Predicts Epirubicin Clearance and Outcomes in Early-Stage Breast Cancer.
abstract: BACKGROUND
  Epirubicin is metabolized by uridine glucuronosyltransferase 2B7 (UGT2B7), an enzyme rich in single nucleotide polymorphisms (SNPs). We studied whether the -161 C > T germline SNP in UGT2B7 was related to epirubicin metabolism and whether differences exist in the toxicity and efficacy of epirubicin-based chemotherapy among patients who were TT homozygotes, CT heterozygotes, and CC homozygotes.
  
  
  METHODS
  A total of 132 women with non-metastatic breast cancer receiving FEC (5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), cyclophosphamide 500 mg/m(2)) were prospectively enrolled. Toxicity was assessed in cycle 1 using the National Cancer Institute Common Toxicity Criteria, version 2.0.
  
  
  RESULTS
  The sequence at -161 was studied in 132 subjects; 37 were TT homozygotes, 63 were CT heterozygotes, 26 were CC homozygotes, and 6 could not be genotyped. The CC genotype patients had decreased epirubicin clearance (median, 103.3 L/hr) compared with the CT/TT genotype patients (median, 134.0 L/hr; P = .002). The CC homozygous patients had an increased risk of grade 3 to 4 leukopenia compared with the TT homozygotes or heterozygotes (P = .038 and P = .032, respectively). TT homozygotes or heterozygotes had an increased risk of early recurrence (P = .039; χ(2) test).
  
  
  CONCLUSIONS
  The results of the present prospective pharmacogenetic study suggest that the UGT2B7 -161 C > T SNP correlate with drug metabolism, toxicity, and efficacy in patients receiving epirubicin chemotherapy. Further studies of this UGT2B7 SNP as a predictor of epirubicin toxicity and efficacy are warranted.
authors.affiliation: Division of Medical Oncology, Cross Cancer Institute, Edmonton, AB, Canada; Division of Experimental Oncology, Cross Cancer Institute, Edmonton, AB, Canada; Department of Oncology, University of Alberta, Edmonton, AB, Canada. Electronic address: michael.sawyer@albertahealthservices.ca.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sawyer
authors.affiliation: Division of Medical Oncology, Cross Cancer Institute, Edmonton, AB, Canada.
authors.forename: Edith
authors.initials: E
authors.lastname: Pituskin
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Sambasivarao
authors.initials: S
authors.lastname: Damaraju
authors.affiliation: Department of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Bies
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Larissa J
authors.initials: LJ
authors.lastname: Vos
authors.affiliation: Division of Medical Oncology, Cross Cancer Institute, Edmonton, AB, Canada; Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Carla M M
authors.initials: CM
authors.lastname: Prado
authors.affiliation: Division of Medical Oncology, Cross Cancer Institute, Edmonton, AB, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Kuzma
authors.affiliation: Division of Medical Oncology, Cross Cancer Institute, Edmonton, AB, Canada; Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Scarfe
authors.affiliation: Division of Medical Oncology, The Ottawa Hospital Cancer Centre and University of Ottawa, Ottawa, ON, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Clemons
authors.affiliation: Division of Medical Oncology, Cross Cancer Institute, Edmonton, AB, Canada; Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Katia
authors.initials: K
authors.lastname: Tonkin
authors.affiliation: Division of Medical Oncology, Cross Cancer Institute, Edmonton, AB, Canada; Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Heather-Jane
authors.initials: HJ
authors.lastname: Au
authors.affiliation: Division of Medical Oncology, Cross Cancer Institute, Edmonton, AB, Canada; Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Sheryl
authors.initials: S
authors.lastname: Koski
authors.affiliation: Division of Medical Oncology, Cross Cancer Institute, Edmonton, AB, Canada; Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Anil A
authors.initials: AA
authors.lastname: Joy
authors.affiliation: Division of Medical Oncology, Cross Cancer Institute, Edmonton, AB, Canada; Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Smylie
authors.affiliation: Division of Medical Oncology, Cross Cancer Institute, Edmonton, AB, Canada; Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: King
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Diana
authors.initials: D
authors.lastname: Carandang
authors.affiliation: Division of Experimental Oncology, Cross Cancer Institute, Edmonton, AB, Canada; Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Vijaya L
authors.initials: VL
authors.lastname: Damaraju
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Hanson
authors.affiliation: Division of Experimental Oncology, Cross Cancer Institute, Edmonton, AB, Canada; Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Carol E
authors.initials: CE
authors.lastname: Cass
authors.affiliation: Division of Medical Oncology, Cross Cancer Institute, Edmonton, AB, Canada; Division of Experimental Oncology, Cross Cancer Institute, Edmonton, AB, Canada; Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Mackey
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D003520:Cyclophosphamide; D015251:Epirubicin; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C491474:UGT2B7 protein, human; C508053:ERBB2 protein, human
keywords: Drug clearance; SNP; Single nucleotide polymorphisms; Toxicity; UGT2B7