title: Functional polymorphisms in UDP-glucuronosyl transferases and recurrence in tamoxifen-treated breast cancer survivors.
abstract: BACKGROUND
  Tamoxifen is oxidized by cytochrome-P450 enzymes (e.g., CYP2D6) to two active metabolites, which are eliminated via glucuronidation by UDP-glucuronosyl transferases (UGT). We measured the association between functional polymorphisms in key UGTs (UGT2B15*2, UGT2B7*2, and UGT1A8*3) and the recurrence rate among breast cancer survivors.
  
  
  METHODS
  We used the Danish Breast Cancer Cooperative Group registry to identify 541 cases of recurrent breast cancer among women with estrogen receptor-positive tumors treated with tamoxifen for at least 1 year (ER(+)/TAM(+)), and 300 cases of recurrent breast cancer among women with estrogen receptor-negative tumors who were not treated with tamoxifen (ER(-)/TAM(-)). We matched one control to each case on ER status, menopausal status, stage, calendar period, and county. UGT polymorphisms were genotyped from archived primary tumors. We estimated the recurrence OR for the UGT polymorphisms by using logistic regression models, with and without stratification on CYP2D6*4 genotype.
  
  
  RESULTS
  No UGT polymorphism was associated with breast cancer recurrence in either the ER(+)/TAM(+) or ER(-)/TAM(-) groups [in the ER(+)/TAM(+) group, compared with two normal alleles: adjusted OR for two UGT2B15*2 variant alleles = 1.0 (95% CI, 0.70-1.5); adjusted OR for two UGT2B7*2 variant alleles = 0.96 (95% CI, 0.65-1.4); adjusted OR for one or two UGT1A8*3 variant alleles = 0.95 (0.49-1.9)]. Associations were similar within strata of CYP2D6*4 genotype.
  
  
  CONCLUSIONS
  Functional polymorphisms in key tamoxifen-metabolizing enzymes were not associated with breast cancer recurrence risk.
  
  
  CONCLUSIONS
  Our results do not support the genotyping of key metabolic enzyme polymorphisms to predict response to tamoxifen therapy.
authors.affiliation: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. nhtpa@channing.harvard.edu
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Ahern
authors.forename: Mariann
authors.initials: M
authors.lastname: Christensen
authors.forename: Deirdre P
authors.initials: DP
authors.lastname: Cronin-Fenton
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lunetta
authors.forename: Håvard
authors.initials: H
authors.lastname: Søiland
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gjerde
authors.forename: Jens Peter
authors.initials: JP
authors.lastname: Garne
authors.forename: Carol L
authors.initials: CL
authors.lastname: Rosenberg
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Silliman
authors.forename: Henrik Toft
authors.initials: HT
authors.lastname: Sørensen
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Lash
authors.forename: Stephen
authors.initials: S
authors.lastname: Hamilton-Dutoit
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000235:genetics*; D011110:Polymorphism, Genetic; D013629:Tamoxifen / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D014453:Glucuronosyltransferase