title: CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients.
abstract: BACKGROUND
  Adjuvant tamoxifen therapy substantially decreases the risk of recurrence and mortality in women with hormone (estrogen and/or progesterone) receptor-positive breast cancer. Previous studies have suggested that metabolic conversion of tamoxifen to endoxifen by cytochrome P450 2D6 (CYP2D6) is required for patient benefit from tamoxifen therapy.
  
  
  METHODS
  Tumor specimens from a subset of postmenopausal patients with hormone receptor-positive early-stage (stages I, II, and IIIA) breast cancer, who were enrolled in the randomized double-blind Arimidex, Tamoxifen, Alone or in Combination (ATAC) clinical trial, were genotyped for variants in CYP2D6 (N = 1203 patients: anastrozole [trade name: Arimidex] group, n = 615 patients; tamoxifen group, n = 588 patients) and UDP-glucuronosyltransferase-2B7 (UGT2B7), whose gene product inactivates endoxifen (N = 1209 patients; anastrozole group, n = 606 patients; tamoxifen group, n = 603 patients). Genotyping was performed using polymerase chain reaction-based TaqMan assays. Based on the genotypes for CYP2D6, patients were classified as poor metabolizer (PM), intermediate metabolizer (IM), or extensive metabolizer (EM) phenotypes. We evaluated the association of CYP2D6 and UGT2B7 genotype with distant recurrence (primary endpoint) and any recurrence (secondary endpoint) by estimating the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) using Cox proportional hazards models. All statistical tests were two-sided.
  
  
  RESULTS
  After a median follow-up of 10 years, no statistically significant associations were observed between CYP2D6 genotype and recurrence in tamoxifen-treated patients (PM vs EM: HR for distant recurrence = 1.25, 95% CI = 0.55 to 3.15, P = .64; HR for any recurrence = 0.99, 95% CI = 0.48 to 2.08, P = .99). A near-null association was observed between UGT2B7 genotype and recurrence in tamoxifen-treated patients. No associations were observed between CYP2D6 and UGT2B7 genotypes and recurrence in anastrozole-treated patients.
  
  
  CONCLUSIONS
  The results do not support the hypothesis that CYP2D6 genotype predicts clinical benefit of adjuvant tamoxifen treatment among postmenopausal breast cancer patients.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA. jimmyrae@umich.edu
authors.forename: James M
authors.initials: JM
authors.lastname: Rae
authors.forename: Suzy
authors.initials: S
authors.lastname: Drury
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
authors.forename: Vered
authors.initials: V
authors.lastname: Stearns
authors.forename: Jacklyn N
authors.initials: JN
authors.lastname: Thibert
authors.forename: Ben P
authors.initials: BP
authors.lastname: Haynes
authors.forename: Janine
authors.initials: J
authors.lastname: Salter
authors.forename: Ivana
authors.initials: I
authors.lastname: Sestak
authors.forename: Jack
authors.initials: J
authors.lastname: Cuzick
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
mesh_terms: D000368:Aged; D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics / Q000517:prevention & control*; D017024:Chemotherapy, Adjuvant; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D005838:Genotype; D018095:Germ-Line Mutation; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics / Q000517:prevention & control*; D009367:Neoplasm Staging; D009570:Nitriles / Q000627:therapeutic use; D016017:Odds Ratio; D017698:Postmenopause; D016032:Randomized Controlled Trials as Topic; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D018570:Risk Assessment; D012307:Risk Factors; D013629:Tamoxifen / Q000627:therapeutic use*; D014230:Triazoles / Q000627:therapeutic use; D006113:United Kingdom
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D009570:Nitriles; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014230:Triazoles; D013629:Tamoxifen; D000077384:Anastrozole; D019389:Cytochrome P-450 CYP2D6; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase