title: CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the breast international group 1-98 trial.
abstract: BACKGROUND
  Adjuvant tamoxifen therapy is effective for postmenopausal women with endocrine-responsive breast cancer. Cytochrome P450 2D6 (CYP2D6) enzyme metabolizes tamoxifen to clinically active metabolites, and CYP2D6 polymorphisms may adversely affect tamoxifen efficacy. In this study, we investigated the clinical relevance of CYP2D6 polymorphisms.
  
  
  METHODS
  We obtained tumor tissues and isolated DNA from 4861 of 8010 postmenopausal women with hormone receptor-positive breast cancer who enrolled in the randomized, phase III double-blind Breast International Group (BIG) 1-98 trial between March 1998 and May 2003 and received tamoxifen and/or letrozole treatment. Extracted DNA was used for genotyping nine CYP2D6 single-nucleotide polymorphisms using polymerase chain reaction-based methods. Genotype combinations were used to categorize CYP2D6 metabolism phenotypes as poor, intermediate, and extensive metabolizers (PM, IM, and EM, respectively; n = 4393 patients). Associations of CYP2D6 metabolism phenotypes with breast cancer-free interval (referred to as recurrence) and treatment-induced hot flushes according to randomized endocrine treatment and previous chemotherapy were assessed. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.
  
  
  RESULTS
  No association between CYP2D6 metabolism phenotypes and breast cancer-free interval was observed among patients who received tamoxifen monotherapy without previous chemotherapy (P = .35). PM or IM phenotype had a non-statistically significantly reduced risk of breast cancer recurrence compared with EM phenotype (PM or IM vs EM, HR of recurrence = 0.86, 95% CI = 0.60 to 1.24). CYP2D6 metabolism phenotype was associated with tamoxifen-induced hot flushes (P = .020). Both PM and IM phenotypes had an increased risk of tamoxifen-induced hot flushes compared with EM phenotype (PM vs EM, HR of hot flushes = 1.24, 95% CI = 0.96 to 1.59; IM vs EM, HR of hot flushes = 1.23, 95% CI = 1.05 to 1.43).
  
  
  CONCLUSIONS
  CYP2D6 phenotypes of reduced enzyme activity were not associated with worse disease control but were associated with increased hot flushes, contrary to the hypothesis. The results of this study do not support using the presence or absence of hot flushes or the pharmacogenetic testing of CYP2D6 to determine whether to treat postmenopausal breast cancer patients with tamoxifen.
authors.affiliation: IBCSG Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. mregan@jimmy.harvard.edu
authors.forename: Meredith M
authors.initials: MM
authors.lastname: Regan
authors.forename: Brian
authors.initials: B
authors.lastname: Leyland-Jones
authors.forename: Mark
authors.initials: M
authors.lastname: Bouzyk
authors.forename: Olivia
authors.initials: O
authors.lastname: Pagani
authors.forename: Weining
authors.initials: W
authors.lastname: Tang
authors.forename: Roswitha
authors.initials: R
authors.lastname: Kammler
authors.forename: Patrizia
authors.initials: P
authors.lastname: Dell'orto
authors.forename: Maria Olivia
authors.initials: MO
authors.lastname: Biasi
authors.forename: Beat
authors.initials: B
authors.lastname: Thürlimann
authors.forename: Maria B
authors.initials: MB
authors.lastname: Lyng
authors.forename: Henrik J
authors.initials: HJ
authors.lastname: Ditzel
authors.forename: Patrick
authors.initials: P
authors.lastname: Neven
authors.forename: Marc
authors.initials: M
authors.lastname: Debled
authors.forename: Rudolf
authors.initials: R
authors.lastname: Maibach
authors.forename: Karen N
authors.initials: KN
authors.lastname: Price
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gelber
authors.forename: Alan S
authors.initials: AS
authors.lastname: Coates
authors.forename: Aron
authors.initials: A
authors.lastname: Goldhirsch
authors.forename: James M
authors.initials: JM
authors.lastname: Rae
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
mesh_terms: D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005838:Genotype; D006801:Humans; D007391:International Cooperation; D053208:Kaplan-Meier Estimate; D000077289:Letrozole; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D013629:Tamoxifen / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D013629:Tamoxifen; D000077289:Letrozole; D019389:Cytochrome P-450 CYP2D6