title: Impaired tamoxifen metabolism reduces survival in familial breast cancer patients.
abstract: OBJECTIVE
  Tamoxifen has been the mainstay adjuvant hormonal treatment for breast cancer for many years. Conversion of tamoxifen to its active metabolite, endoxifen, is reduced by low activity of the cytochrome P450 enzyme, CYP2D6. We examined the effect of reduced CYP2D6 activity on the response to tamoxifen in patients with familial early-onset breast cancer.
  
  
  METHODS
  We conducted a case note review and genotyping for the CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*41 alleles in 115 patients (47 BRCA1, 68 BRCA2) with familial breast cancer who had been treated with 20-mg tamoxifen following surgery.
  
  
  RESULTS
  Eight (7%) individuals had genotypes consistent with poor metabolizer status, and 4 (3.5%) individuals took CYP2D6 inhibitor drugs concomitant with their tamoxifen and were also considered poor metabolizer. Time to tumor recurrence, disease-free survival, and overall survival were reduced in the patient group with poor metabolizer CYP2D6 activity. However, a significant effect was confined to patients with BRCA2 mutations with a worse overall survival (median survival, 7 versus 28 years; P = 0.008; adjusted hazard ratio, 9.7).
  
  
  CONCLUSIONS
  Poor metabolizer status for CYP2D6 predicts worse overall survival in patients with familial breast cancer. Therefore, CYP2D6 inhibitor drugs should not be prescribed concomitantly with tamoxifen. Prospective studies should be undertaken to establish the effect of CYP2D6 status on outcome in familial breast cancer patients treated with tamoxifen.
authors.affiliation: Department of Medical Genetics, St. Mary's Hospital, University of Manchester, Manchester, United Kingdom. William.newman@manchester.ac.uk
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.forename: Kristen D
authors.initials: KD
authors.lastname: Hadfield
authors.forename: Ayshe
authors.initials: A
authors.lastname: Latif
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Roberts
authors.forename: Andrew
authors.initials: A
authors.lastname: Shenton
authors.forename: Christopher
authors.initials: C
authors.lastname: McHague
authors.forename: Fiona
authors.initials: F
authors.lastname: Lalloo
authors.forename: Sacha
authors.initials: S
authors.lastname: Howell
authors.forename: D Gareth
authors.initials: DG
authors.lastname: Evans
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004965:Estrogen Antagonists / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D016019:Survival Analysis; D013629:Tamoxifen / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D004965:Estrogen Antagonists; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6