title: Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes.
abstract: OBJECTIVE
  Polymorphisms in tamoxifen metabolizing genes affect the plasma concentration of tamoxifen metabolites, but their effect on clinical outcome is unknown.
  
  
  METHODS
  We determined cytochrome P450 (CYP)2D6 (*4 and *6) and CYP3A5 (*3) genotype from paraffin-embedded tumor samples and buccal cells (living patients) in tamoxifen-treated women enrolled onto a North Central Cancer Treatment Group adjuvant breast cancer trial. The relationship between genotype and disease outcome was determined using the log-rank test and Cox proportional hazards modeling.
  
  
  RESULTS
  Paraffin blocks were obtained from 223 of 256 eligible patients, and buccal cells were obtained from 17 living women. CYP2D6 (*4 and *6) and CYP3A5 (*3) genotypes were determined from 190, 194, and 205 patient samples and in 17 living women. The concordance rate between buccal and tumor genotype was 100%. Women with the CYP2D6 *4/*4 genotype had worse relapse-free time (RF-time; P = .023) and disease-free survival (DFS; P = .012), but not overall survival (P = .169) and did not experience moderate to severe hot flashes relative to women heterozygous or homozygous for the wild-type allele. In the multivariate analysis, women with the CYP2D6 *4/*4 genotype still tended to have worse RFS (hazard ratio [HR], 1.85; P = .176) and DFS (HR, 1.86; P = .089). The CYP3A5*3 variant was not associated with any of these clinical outcomes.
  
  
  CONCLUSIONS
  In tamoxifen-treated patients, women with the CYP2D6 *4/*4 genotype tend to have a higher risk of disease relapse and a lower incidence of hot flashes, which is consistent with our previous observation that CYP2D6 is responsible for the metabolic activation of tamoxifen to endoxifen.
authors.affiliation: Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. goetz.matthew@mayo.edu
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Goetz
authors.forename: James M
authors.initials: JM
authors.lastname: Rae
authors.forename: Vera J
authors.initials: VJ
authors.lastname: Suman
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Safgren
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Visscher
authors.forename: Carol
authors.initials: C
authors.lastname: Reynolds
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.forename: Wilma L
authors.initials: WL
authors.lastname: Lingle
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
authors.forename: Edith A
authors.initials: EA
authors.lastname: Perez
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D019584:Hot Flashes / Q000139:chemically induced; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D012307:Risk Factors; D013629:Tamoxifen / Q000009:adverse effects / Q000378:metabolism*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A