title: The CYP2C19*2 genotype predicts tamoxifen treatment outcome in advanced breast cancer patients.
abstract: OBJECTIVE
  Tamoxifen is metabolized by cytochrome P450s, with an important role for CYP2D6. Recently, we demonstrated in 80 patients that CYP2C19*2 is associated with increased survival in breast cancer patients using tamoxifen. Here, we aimed to confirm this in a large group of 499 patients.
  
  
  METHODS
  A total of 499 estrogen receptor-positive primary breast tumor specimens of advanced disease patients treated with first-line tamoxifen were genotyped for CYP2C19*2 and *17 variant alleles, with primary end point time-to-treatment failure (TTF). Effects of CYP2C19, independent of treatment, were analyzed in 243 primary systematic untreated patients.
  
  
  RESULTS
  CYP2C19*2 hetero- and homozygote patients combined showed significantly longer TTFs (hazard ratio [HR]: 0.72; 95% CI: 0.57-0.90; p = 0.004). In multivariate analysis, including CYP2D6*4 status, CYP2C19*2 remained independently associated with TTF (HR: 0.73; 95% CI: 0.58-0.91; p = 0.007). In untreated patients, the CYP2C19*17 allele was significantly associated with a longer disease-free interval (HR: 0.66; 95%CI: 0.46-0.95; p = 0.025).
  
  
  CONCLUSIONS
  CYP2C19 genotyping is potentially important for tamoxifen therapy for advanced disease and for breast cancer prognosis.
authors.affiliation: Erasmus MC Rotterdam, The Netherlands. r.vanschaik@erasmusmc.nl
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: Marleen
authors.initials: M
authors.lastname: Kok
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.forename: Martin
authors.initials: M
authors.lastname: van Vliet
authors.forename: Marianne
authors.initials: M
authors.lastname: van Fessem
authors.forename: Marion E
authors.initials: ME
authors.lastname: Meijer-van Gelder
authors.forename: Caroline
authors.initials: C
authors.lastname: Seynaeve
authors.forename: Jan
authors.initials: J
authors.lastname: Lindemans
authors.forename: Jelle
authors.initials: J
authors.lastname: Wesseling
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Van 't Veer
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
authors.forename: Hanneke
authors.initials: H
authors.lastname: van Laarhoven
authors.forename: Stefan
authors.initials: S
authors.lastname: Sleijfer
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Linn
authors.forename: Els M J J
authors.initials: EM
authors.lastname: Berns
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D003131:Combined Modality Therapy; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D003627:Data Interpretation, Statistical; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008207:Lymphatic Metastasis / Q000473:pathology; D008593:Menopause; D008875:Middle Aged; D010597:Pharmacogenetics; D011237:Predictive Value of Tests; D011379:Prognosis; D011980:Receptors, Progesterone / Q000378:metabolism; D012189:Retrospective Studies; D016019:Survival Analysis; D013629:Tamoxifen / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004273:DNA, Neoplasm; D011980:Receptors, Progesterone; D013629:Tamoxifen; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6