title: Evaluation of CYP2D6 and efficacy of tamoxifen and raloxifene in women treated for breast cancer chemoprevention: results from the NSABP P1 and P2 clinical trials.
abstract: BACKGROUND
  Controversy exists regarding the association between CYP2D6 enzyme activity and tamoxifen effectiveness in the adjuvant treatment of invasive breast cancer; however, this association in the primary prevention of breast cancer is unknown.
  
  
  METHODS
  We conducted a nested case-control study in the context of the NSABP P1 and P2 prevention trials to determine the impact of CYP2D6 genotype, CYP2D6 inhibitor use, and metabolizer status (CYP2D6 genotype combined with CYP2D6 inhibitor use), on breast cancer events. Women who developed breast cancer (both noninvasive and invasive) while on 5 years of selective estrogen receptor modulators therapy (cases) were matched to controls free of breast cancer. Comprehensive CYP2D6 genotyping was conducted for alleles associated with absent (*3, *4, *5, and *6), reduced (*10, *17, and *41), and increased (*1XN and *2XN) enzyme activity. Information regarding the use of CYP2D6 inhibitors was recorded.
  
  
  RESULTS
  A total of 591 cases were matched to 1,126 controls and DNA was genotyped in more than 97%. In patients treated with tamoxifen, there was no association of CYP2D6 genotype [OR (extensive/poor metabolizer): 0.90; 95% CI: 0.46-1.74, P = 0.74), use of a potent CYP2D6 inhibitor (OR 0.92; 95% CI: 0.575-1.486), or CYP2D6 metabolizer status (OR 1.03; 95% CI: 0.669-1.607) with breast cancer occurrence. Likewise, there was no association between any CYP2D6 metabolism parameter with breast cancer events in raloxifene-treated patients.
  
  
  CONCLUSIONS
  In the NSABP P1 and P2 clinical trials, alterations in CYP2D6 metabolism are not associated with either tamoxifen or raloxifene efficacy.
authors: Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA. goetz.matthew@mayo.edu
authors: Matthew P
authors: MP
authors: Goetz
authors: Daniel J
authors: DJ
authors: Schaid
authors: D Lawrence
authors: DL
authors: Wickerham
authors: Stephanie
authors: S
authors: Safgren
authors: Taisei
authors: T
authors: Mushiroda
authors: Michiaki
authors: M
authors: Kubo
authors: Anthony
authors: A
authors: Batzler
authors: Joseph P
authors: JP
authors: Costantino
authors: Victor G
authors: VG
authors: Vogel
authors: Soonmyung
authors: S
authors: Paik
authors: Erin E
authors: EE
authors: Carlson
authors: David A
authors: DA
authors: Flockhart
authors: Norman
authors: N
authors: Wolmark
authors: Yusuke
authors: Y
authors: Nakamura
authors: Richard M
authors: RM
authors: Weinshilboum
authors: James N
authors: JN
authors: Ingle
authors: Matthew M
authors: MM
authors: Ames
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D016022:Case-Control Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D005260:Female; D006801:Humans; D008875:Middle Aged; D017698:Postmenopause / Q000235:genetics / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000627:therapeutic use*; D013629:Tamoxifen / Q000627:therapeutic use*
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride; D019389:Cytochrome P-450 CYP2D6