title: Evaluation of CYP2D6 enzyme activity using a 13C-dextromethorphan breath test in women receiving adjuvant tamoxifen.
abstract: BACKGROUND
  In tamoxifen-treated patients, breast cancer recurrence differs according to CYP2D6 genotype and endoxifen steady-state concentrations (Endx Css). The ¹³C-dextromethorphan breath test (DM-BT), labeled with ¹³C at the O-CH3 moiety, measures CYP2D6 enzyme activity. We sought to examine the ability of the DM-BT to identify known CYP2D6 genotypic poor metabolizers and examine the correlation between DM-BT and Endx Css.
  
  
  METHODS
  DM-BT and tamoxifen pharmacokinetics were obtained at baseline, 3, and 6 months following tamoxifen initiation. Potent CYP2D6 inhibitors were prohibited. The correlation between baseline DM-BT with CYP2D6 genotype and Endx Css was determined. The association between baseline DM-BT (where values ≤0.9 is an indicator of poor in vivo CYP2D6 metabolism) and Endx Css (using values≤11.2 known to be associated with poorer recurrence free survival) was explored.
  
  
  RESULTS
  A total of 91 patients were enrolled and 77 were eligible. CYP2D6 genotype was positively correlated with baseline, 3, and 6 months DM-BT (r ranging from 0.457-0. 60; P<0.001). Both CYP2D6 genotype (r=0.47, 0.56, P<0.0001), and baseline DM-BT (r=0.60, 0.54, P<0.001) were associated with 3 and 6 months Endx Css, respectively. Seven (78%) of nine patients with low (≤11.2 nmol/l) 3 month Endx Css also had low DM-BT (≤0.9) including 2/2 CYP2D6 PM/PM and 5/5 IM/PM. In contrast, one (2%) of 48 patients with a low DM-BT had Endx Css more than 11.2 nmol/l.
  
  
  CONCLUSIONS
  In patients not taking potent CYP2D6 inhibitors, DM-BT was associated with CYP2D6 genotype and 3 and 6 months Endx Css but did not provide better discrimination of Endx Css compared with CYP2D6 genotype alone. Further studies are needed to identify additional factors which alter Endx Css.
authors.affiliation: Departments of aOncology bMolecular Pharmacology and Experimental Therapeutics cBiostatistics dLaboratory Medicine, Mayo Clinic, Rochester, Minnesota eDepartment of Hematology and Oncology, Mayo Clinic, Scottsdale, Arizona fCambridge Isotope Laboratories Inc. gPhysical Sciences Inc., Andover, Massachusetts, USA.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Safgren
authors.forename: Vera J
authors.initials: VJ
authors.lastname: Suman
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Kosel
authors.forename: Judith A
authors.initials: JA
authors.lastname: Gilbert
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Buhrow
authors.forename: John L
authors.initials: JL
authors.lastname: Black
authors.forename: Donald W
authors.initials: DW
authors.lastname: Northfelt
authors.forename: Anil S
authors.initials: AS
authors.lastname: Modak
authors.forename: David
authors.initials: D
authors.lastname: Rosen
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Goetz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000996:Antitussive Agents; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D001944:Breath Tests / Q000379:methods*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003915:Dextromethorphan; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013629:Tamoxifen / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D000996:Antitussive Agents; D013629:Tamoxifen; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6