The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen.
BACKGROUND
Tamoxifen is biotransformed to the potent anti-estrogen, endoxifen, by the cytochrome P450 (CYP) 2D6 enzyme. CYP2D6 genetic variation and inhibitors of the enzyme markedly reduce endoxifen plasma concentrations in tamoxifen-treated patients. Using a North Central Cancer Treatment Group adjuvant tamoxifen trial, we performed a comprehensive evaluation of CYP2D6 metabolism by assessing the combined effect of genetic variation and inhibition of the enzyme system on breast cancer recurrence and death.


METHODS
Medical records were reviewed at each randomizing site to determine whether CYP2D6 inhibitors were co-prescribed with tamoxifen. Extensive metabolizers were defined as patients without a *4 allele (i.e., wt/wt) who were not co-prescribed a CYP2D6 inhibitor. Patients with decreased CYP2D6 metabolism were classified as intermediate or poor metabolizers (PM) based on the presence of one or two CYP2D6*4 alleles or the co-administration of a moderate or potent CYP2D6 inhibitor. The association between CYP2D6 metabolism and clinical outcome was assessed using Cox modeling.


RESULTS
Medication history was available in 225/256 eligible patients and CYP2D6*4 genotype in 190 patients. Thirteen patients (6%) were co-prescribed a CYP2D6 inhibitor [potent (n = 3), moderate (n = 10)], resulting in the following CYP2D6 metabolism: extensive (n = 115) and decreased (n = 65). In the multivariate analysis, patients with decreased metabolism had significantly shorter time to recurrence (p = 0.034; adj HR = 1.91; 95% CI 1.05-3.45) and worse relapse-free survival (RFS) (p = 0.017; adj HR = 1.74; 1.10-2.74); relative to patients with extensive metabolism. Cox' modeling demonstrated that compared to extensive metabolizers, PM had the most significant risk of breast cancer relapse (HR 3.12, p = 0.007).


CONCLUSIONS
CYP2D6 metabolism, as measured by genetic variation and enzyme inhibition, is an independent predictor of breast cancer outcome in post-menopausal women receiving tamoxifen for early breast cancer. Determination of CYP2D6 genotype may be of value in selecting adjuvant hormonal therapy and it appears CYP2D6 inhibitors should be avoided in tamoxifen-treated women.
Goetz
Matthew P
MP
Department of Oncology, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN , 55905, USA, goetz.matthew@mayo.edu.
Knox
Stacey K
SK
Suman
Vera J
VJ
Rae
James M
JM
Safgren
Stephanie L
SL
Ames
Matthew M
MM
Visscher
Daniel W
DW
Reynolds
Carol
C
Couch
Fergus J
FJ
Lingle
Wilma L
WL
Weinshilboum
Richard M
RM
Fritcher
Emily G Barr
EG
Nibbe
Andrea M
AM
Desta
Zeruesenay
Z
Nguyen
Anne
A
Flockhart
David A
DA
Perez
Edith A
EA
Ingle
James N
JN
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D017024:Chemotherapy, Adjuvant / Q000379:methods / Q000706:statistics & numerical data; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D005260:Female; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D016016:Proportional Hazards Models; D013629:Tamoxifen / Q000627:therapeutic use*; D016896:Treatment Outcome
D018931:Antineoplastic Agents, Hormonal; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6