Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes.
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.
Goetz
Matthew P
MP
Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. goetz.matthew@mayo.edu
Rae
James M
JM
Suman
Vera J
VJ
Safgren
Stephanie L
SL
Ames
Matthew M
MM
Visscher
Daniel W
DW
Reynolds
Carol
C
Couch
Fergus J
FJ
Lingle
Wilma L
WL
Flockhart
David A
DA
Desta
Zeruesenay
Z
Perez
Edith A
EA
Ingle
James N
JN
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*
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