Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients.
OBJECTIVE
The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen.


METHODS
We studied 282 patients with hormone receptor-positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d.


RESULTS
CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio [HR] = 9.52; 95% CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with <or= one risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4-hydroxytamoxifen (P = .0000043 and .00052), whereas no significant difference was found among ABCC2 genotype groups.


CONCLUSIONS
Our results suggest that polymorphisms in CYP2D6 and ABCC2 are important predictors for the prognosis of patients with breast cancer treated with tamoxifen.
Kiyotani
Kazuma
K
Laboratories for Pharmacogenetics, Genotyping Development, and Medical Informatics, RIKEN Center for Genomic Medicine, Yokohama, Japan.
Mushiroda
Taisei
T
Imamura
Chiyo K
CK
Hosono
Naoya
N
Tsunoda
Tatsuhiko
T
Kubo
Michiaki
M
Tanigawara
Yusuke
Y
Flockhart
David A
DA
Desta
Zeruesenay
Z
Skaar
Todd C
TC
Aki
Fuminori
F
Hirata
Koichi
K
Takatsuka
Yuichi
Y
Okazaki
Minoru
M
Ohsumi
Shozo
S
Yamakawa
Takashi
T
Sasa
Mitsunori
M
Nakamura
Yusuke
Y
Zembutsu
Hitoshi
H
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D017024:Chemotherapy, Adjuvant; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D007564:Japan; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016019:Survival Analysis; D013629:Tamoxifen / Q000494:pharmacology*
C000715087:ABCC2 protein, human; D018528:ATP-Binding Cassette Transporters; D018931:Antineoplastic Agents, Hormonal; D000089762:Multidrug Resistance-Associated Protein 2; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6