Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer

Abstract

Introduction: Tamoxifen therapy reduces the risk of recurrence and prolongs the survival of oestrogen-receptor-positive patients with breast cancer. Even if most patients benefit from tamoxifen, many breast tumours either fail to respond or become resistant. Because tamoxifen is extensively metabolised by polymorphic enzymes, one proposed mechanism underlying the resistance is altered metabolism. In the present study we investigated the prognostic and/or predictive value of functional polymorphisms in cytochrome P450 3A5 CYP3A5 (*3), CYP2D6 (*4), sulphotransferase 1A1 (SULT1A1; *2) and UDP-glucuronosyltransferase 2B15 (UGT2B15; *2) in tamoxifen-treated patients with breast cancer.

Methods: In all, 677 tamoxifen-treated postmenopausal patients with breast cancer, of whom 238 were randomised to either 2 or 5 years of tamoxifen, were genotyped by using PCR with restriction fragment length polymorphism or PCR with denaturing high-performance liquid chromatography.

Results: The prognostic evaluation performed in the total population revealed a significantly better disease-free survival in patients homozygous for CYP2D6*4. For CYP3A5, SULT1A1 and UGT2B15 no prognostic significance was observed. In the randomised group we found that for CYP3A5, homozygous carriers of the *3 allele tended to have an increased risk of recurrence when treated for 2 years with tamoxifen, although this was not statistically significant (hazard ratio (HR) = 2.84, 95% confidence interval (CI) = 0.68 to 11.99, P = 0.15). In the group randomised to 5 years' tamoxifen the survival pattern shifted towards a significantly improved recurrence-free survival (RFS) among CYP3A5*3-homozygous patients (HR = 0.20, 95% CI = 0.07 to 0.55, P = 0.002). No reliable differences could be seen between treatment duration and the genotypes of CYP2D6, SULT1A1 or UGT2B15. The significantly improved RFS with prolonged tamoxifen treatment in CYP3A5*3 homozygotes was also seen in a multivariate Cox model (HR = 0.13, CI = 0.02 to 0.86, P = 0.03), whereas no differences could be seen for CYP2D6, SULT1A1 and UGT2B15.

Conclusion: The metabolism of tamoxifen is complex and the mechanisms responsible for the resistance are unlikely to be explained by a single polymorphism; instead it is a combination of several mechanisms. However, the present data suggest that genetic variation in CYP3A5 may predict response to tamoxifen therapy.

Figure 1

Kaplan–Meier estimates for recurrence-free survival between CYP2D6 genotypes in oestrogen-receptor-positive postmenopausal breast cancer patients. The black solid line represents patients homozygous for CYP2D6*1, the grey solid line represents heterozygous patients, and the dotted line represents patients homozygous for CYP2D6*4. P = 0.05 between *4/*4 and *1/*1; P = 0.04 between *4/*4 and *1/*4; P = 0.16 between *1/*1 and *1/*4.

Figure 2

Recurrence-free survival in ER-positive patients with different genotypes of SULT1A1 and tamoxifen randomisation. The solid line represents patients homozygous for the SULT1A1*1 allele, and the dotted line represents patients homozygous or heterozygous for the SULT1A1*2 allele. (a) SULT1A1 and 2 years of tamoxifen therapy; (b) SULT1A1 and 5 years of tamoxifen therapy.

Figure 3

Recurrence-free survival in ER-positive patients with different genotypes of CYP3A5 and tamoxifen randomisation. The solid line represents patients homozygous or heterozygous for the CYP3A5*1 allele, and the dotted line represents patients homozygous for the CYP3A5*3 allele. (a) CYP3A5 and 2 years of tamoxifen therapy; (b) CYP3A5 and 5 years of tamoxifen therapy.

Figure 4

Recurrence-free survival in ER-positive patients with different genotypes of CYP2D6 and tamoxifen randomisation. The solid line represents patients homozygous for the CYP2D6*1 allele, and the dotted line represents patients homozygous or heterozygous for the CYP2D6*4 allele. (a) CYP2D6 and 2 years of tamoxifen therapy; (b) CYP2D6 and 5 years of tamoxifen therapy.

Figure 5

Recurrence-free survival in ER-positive patients with different genotypes of UGT2B15 and tamoxifen randomisation. The solid line represents patients homozygous for the UGT2B15*1 allele, and the dotted line represents patients homozygous or heterozygous for the UGT2B15*2 allele. (a) UGT2B15 and 2 years of tamoxifen therapy; (b) UGT2B15 and 5 years of tamoxifen therapy.