Tumor specimens from a subset of postmenopausal patients with hormone receptor-positive early-stage (stages I, II, and IIIA) breast cancer, who were enrolled in the randomized double-blind Arimidex, Tamoxifen, Alone or in Combination (ATAC) clinical trial, were genotyped for variants in CYP2D6 (N = 1203 patients: anastrozole [trade name: Arimidex] group, n = 615 patients; tamoxifen group, n = 588 patients) and UDP-glucuronosyltransferase-2B7 (UGT2B7), whose gene product inactivates endoxifen (N = 1209 patients; anastrozole group, n = 606 patients; tamoxifen group, n = 603 patients).
The breast cancer patients who are heterozygous and homozygous for decreased-function and null alleles of CYP2D6 showed lower plasma concentrations of endoxifen and 4-hydroxytamoxifen compared to patients with homozygous-wild-type allele, resulting in worse clinical outcome in tamoxifen therapy.
Because CYP2D6 is known to be a key enzyme responsible for the generation of an active tamoxifen metabolite, 'endoxifen', some studies reported that genetic polymorphisms of CYP2D6 that reduced its enzyme activity or coadministration of CYP2D6 inhibitors were associated with the poor clinical outcomes of breast cancer patients treated with tamoxifen.
Ten epidemiology studies on the association between CYP2D6 genotype and breast cancer recurrence report widely heterogeneous results with relative-risk estimates outside the range of reasonable bounds.
Blood samples from 279 Polish women with breast cancer receiving tamoxifen 20 mg daily were analyzed for CYP2D6 genotype and drug metabolite concentration.
The aim of this study was to evaluate the relation of CYP2D6 genotyping and phenotyping with EDF levels and [NDT]/[EDF] metabolic ratio in breast cancer patients from South of Brazil under TAM therapy.
This case-control study demonstrated no significant effect of CYP2D6 genotype on risk of recurrence in breast cancer patients who received adjuvant tamoxifen therapy.
This translational research study has led to increased awareness among clinicians of the potential benefits of CYP2D6 genotyping to facilitate prevention of cumulative risk in a high-risk genetic subgroup of breast cancer patients considered for concomitant treatment of TAM and antidepressants that may reduce enzyme function.
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.
Since there are controversies regarding associations between CYP2D6 polymorphisms and outcomes among women with early breast cancer (EBC) treated with tamoxifen, the present evaluation of links with clinical outcomes was conducted.
These results are consistent with the relatively few other large, population-based studies conducted to date that have not observed an increased risk of adverse BC outcomes associated with CYP2D6 inhibition.