CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients

Abstract

Background: Adjuvant tamoxifen therapy substantially decreases the risk of recurrence and mortality in women with hormone (estrogen and/or progesterone) receptor-positive breast cancer. Previous studies have suggested that metabolic conversion of tamoxifen to endoxifen by cytochrome P450 2D6 (CYP2D6) is required for patient benefit from tamoxifen therapy.

Methods: 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). Genotyping was performed using polymerase chain reaction-based TaqMan assays. Based on the genotypes for CYP2D6, patients were classified as poor metabolizer (PM), intermediate metabolizer (IM), or extensive metabolizer (EM) phenotypes. We evaluated the association of CYP2D6 and UGT2B7 genotype with distant recurrence (primary endpoint) and any recurrence (secondary endpoint) by estimating the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) using Cox proportional hazards models. All statistical tests were two-sided.

Results: After a median follow-up of 10 years, no statistically significant associations were observed between CYP2D6 genotype and recurrence in tamoxifen-treated patients (PM vs EM: HR for distant recurrence = 1.25, 95% CI = 0.55 to 3.15, P = .64; HR for any recurrence = 0.99, 95% CI = 0.48 to 2.08, P = .99). A near-null association was observed between UGT2B7 genotype and recurrence in tamoxifen-treated patients. No associations were observed between CYP2D6 and UGT2B7 genotypes and recurrence in anastrozole-treated patients.

Conclusion: The results do not support the hypothesis that CYP2D6 genotype predicts clinical benefit of adjuvant tamoxifen treatment among postmenopausal breast cancer patients.

Figure 1

CONSORT diagram showing the number of patients from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) clinical trial included in the genetic substudy. CYP2D6 = cytochrome P450 2D6; UGT2B7 = UDP-glucuronosyltransferase-2B7.

Figure 2

Probability of recurrence in patients enrolled in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial according to cytochrome P450 2D6 (CYP2D6) phenotype. Recurrence was assessed in patients who were randomly assigned to the tamoxifen group using a Cox proportional hazard model. A CYP2D6 activity score was assigned to each patient, which most accurately predicts a patient's CYP2D6 metabolic phenotype based on her genotype (31). The phenotypic scores are indicated in parentheses. Two-sided P values were calculated using an adjusted Cox proportional hazard model. A) Distant recurrence. B) Any recurrence. CI = confidence intervalHR = hazard ratio; EM = extensive metabolizer; IM = intermediate metabolizer; PM = poor metabolizer.