CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the breast international group 1-98 trial

Abstract

Background: Adjuvant tamoxifen therapy is effective for postmenopausal women with endocrine-responsive breast cancer. Cytochrome P450 2D6 (CYP2D6) enzyme metabolizes tamoxifen to clinically active metabolites, and CYP2D6 polymorphisms may adversely affect tamoxifen efficacy. In this study, we investigated the clinical relevance of CYP2D6 polymorphisms.

Methods: We obtained tumor tissues and isolated DNA from 4861 of 8010 postmenopausal women with hormone receptor-positive breast cancer who enrolled in the randomized, phase III double-blind Breast International Group (BIG) 1-98 trial between March 1998 and May 2003 and received tamoxifen and/or letrozole treatment. Extracted DNA was used for genotyping nine CYP2D6 single-nucleotide polymorphisms using polymerase chain reaction-based methods. Genotype combinations were used to categorize CYP2D6 metabolism phenotypes as poor, intermediate, and extensive metabolizers (PM, IM, and EM, respectively; n = 4393 patients). Associations of CYP2D6 metabolism phenotypes with breast cancer-free interval (referred to as recurrence) and treatment-induced hot flushes according to randomized endocrine treatment and previous chemotherapy were assessed. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.

Results: No association between CYP2D6 metabolism phenotypes and breast cancer-free interval was observed among patients who received tamoxifen monotherapy without previous chemotherapy (P = .35). PM or IM phenotype had a non-statistically significantly reduced risk of breast cancer recurrence compared with EM phenotype (PM or IM vs EM, HR of recurrence = 0.86, 95% CI = 0.60 to 1.24). CYP2D6 metabolism phenotype was associated with tamoxifen-induced hot flushes (P = .020). Both PM and IM phenotypes had an increased risk of tamoxifen-induced hot flushes compared with EM phenotype (PM vs EM, HR of hot flushes = 1.24, 95% CI = 0.96 to 1.59; IM vs EM, HR of hot flushes = 1.23, 95% CI = 1.05 to 1.43).

Conclusions: CYP2D6 phenotypes of reduced enzyme activity were not associated with worse disease control but were associated with increased hot flushes, contrary to the hypothesis. The results of this study do not support using the presence or absence of hot flushes or the pharmacogenetic testing of CYP2D6 to determine whether to treat postmenopausal breast cancer patients with tamoxifen.

Trial registration: ClinicalTrials.gov NCT00004205.

Figure 1

Flow diagram of the Breast International Group (BIG) 1-98 trial participants included in the study. Collection of tumor tissue blocks, DNA extraction, CYP2D6 genotyping, and patient cohorts for analysis are shown. BCFI = breast cancer-free interval; CYP2D6 = Cytochrome P450 2D6; ER = estrogen receptor; FFPE = formalin-fixed paraffin-embedded.

Figure 2

Kaplan–Meier estimates of breast cancer-free interval (BCFI) according to CYP2D6 metabolism phenotype, endocrine treatment, and previous chemotherapy use in the Breast International Group (BIG) 1-98 trial. Outcome of 1243 patients randomly assigned to 5 years of tamoxifen monotherapy or 1294 patients randomly assigned to 5 years of letrozole monotherapy in the BIG 1-98 trial is shown. Based on CYP2D6 genotyping, metabolism phenotypes were classified as poor metabolizer (PM), intermediate metabolizer (IM), and extensive metabolizer (EM). A) Tamoxifen without previous chemotherapy. B) Tamoxifen after chemotherapy. C) Letrozole without previous chemotherapy. D) Letrozole after chemotherapy. P values were calculated using two-sided Wald tests with 2 df for association of CYP2D6 metabolism phenotype with BCFI within an adjusted Cox proportional hazards model. CI = confidence interval; CYP2D6 = Cytochrome P450 2D6; HR = hazard ratio.

Figure 3

Kaplan–Meier estimates of breast cancer-free interval (BCFI) among tamoxifen-treated patients in the Breast International Group (BIG) 1-98 trial according to CYP2D6 metabolism phenotype. Outcome of 973 patients without previous chemotherapy who were randomly assigned to 5 years of tamoxifen monotherapy. P values were calculated using two-sided Wald tests with 2 df for association of CYP2D6 metabolism phenotype with BCFI within adjusted Cox proportional hazards models. A) Phenotype classification based only on CYP2D6*4 allele. Homozygous CYP2D6*4/*4 (shown as *4/*4) is analogous to the poor metabolizer (PM) phenotype; heterozygous CYP2D6*4/WT (shown as *4/WT) is analogous to the intermediate metabolizer (IM) phenotype; homozygous for wild-type alleles (WT/WT) is analogous to the extensive metabolizer (EM) phenotype. B) Phenotype classification with separation of two IM phenotype subgroups, defined as carriers of either homozygous CYP2D6*41 alleles or a CYP2D6*41 allele in combination with a PM allele (ie, IM/IM or IM/PM alleles, respectively), or defined as heterozygous carriers of one PM or IM allele and one EM allele (ie, heterozygous for EM alleles [hetEM]). CI = confidence interval; CYP2D6 = Cytochrome P450 2D6; HR = hazard ratio.

Figure 4

Cumulative incidence of new or worsening hot flushes during the first 2 years of treatment in the Breast International Group (BIG) 1-98 trial according to CYP2D6 metabolism phenotype. Results of all 4393 patients whose phenotypes were poor metabolizer (PM), intermediate metabolizer (IM), and extensive metabolizer (EM). All P values were calculated using two-sided Wald tests with 2 df for association of CYP2D6 metabolism phenotype with onset of hot flushes within an adjusted Cox proportional hazards model. A) Tamoxifen without previous chemotherapy. B) Tamoxifen after previous chemotherapy. C) Letrozole without previous chemotherapy. D) Letrozole after previous chemotherapy. CI = confidence interval; CYP2D6 = Cytochrome P450 2D6.