Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen

Abstract

Context: The growth inhibitory effect of tamoxifen, which is used for the treatment of hormone receptor-positive breast cancer, is mediated by its metabolites, 4-hydroxytamoxifen and endoxifen. The formation of active metabolites is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6) enzyme.

Objective: To determine whether CYP2D6 variation is associated with clinical outcomes in women receiving adjuvant tamoxifen.

Design, setting, and patients: Retrospective analysis of German and US cohorts of patients treated with adjuvant tamoxifen for early stage breast cancer. The 1325 patients had diagnoses between 1986 and 2005 of stage I through III breast cancer and were mainly postmenopausal (95.4%). Last follow-up was in December 2008; inclusion criteria were hormone receptor positivity, no metastatic disease at diagnosis, adjuvant tamoxifen therapy, and no chemotherapy. DNA from tumor tissue or blood was genotyped for CYP2D6 variants associated with reduced (*10, *41) or absent (*3, *4, *5) enzyme activity. Women were classified as having an extensive (n=609), heterozygous extensive/intermediate (n=637), or poor (n=79) CYP2D6 metabolism.

Main outcome measures: Time to recurrence, event-free survival, disease-free survival, and overall survival.

Results: Median follow-up was 6.3 years. At 9 years of follow-up, the recurrence rates were 14.9% for extensive metabolizers, 20.9% for heterozygous extensive/intermediate metabolizers, and 29.0% for poor metabolizers, and all-cause mortality rates were 16.7%, 18.0%, and 22.8%, respectively. Compared with extensive metabolizers, there was a significantly increased risk of recurrence for heterozygous extensive/intermediate metabolizers (time to recurrence adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.04-1.90) and for poor metabolizers (time to recurrence HR, 1.90; 95% CI, 1.10-3.28). Compared with extensive metabolizers, those with decreased CYP2D6 activity (heterozygous extensive/intermediate and poor metabolism) had worse event-free survival (HR, 1.33; 95% CI, 1.06-1.68) and disease-free survival (HR, 1.29; 95% CI, 1.03-1.61), but there was no significant difference in overall survival (HR, 1.15; 95% CI, 0.88-1.51).

Conclusion: Among women with breast cancer treated with tamoxifen, there was an association between CYP2D6 variation and clinical outcomes, such that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes and the presence of nonfunctional or reduced-function alleles with worse outcomes.

Figure 1. Kaplan-Meier Estimates of Time to Recurrence, Event-Free Survival, and Disease-Free Survival

EM indicates extensive metabolism (ie, patients with 2 functional CYP2D6 alleles, including patients with ultrarapid metabolism); hetEM/IM, patients with intermediate or 1 poor metabolism allele; PM, patients homozygous for poor metabolism alleles. The curves were truncated at 15 years after diagnosis and calculations included overall time (median follow-up, 6.3 years). Percentage differences vs unstratified are as follows: for time to recurrence, at 9 years, 3.4% for EM and 10.7% for PM, and at 15 years, 7.2% for EM and 19.0% for PM; for event-free survival, at 9 years, 3.3% for EM and 6.4% for PM, and at 15 years, 5.7% for EM and 10.9% for PM; and for disease-free survival, at 9 years, 2.3% for EM and 4.5% for PM, and at 15 years, 6.4% for EM and 17.9% for PM.

Figure 2. Cox Proportional Hazards Model Estimates of CYP2D6 Phenotypes for Various End Points and Patient Subgroups

CYP indicates cytochrome P450; EM, extensive metabolism (ie, patients with 2 functional alleles, including patients with ultrarapid metabolism); hetEM/IM, patients with intermediate or 1 poor metabolism allele; PM, patients homozygous for poor metabolism alleles; decreased, combined group of PM and hetEM/IM. Non-adjusted hazard ratios were calculated for the entire patient cohort and subgroups. Subgroups were analyzed with respect to mode of patient sampling and clinical prognostic factors. All comparisons refer to CYP2D6 EM as the reference. The size of the data markers is inversely proportional to the standard error of the hazard ratio.

Figure 3. Kaplan-Meier Estimates of Recurrence Probabilities Comparing Tamoxifen With a Hypothetical AI Curve

EM indicates extensive metabolism (ie, patients with 2 functional cytochrome P450 (CYP) 2D6 alleles, including patients with ultrarapid metabolism); decreased, patients with any intermediate or poor metabolism alleles. Nonadjusted, heterogeneity-corrected Kaplan-Meier estimates for the CYP2D6 decreased and EM phenotypes as well as the entire tamoxifen cohort unselected by genotype; 95% confidence interval (CI) is shown for EM patients. Assuming the Cox proportional hazards assumption, a hypothetical aromatase inhibitor (AI) survival curve (blue) was estimated based on a hazard ratio of 0.76 for anastrozole relative to tamoxifen and the Kaplan-Meier estimate of the entire tamoxifen cohort (eAppendix).