Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients

Abstract

Purpose: The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen.

Patients and methods: We studied 282 patients with hormone receptor-positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d.

Results: CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio [HR] = 9.52; 95% CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with <or= one risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4-hydroxytamoxifen (P = .0000043 and .00052), whereas no significant difference was found among ABCC2 genotype groups.

Conclusion: Our results suggest that polymorphisms in CYP2D6 and ABCC2 are important predictors for the prognosis of patients with breast cancer treated with tamoxifen.

Fig 1.

Kaplan-Meier estimates of recurrence-free survival for CYP2D6 and ABCC2 rs3740065 genotypes. (A) Comparison of 282 patients with wt/wt, wt/V, and V/V of CYP2D6. (B) Comparison of 282 patients with AA, AG, and GG genotypes at rs3740065 in ABCC2.

Fig 2.

Kaplan-Meier estimates of recurrence-free survival for combination effects of CYP2D6 and ABCC2 genotypes. The patients were classified into five groups (zero, one, two, three, or four alleles) based on the number of risk alleles of these two genes.

Fig 3.

Steady-state plasma concentrations of (A, B) endoxifen and (C, D) 4-hydroxytamoxifen (4-OH tamoxifen) according to genotypes. (A, C) Comparison among wt/wt, wt/V, and V/V of CYP2D6. (B, D) Comparison among AA, AG, and GG genotypes at rs3740065 in ABCC2. The horizontal line indicates the median concentration, the box covers the 25th to 75th percentiles, and the maximum length of each whisker is 1.5 × the interquartile range; dots outside the whiskers are outliers.

Fig A1.

Association of CYP2D6*10 with recurrence-free survival and plasma concentrations of tamoxifen metabolites in patients with breast cancer. (A) Kaplan-Meier estimates of recurrence-free survival for patients with CYP2D6*1/*1, *1/*10, and *10/*10 genotypes. Steady-state plasma concentrations of (B) endoxifen and (C) 4-hydroxytamoxifen (4-OH tamoxifen) according to CYP2D6*10 genotypes. The horizontal line indicates the median concentration, the box covers the 25th to 75th percentiles, and the maximum length of each whisker is 1.5 × the interquartile range; dots outside the whiskers are outliers.