Significant Effect of Polymorphisms in CYP2D6 and ABCC2 on Clinical Outcomes of Adjuvant Tamoxifen Therapy for Breast Cancer Patients

Abstract

A B S T R A C T PurposeThe 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 MethodsWe 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 CYP2D6variants were significantly associated with shorter recurrence-free survival (P ϭ .000036; hazard ratio [HR] ϭ 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 ϭ .00017; HR ϭ 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 ϭ .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with Յ one risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4-hydroxytamoxifen (P ϭ .0000043 and .00052), whereas no significant difference was found among ABCC2 genotype groups. ConclusionOur results suggest that polymorphisms in CYP2D6 and ABCC2 are important predictors for the prognosis of patients with breast cancer treated with tamoxifen.

Does CYP2D6 Genotyping have a Role in Guiding Tamoxifen Therapy?

“…The prospective studies [20,32], however, were also retrospective in nature since CYP2D6 genotyping has been performed after the relapse had eventuated. Nonparametric analyses and substantial overlaps in the patients' data were also reported in the following studies [10,[33][34][35]. Nevertheless, two prospective yet small studies [36,38] and two large trials (n>1300) [35,40] have reported statistically strong correlation between CYP2D6 genotype and clinical outcome in patients with breast cancer taking tamoxifen.…”

“…*4/*10/*41) are robust predictors of tamoxifen's antitumoral efficacy [10,20,34,37]. Moreover, findings from a prospective study found that CYP2D6 polymorphisms were strongly associated with Ki-67 response, implying that CYP2D6 genetic variation is an important predictor for efficacy of tamoxifen in women with breast cancer [38].…”

“…Various studies regarding treatment outcomes in the adjuvant and/or metastatic settings have reported that those with genetically impaired CYP2D6 appear to have experienced significantly higher rate of breast cancer recurrence and mortality than those with normal CYP2D6 enzymatic activity [10,20,[32][33][34][35][36][37][38], suggesting that variants associated with reduced function alleles (e.g. *4/*10/*41) are robust predictors of tamoxifen's antitumoral efficacy [10,20,34,37].…”

“…role in the high degree of interindividual differences in response to tamoxifen therapy [7][8][9][10].…”

“…Hence, tamoxifen remains the gold standard for ER (+) breast cancer. However, tamoxifen efficacy varies widely, many breast cancer patients with adjuvant tamoxifen remain free of recurrence but 30-50% suffer relapse [7][8][9][10].…”