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Pharmacogenetics and breast cancer endocrine therapy: CYP2D6 as a predictive factor for tamoxifen metabolism and drug response?

ABSTRACT: The identification of genetic polymorphisms that influence the efficacy and safety of therapies for breast cancer may allow future treatments to be individualised based not only on tumour characteristics but also on host genetics. Genetic factors that affect the metabolism, efficacy and safety of tamoxifen, one of the most common drugs used for the treatment and prevention of breast cancer, have received particular attention. Cytochrome P450 2D6 (CYP2D6) is crucial in the metabolism of tamoxifen to its active metabolite endoxifen. Women with genetic variants of CYP2D6 or who take drugs that inhibit the enzyme have low endoxifen plasma concentrations and may show reduced benefits to tamoxifen treatment. CYP2D6 polymorphisms and variants in other candidate genes may also influence secondary benefits and side effects of tamoxifen. Here, we summarise data suggesting that CYP2D6 status may be an important predictor of the benefits of tamoxifen to an individual; in addition, we briefly discuss the role of variants in other candidate genes. Whether CYP2D6 status should be determined prior to initiating tamoxifen therapy is currently under debate and may be appropriate only for select women who are candidates for tamoxifen alone but for whom alternative standard options are available.

SUBMITTER: Stearns V

PROVIDER: S-EPMC3133663 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Pharmacogenetics and breast cancer endocrine therapy: CYP2D6 as a predictive factor for tamoxifen metabolism and drug response?

Stearns Vered V Rae James M JM

Expert reviews in molecular medicine 20081120

The identification of genetic polymorphisms that influence the efficacy and safety of therapies for breast cancer may allow future treatments to be individualised based not only on tumour characteristics but also on host genetics. Genetic factors that affect the metabolism, efficacy and safety of tamoxifen, one of the most common drugs used for the treatment and prevention of breast cancer, have received particular attention. Cytochrome P450 2D6 (CYP2D6) is crucial in the metabolism of tamoxifen ...[more]

PMID: 19019258

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Project description: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.

Project description:Background: Current reports suggest that a certain minimum plasma concentration of (Z)-endoxifen is required for breast cancer patient to benefit from tamoxifen therapy. A reliable prediction of which patients are at risk for insufficient exposure to (Z)-endoxifen would be relevant for optimizing treatment, e.g. by adjusting the dose, from the very beginning. The objective of this study was to search for new DNA variants that could be helpful in the preemptive prediction of impaired tamoxifen to endoxifen metabolism. Methods: The molecular ratio (MR) was defined as (Z)-endoxifen plasma concentration divided by the sum of concentrations of tamoxifen and other measured metabolites. The MR of 0.0146, previously delineated as corresponding to (Z)-endoxifen 6 ng/ml efficacy threshold level, was adopted as a cut-off value in a genome-wide association study (GWAS) comprising 287 breast cancer patients receiving tamoxifen 20 mg daily. Multivariate binary logistic regression was used for the pre-selection of variables that showed independent impact on MR and to develop models predictive for MR value below the threshold. Results: In total, 13 GWAS-selected single nucleotide polymorphisms (SNPs) located outside the CYP2D6 gene and two known CYP2D6 variants were significantly associated with the MR value below 0.0146. The strongest association was observed for rs8138080 in WBP2NL (p = 1.78 x 10-15). The minor allele of six SNPs was associated with a decreased risk of impaired tamoxifen metabolism. CYP2D6 genotype was found by Nagelkerke pseudo-R2 to explain 42.7% of a total variation observed in MR, while rs8138080 alone explained 33.7% of this variability. Two alternative models for MR prediction have been developed. The prediction accuracy of Model 1, including rs7245, rs6950784 and rs1320308 in addition to CYP2D6 genotype, was considerably higher than predictive performance of CYP2D6 genotype alone (AUC increase from 0.758 to 0.879). The AUC of 0.830 achieved for the Model 2, developed with the same three SNPs as in Model 1 and rs8138080 instead of CYP2D6 genotype, makes it an interesting, simplified alternative to the costly and time-consuming testing of full CYP2D6 genotype. Conclusions: The four novel SNPs, tested alone or in addition to CYP2D6 genotype, improved the prediction of impaired tamoxifen to endoxifen metabolism, allowing for adjustments in dosing regimen before the treatment begins.

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Pharmacogenetics and breast cancer endocrine therapy: CYP2D6 as a predictive factor for tamoxifen metabolism and drug response?

Publications

Pharmacogenetics and breast cancer endocrine therapy: CYP2D6 as a predictive factor for tamoxifen metabolism and drug response?

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