Dataset Information

Relationship between genotypes Sult1a2 and Cyp2d6 and tamoxifen metabolism in breast cancer patients.

ABSTRACT: Tamoxifen is a pro-drug widely used in breast cancer patients to prevent tumor recurrence. Prior work has revealed a role of cytochrome and sulfotransferase enzymes in tamoxifen metabolism. In this descriptive study, correlations were examined between concentrations of tamoxifen metabolites and genotypes for CYP2D6, CYP3A4, CYP3A5, SULT1A1, SULT1A2 and SULT1E1 in 135 patients with estrogen receptor-positive breast cancer. Patients were genotyped using the Roche-AmpliChip® CYP450 Test, and Real-Time and conventional PCR-RFLP. Plasma tamoxifen, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen, endoxifen and tamoxifen-N-oxide were isolated and quantified using a high-pressure liquid chromatography-tandem mass spectrometry system. Significantly higher endoxifen levels were detected in patients with the wt/wt CYP2D6 compared to the v/v CYP2D6 genotype (p<0.001). No differences were detected in the remaining tamoxifen metabolites among CYP2D6 genotypes. Patients featuring the SULT1A2*2 and SULT1A2*3 alleles showed significantly higher plasma levels of 4-hydroxy-tamoxifen and endoxifen (p?=?0.025 and p?=?0.006, respectively), as likely substrates of the SULT1A2 enzyme. Our observations indicate that besides the CYP2D6 genotype leading to tamoxifen conversion to potent hydroxylated metabolites in a manner consistent with a gene-dose effect, SULT1A2 also seems to play a role in maintaining optimal levels of both 4-hydroxy-tamoxifen and endoxifen.

SUBMITTER: Fernandez-Santander A

PROVIDER: S-EPMC3726442 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Relationship between genotypes Sult1a2 and Cyp2d6 and tamoxifen metabolism in breast cancer patients.

Fernández-Santander Ana A Gaibar María M Novillo Apolonia A Romero-Lorca Alicia A Rubio Margarita M Chicharro Luis Miguel LM Tejerina Armando A Bandrés Fernando F

PloS one 20130729 7

Tamoxifen is a pro-drug widely used in breast cancer patients to prevent tumor recurrence. Prior work has revealed a role of cytochrome and sulfotransferase enzymes in tamoxifen metabolism. In this descriptive study, correlations were examined between concentrations of tamoxifen metabolites and genotypes for CYP2D6, CYP3A4, CYP3A5, SULT1A1, SULT1A2 and SULT1E1 in 135 patients with estrogen receptor-positive breast cancer. Patients were genotyped using the Roche-AmpliChip® CYP450 Test, and Real-T ...[more]

PMID: 23922954

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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.

Dataset Information

Relationship between genotypes Sult1a2 and Cyp2d6 and tamoxifen metabolism in breast cancer patients.

Publications

Relationship between genotypes Sult1a2 and Cyp2d6 and tamoxifen metabolism in breast cancer patients.

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