Laboratory testing of CYP2D6 alleles in relation to tamoxifen therapy

Lyon, Elaine; Foster, Julie Gastier; Palomaki, Glenn E.; Pratt, Victoria M.; Reynolds, Kristen K.; Sabato, Mariangela; Scott, Stuart A.; Vitazka, Patrik

doi:10.1038/gim.2012.108

Cited by 38 publications

(28 citation statements)

References 32 publications

(40 reference statements)

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“…The NCBI single nucleotide polymorphism (SNP) database currently lists the allele frequency of CYP2D6 g.2470T>C as 0.74% in the ExAc_Aggregated_Populations population. However, this value is likely underestimated, since the majority of CYP2D6 variant testing commonly only include variations with >1% allele frequency and/or functional relevant variants [18]. Indeed, we genotyped the CYP2D6 g.2470 position in 365 samples using Sanger sequencing and hydrolyis probe assays, and found that the variant allele had a frequency of 2.47%.…”

Section: Resultsmentioning

confidence: 99%

Allele Drop Out Conferred by a Frequent CYP2D6 Genetic Variation For Commonly Used CYP2D6*3 Genotyping Assays

Scantamburlo¹,

Tziolia

Zopf³

et al. 2017

Cell Physiol Biochem

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Background/Aim: Accurate genotyping of CYP2D6 is challenging due to its inherent genetic variation, copy number variation (duplications and deletions) and hybrid formation with highly homologous pseudogenes. Because a relatively high percentage (∼25%) of clinically prescribed drugs are substrates for this enzyme, accurate determination of its genotype for phenotype prediction is essential. Methods: A cohort of 365 patient samples was genotyped for CYP2D6 using Sanger sequencing (as the gold standard), hydrolysis probe assays or pyrosequencing. Results: A discrepant result between the three genotyping methods for the loss of function CYP2D6*3 (g.2549delA, rs35742686) genetic variant was found in one of the samples. This sample also contained the CYP2D6 g.2470T>C (rs17002852) variation, which had an allele frequency of 2.47% in our cohort. Redesign of the CYP2D6*3 pyrosequencing and hydrolysis probe assays to avoid CYP2D6 g.2470 corrected the anomaly. Conclusion: To evidence allele drop out and increase the accuracy of genotyping, intra-patient validation of the same genetic variation with at least two separate methods should be considered.

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Section: Resultsmentioning

confidence: 99%

Allele Drop Out Conferred by a Frequent CYP2D6 Genetic Variation For Commonly Used CYP2D6*3 Genotyping Assays

Scantamburlo¹,

Tziolia

Zopf³

et al. 2017

Cell Physiol Biochem

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“…Tamoxifen, a selective estrogen receptor modulator (SERM), is widely used as an efficient therapeutic option in the treatment and relapse prevention of estrogen receptor-positive breast cancer [12]. Tamoxifen is transformed predominantly by the drug metabolizing enzymes CYP3A4 and CYP2D6 into the therapeutically more efficient drug metabolites 4-hydroxytamoxifen (4-OH-tamoxifen) and endoxifen.…”

Section: Introductionmentioning

confidence: 99%

Impact of variable CYP genotypes on breast cancer relapse in patients undergoing adjuvant tamoxifen therapy

Mwinyi

Vokinger

Jetter

et al. 2014

Cancer Chemother Pharmacol

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BACKGROUND Tamoxifen is frequently used for the treatment of hormone receptor positive breast cancer (BC). Mainly CYP2D6 is responsible for the transformation to therapeutically active metabolites, but CYP2C19, CYP2C9 and CYP2B6 also are involved. We investigated the impact of polymorphisms within the genes encoding these CYP enzymes on the relapse-free time (RFT) in patients with BC. METHODS Ninety-nine patients with hormone receptor positive BC, who had undergone adjuvant tamoxifen therapy, were genotyped for seventeen common variants within the genes encoding CYP2D6, CYP2C9, CYP2C19 and CYP2B6 using TaqMan and PCR-RFLP technology. KaplanMeier and Cox regression analyses were performed to elucidate the impact of genetic variants on RFT. Furthermore, CYP2D6 metabolic activity was determined in a subset of 50 patients by assessing dextromethorphan/dextrorphan urinary excretion ratios. CYP2D6 activity was compared to the CYP2D6 allelic combinations to evaluate the predictive value of the CYP2D6 genotyping results on phenotype. RESULTS Although a trend toward longer RFTs in carriers of CYP2D6 allele combinations encoding for extensive and ultrafast metabolizer phenotypes was observed, none of the investigated genetic variants had a statistically significant impact on RFT. The combined analysis of five major CYP2D6 variants was useful for the discrimination between poor and non-poor metabolizers. CONCLUSIONS Comprehensive CYP2D6 genotyping has a good predictive value for CYP2D6 activity.

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“…Loss of CYP2D6 function was found to reduce the clinical efficacy of tamoxifen treatment 11, although two more recent articles have stimulated debate about the association of the CYP2D6 genotype with the pharmacodynamics of tamoxifen 14, 16. Moreover, the clinical validity of CYP2D6 genotyping is not well established in breast cancer patients who are candidates for tamoxifen treatment 17.…”

Section: Introductionmentioning

confidence: 99%

Influence of CYP2D6 Polymorphisms on Serum Levels of Tamoxifen Metabolites in Spanish Women with Breast Cancer

Zafra-Ceres

Haro²,

Farez-Vidal³

et al. 2013

Int. J. Med. Sci.

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Background Estrogen receptor-positive breast cancer tumors depend on estrogen signaling for their growth and replication and can be treated by anti-estrogen therapy with tamoxifen. Polymorphisms of the CYP2D6 and CYP2C19 genes are associated with an impaired response to tamoxifen. The study objective was to investigate the impact of genetic polymorphisms in CYP2D6 and CYP2C19 on the pharmacokinetics of tamoxifen and its metabolites in Spanish women with estrogen receptor-positive breast cancer who were candidates for tamoxifen therapy.Methods: We studied 90 women with estrogen receptor-positive breast cancer, using the AmpliChip CYP450 test to determine CYP2D6 and CYP2C19 gene variants. Plasma levels of tamoxifen and its metabolites were quantified by high-performance liquid chromatography.Results The CYP2D6 phenotype was extensive metabolizer in 80%, intermediate metabolizer in 12.2%, ultra-rapid metabolizer in 2.2%, and poor metabolizer in 5.6% of patients, and the allele frequency was 35.0% for allele *1, 21.0% for *2, and 18.9% for *4. All poor metabolizers in this series were *4/*4, and their endoxifen and 4-hydroxy tamoxifen levels were 25% lower than those of extensive metabolizers. CYP2C19*2 allele, which has been related to breast cancer outcomes, was detected in 15.6% of the studied alleles.Conclusion CYP2D6*4/*4 genotype was inversely associated with 4-hydroxy tamoxifen and endoxifen levels. According to these results, CYP2D6 and CYP2C19 genotyping appears advisable before the prescription of tamoxifen therapy.

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Laboratory testing of CYP2D6 alleles in relation to tamoxifen therapy

Cited by 38 publications

References 32 publications

Allele Drop Out Conferred by a Frequent CYP2D6 Genetic Variation For Commonly Used CYP2D6*3 Genotyping Assays

Allele Drop Out Conferred by a Frequent CYP2D6 Genetic Variation For Commonly Used CYP2D6*3 Genotyping Assays

Impact of variable CYP genotypes on breast cancer relapse in patients undergoing adjuvant tamoxifen therapy

Influence of CYP2D6 Polymorphisms on Serum Levels of Tamoxifen Metabolites in Spanish Women with Breast Cancer

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