Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: Implication for optimization of breast cancer treatment

Borges, Stephanie Carvalho; Desta, Zeruesenay; Li, Lang; Skaar, Todd C.; Ward, Bryan A.; Nguyen, Anne; Jin, Yan; Storniolo, Anna Maria; Nikoloff, D. Michele; Wu, Lin; Hillman, Grant; Hayes, Daniel F.; Stearns, Vered; Flockhart, David A.

doi:10.1016/j.clpt.2006.03.013

Cited by 434 publications

(418 citation statements)

References 29 publications

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“…The blood concentrations of tamoxifen's most potent and abundant metabolite, endoxifen, have been shown to correlate significantly with the CYP2D6 phenotype. 21,29 Furthermore, Goetz et al 22 reported that patients with impaired CYP2D6 metabolism have nearly a twofold higher risk of BC recurrence when treated with tamoxifen in the adjuvant setting. Moreover, the subjects' phenotype appeared to result from the combination of the genotype and drugs (or nutrients) that may interact with CYP450, in particular antidepressants and CYP2D6, as reported by Goetz et al, 31 with a fourfold increase of BC relapse in PM subjects.…”

Section: Discussionmentioning

confidence: 99%

“…Genotypically, PM patients or patients receiving CYP2D6-inhibiting drugs have reduced plasma concentrations of endoxifen. 14,15,21 At the clinical level, PM subjects with BC on adjuvant tamoxifen tend to have a higher risk of relapse. 22,23 This worse clinical outcome has been associated with a decreased prevalence of hot flashes, a putative marker of tamoxifen activity.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

et al. 2010

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The role of pharmacogenomics and tamoxifen was investigated by analyzing several polymorphisms of cytochrome P450 and SULT1A1 gene in a nested case control study from the Italian Tamoxifen Prevention Trial. This study included 182 Caucasian subjects, 47 breast cancer (BC) cases and 135 matched controls. We used the AmpliChip CYP450 Test to screen 33 alleles of CYP2D6 and 3 of CYP2C19. One more variant for CYP2C19*17 and two single-nucleotide polymorphisms for the gene SULT1A1 were also performed. By using the AmpliChip CYP450 Test, out of 182 subjects, we identified 8 poor metabolizer (PM), 17 intermediate metabolizer (IM), 151 extensive metabolizer (EM) and 3 ultrarapid metabolizer (UM). PM women allocated to the tamoxifen arm showed a higher risk of developing BC compared to the remaining phenotypes (P ¼ 0.035). In an exploratory analysis, among 58 women with a CYP2D6*2A allele, 9 BCs were diagnosed in the placebo arm and only 1 in the tamoxifen arm (P ¼ 0.0001). CYP2C19 and SULT1A1 polymorphisms did not show any correlation with tamoxifen efficacy. Tamoxifen showed reduced efficacy in CYP2D6 PMs in the chemoprevention setting. Conversely, the CYP2D6*2A allele may be associated with increased efficacy of tamoxifen. These findings support the relevance of pharmacogenomics in tailoring tamoxifen treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

et al. 2010

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“…For that drugegene pair, multiple studies have demonstrated that patients with poor metabolizer genotypes are more likely to have worse outcomes. This is due to suboptimal conversion (primarily via CYP2D6) of tamoxifen into the more potent, active antiestrogenic metabolites, endoxifen and 4-hydroxytamoxifen (Higgins and Stearns, 2010), a relationship which is supported by pharmacokinetic data showing that patients with these genotypes have lower levels of endoxifen (Borges et al, 2006). In one study, 206 tamoxifen-treated patients receiving the drug in the adjuvant setting were compared based upon genotype groups (Schroth et al, 2007) for disease-related outcomes.…”

Section: Fcgriia Fcgriiiamentioning

confidence: 99%

Germline pharmacogenomics in oncology: Decoding the patient for targeting therapy

O’Donnell

Ratain

2012

Molecular Oncology

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A B S T R A C TPharmacogenomics is the study of genetic factors determining drug response or toxicity.The use of pharmacogenomics is especially desirable in oncology because the therapeutic index of oncology drugs is often narrow, the need for favorable drug response is often acute, and the consequences of drug toxicity can be life-threatening. In this review, we examine the state of pharmacogenomics in oncology, focusing only on germline pharmacogenomic variants. We consider several critical points when assessing the quality of pharmacogenomic findings and their relevance to clinical use, and discuss potential confounding factors limiting interpretation and implementation. Several of the most extensively studied drugegene pairs (irinotecan and UGT1A1; tamoxifen and CYP2D6; 5-fluorouracil and DPYD) are inspected in depth as illustrations of both the state of advancementdand the current limitations ofdpresent knowledge. We argue that there will likely soon be a critical mass of important germline pharmacogenomic biomarkers in oncology which deserve clinical implementation to provide optimal, personalized oncologic care.We conclude with a vision of how routine clinical testing of such germline markers could one day change the paradigm for cancer care.

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“…These metabolites compete with estrogen for the ligand-binding domain (LBD) of the ER, blocking the potential for estrogen stimulation and preventing conformational changes in the receptor critical for the association of cofactors and the transcription of estrogen-responsive genes [43]. Variations in this isoform, whether genetic (e.g., wild-type variant CYP2D61*) or as a result of inhibition by selective serotonin reuptake inhibitors (e.g., fluoxetine and paroxetine) [44], may alter the metabolism of tamoxifen, blunting its antiestrogenic activity [45].…”

Section: Endocrine Resistance In Breast Cancermentioning

confidence: 99%

Interactions between the estrogen receptor, its cofactors and microRNAs in breast cancer

McCafferty

McNeill

Miller

et al. 2009

Breast Cancer Res Treat

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Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: Implication for optimization of breast cancer treatment

Abstract: CYP2D6 genotype and concomitant potent CYP2D6 inhibitors are highly associated with endoxifen plasma concentration and may have an impact on the response to tamoxifen therapy. These iterative approaches may be valuable in the study of other complex genotype-phenotype relationships.

Cited by 434 publications

References 29 publications

Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

Germline pharmacogenomics in oncology: Decoding the patient for targeting therapy

Interactions between the estrogen receptor, its cofactors and microRNAs in breast cancer

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