Genotype-Guided Tamoxifen Dosing Increases Active Metabolite Exposure in Women With Reduced CYP2D6 Metabolism: A Multicenter Study

Irvin, William; Walko, Christine M.; Weck, Karen E.; Ibrahim, Joseph G.; Chiu, Wing Keung; Dees, Elizabeth Claire; Moore, Susan; Olajide, Oludamilola; Graham, Mark L.; T., Canale, Sean; Raab, R.; Corso, Steven; Peppercorn, Jeffrey; Anderson, Steven M.; Friedman, Kenneth J.; Ogburn, Evan T.; Desta, Zeruesenay; Flockhart, David A.; McLeod, Howard L.; Evans, James P.; Carey, Lisa A.

doi:10.1200/jco.2010.31.4427

Cited by 165 publications

(142 citation statements)

References 43 publications

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“…It could be additionally demonstrated that a daily dose adjustment from 20 to 40 mg could sufficiently increase the endoxifen concentration in patients with impaired CYP2D6 function. Although this data indirectly support the main hypothesis, there is no strong evidence about the influence of endoxifen levels on the clinical course of breast cancer [30] .…”

Section: Discussioncontrasting

confidence: 71%

“…A recent work of Zafra-Ceres et al [29] studied 90 Spanish women with ER positive breast cancer concluded that the CYP2D6*4/*4 genotype was associated with statistically significant lower 4-OH tamoxifen and endoxifen levels. Irvin et al [30] examined a brighter combination of CYP2D6 alleles and reported similar results. It could be additionally demonstrated that a daily dose adjustment from 20 to 40 mg could sufficiently increase the endoxifen concentration in patients with impaired CYP2D6 function.…”

Section: Discussionmentioning

confidence: 70%

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Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

Markopoulos

Kykalos

Mantas

2014

WJCO

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Biotransformation of tamoxifen to the potent antiestrogen endoxifen is performed by cytochrome P450 (CYP) enzymes, in particular the CYP2D6 isoform. CYP2D6*4 is one of the most frequent alleles associated with loss of enzymatic activity. The incidence of CYP2D6*4 among Caucasians is estimated up to 27%, while it is present in up to 90% of all poor metabolizers within the Caucasian population. The hypothesis under question is whether the presence of one or two non-functioning (null) alleles predicts an inferior outcome in postmenopausal women with breast cancer receiving adjuvant treatment with tamoxifen. The numerous existing studies investigating the association of CYP2D6 with treatment failure in breast cancer are inconsistent and give rather conflicting results. Currently, routine CYP2D6 testing among women with breast cancer is not recommended and the significance of CYP2D6 phenotype in decision making regarding the administration of tamoxifen is unclear. The present study summarizes current literature regarding clinical studies on CYP2D6*4, particularly in terms of response to tamoxifen therapy and breast cancer outcome.© 2014 Baishideng Publishing Group Inc. All rights reserved.Key words: CYP2D6; Tamoxifen; Breast cancer; Adjuvant treatment Core tip: Currently, routine cytochrome P450 (CYP)2D6 testing among women with breast cancer is not recommended and the significance of CYP2D6 phenotype in decision making regarding the administration of tamoxifen is unclear. The present study summarizes current literature regarding clinical studies on CYP2D6*4, particularly in terms of response to tamoxifen therapy and breast cancer outcome.Markopoulos C, Kykalos S, Mantas D. Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen.

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Section: Discussioncontrasting

confidence: 71%

Section: Discussionmentioning

confidence: 70%

Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

Markopoulos

Kykalos

Mantas

2014

WJCO

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“…Blant kaukasere mangler 5 -10 % CYP2D6-funksjon som følge av homozygot nedarving av inaktiverende variantalleler i dette genet. Videre er naermere 40 % heterozygote baerere av genvarianter som medfører nedsatt CYP2D6-funksjon (4,5).…”

Section: Genetisk Variasjonunclassified

Genetisk betinget variasjon i bioaktivering av tamoksifen og klopidogrel

Solhaug¹,

Molden²

2016

Tidsskriftet

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“…15,[20][21][22] Thus, legitimate concerns have been raised over concurrent use of TAM with drugs that inhibit this enzyme or in patients with inherited CYP2D6 deficiency. Like TAM, TOR is readily N-demethylated to produce its major circulating metabolite NDM TOR.…”

mentioning

confidence: 99%

“…19 CYP2D6 is a clinically relevant enzyme for TAM as decreased activity by allelic variation or competitive inhibition (e.g., selective serotonin reuptake inhibitor (SSRI) antidepressants) results in lower conversion of TAM to its active metabolites. 15,[20][21][22] Thus, legitimate concerns have been raised over concurrent use of TAM with drugs that inhibit this enzyme or in patients with inherited CYP2D6 deficiency. Like TAM, TOR is readily N-demethylated to produce its major circulating metabolite NDM TOR.…”

mentioning

confidence: 99%

Role and pharmacologic significance of cytochrome P‐450 2D6 in oxidative metabolism of toremifene and tamoxifen

Kim

Coss

Barrett

et al. 2012

Intl Journal of Cancer

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We investigated the in vitro metabolism and estrogenic and antiestrogenic activity of toremifene (TOR), tamoxifen (TAM) and their metabolites to better understand the potential effects of cytochrome P-450 2D6 (CYP2D6) status on the activity of these drugs in women with breast cancer. The plasma concentrations of TOR and its N-desmethyl (NDM) and 4-hydroxy (4-OH) metabolites during steady-state dosing with TOR were also determined. Unlike TOR, TAM and its NDM metabolite were extensively oxidized to 4-OH TAM and 4-OH-NDM TAM by CYP2D6, and the rate of metabolism was affected by CYP2D6 status. 4-OH-NDM TOR concentrations were not measurable at steady state in plasma of subjects taking 80 mg of TOR. Molecular modeling provided insight into the lack of 4-hydroxylation of TOR by CYP2D6. The 4-OH and 4-OH-NDM metabolites of TOR and TAM bound to estrogen receptor (ER) subtypes with fourfold to 30-fold greater affinity were 35-to 187-fold more efficient at antagonizing ER transactivation and had antiestrogenic potency that was up to 360-fold greater than their parent drugs. Our findings suggest that variations in CYP2D6 metabolic capacity may cause significant differences in plasma concentrations of active TAM metabolites (i.e., 4-OH TAM and 4-OH-NDM TAM) and contribute to variable pharmacologic activity. Unlike TAM, the clinical benefits in subjects taking TOR to treat metastatic breast cancer would not likely be subject to allelic variation in CYP2D6 status or affected by coadministration of CYP2D6-inhibiting medications.Tamoxifen (TAM) is the most widely used hormone therapy for breast cancer. Toremifene (TOR), a chlorinated derivative of TAM, is also an approved treatment for metastatic breast cancer in postmenopausal women.1,2 Although TAM is the prototypical drug in the selective estrogen receptor modulator (SERM) class, its clinical efficacy and safety are known to vary widely among individuals.3 TOR is equally effective in breast cancer treatment.4-7 However, TOR may have reduced genotoxicity and lower potential to induce secondary endometrial cancers 8,9 and may therefore be considered as an alternative to TAM as firstline therapy for patients with ER-positive advanced breast cancer.TAM is extensively metabolized. The clinical benefit of TAM is thought to arise from its conversion to active metabolites, chiefly 4-hydroxy TAM (4-OH TAM) and 4-OH-N-desmethyl TAM (4-OH-NDM TAM, otherwise known as endoxifen; Fig. 1). [10][11][12] These metabolites bind to the ER with up to 30-fold greater affinity than TAM, and this increased potency for binding translates into enhanced antiestrogen activity. 13-16Whether these metabolites are responsible for TAM's variable clinical efficacy is a topic of considerable controversy. TAM is known to be metabolized extensively by the cytochrome P450 (CYP) enzyme system, primarily by the CYP3A4 and 2D6 isoforms. 17 CYP3A4 generates the major circulating metabolite mono-NDM TAM 18; however, the formation of the active TAM metabolites apparently requires cytochrome P-450 2D6 (CYP2D6).19 CY...

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Genotype-Guided Tamoxifen Dosing Increases Active Metabolite Exposure in Women With Reduced CYP2D6 Metabolism: A Multicenter Study

Abstract: This study demonstrates the feasibility of genotype-driven tamoxifen dosing and demonstrates that doubling the tamoxifen dose can increase endoxifen concentrations in IM and PM patients.

Cited by 165 publications

References 43 publications

Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

Genetisk betinget variasjon i bioaktivering av tamoksifen og klopidogrel

Role and pharmacologic significance of cytochrome P‐450 2D6 in oxidative metabolism of toremifene and tamoxifen

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