Factors Affecting Tamoxifen Metabolism in Patients With Breast Cancer: Preliminary Results of the French PHACS Study

Puszkiel, Alicja; Arellano, Cécile; Vachoux, Christelle; Evrard, Alexandre; Morvan, Valérie Le; Boyer, Jean-Christophe; Robert, Jacques; Delmas, Caroline; Debled, Marc; Vénat-Bouvet, Laurence; Jacot, William; Suc, Etienne; Sillet-Bach, I.; Filleron, Thomas; Roché, Henri; Chatelut, Étienne; White-Koning, Mélanie; Thomas, Fabienne

doi:10.1002/cpt.1404

Cited by 17 publications

(21 citation statements)

References 30 publications

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“…Both in the present study and in earlier reports 17,21,26 patients with higher concentrations of endoxifen were predominantly carriers of CYP2D6*1. However, a considerable variability among CYP2D6*1 carriers was evident ( Figure 1) and, in analogy with earlier observations, 17,21,26 some patients genotyped as extensive metabolizers were associated with low plasma levels of endoxifen.…”

Section: Discussionsupporting

confidence: 83%

Impairment of endoxifen formation in tamoxifen‐treated premenopausal breast cancer patients carrying reduced‐function CYP2D6 alleles

Thorén

Lindh

Ackehed

et al. 2020

Brit J Clinical Pharma

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Aims: Tamoxifen is bioactivated to endoxifen by polymorphic CYP2D6-dependent metabolism. Here, endoxifen levels were compared to CYP2D6 diplotypes, tentative target concentrations and side effects. Methods: In total, 118 Swedish premenopausal breast cancer patients diagnosed 2006-2014, with ongoing postoperative tamoxifen treatment January 2017, were included. Biobanked DNA from peripheral blood was used for CYP2D6 genotyping by TaqMan real-time polymerase chain reaction (CYP2D6*1, *3, *4, *5, *6, *9, *10, *41, *1xN). Plasma levels of tamoxifen and 3 major metabolites were quantified by liquid chromatography-tandem mass spectrometry. Clinical information on treatment and side effects was retrospectively obtained from medical records. Results: In the final analysis of 114 patients, a clear relationship between CYP2D6 genotype and plasma endoxifen levels was evident. Low endoxifen (1.6-5.2 ng/mL), i.e. below the suggested threshold for clinical efficacy, was found in all patients with 2 reduced-function alleles, 2 null-alleles, or a null/reduced-function combination. CYP2D6*41 was the most common reduced-function allele (82%) and 17 of 21 CYP2D6*41-carriers exhibited a lower CYP2D6 activity than predicted from published guidelines. No difference in endoxifen levels was observed between carriers of 2 null-alleles vs patients homozygous for CYP2D6*41 or the corresponding heterozygous combination (P = .338). In patients with endoxifen levels <5.9 ng/mL (36/114), side effects were either mild or absent. At higher endoxifen levels moderateto-severe side effects were reported in a concentration-dependent manner. Conclusion: Significantly reduced endoxifen levels were observed not only in all homozygous carriers of CYP2D6 null-alleles, but also in carriers of 2 reduced-function alleles. This finding may be highly relevant for future, genotype-based dose considerations.

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Section: Discussionsupporting

confidence: 83%

Impairment of endoxifen formation in tamoxifen‐treated premenopausal breast cancer patients carrying reduced‐function CYP2D6 alleles

Thorén

Lindh

Ackehed

et al. 2020

Brit J Clinical Pharma

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“…Although CYP2D6 is involved in various tamoxifen metabolic pathways, it is the sole enzyme responsible for the formation of endoxifen from NDM [1]. Previous studies have consistently demonstrated a significant gene-dose effect of CYP2D6 polymorphism for tamoxifen metabolism [3,6,7,8]. Our study also showed an increase in endoxifen concentration and MR E /NDM with increase in CYP2D6 activity score, indicating a gene-dose effect of endoxifen formation.…”

Section: Discussionsupporting

confidence: 71%

“…The bioactivation of tamoxifen involves several CYP450 drug metabolizing enzymes (DMEs) including, CYP2D6, CYP3A4, CYP3A5, CYP2C9, and CYP2C19 , with key roles for CYP2D6 and CYP3A [5]. The wide interindividual variability in the concentration of tamoxifen and its metabolites was mainly attributed to genetic polymorphism in CYP2D6 [3,6,7,8]. Previous studies showed that patients with low CYP2D6 enzyme activity or taking medication which inhibit CYP2D6 activity were associated with lower endoxifen concentration [7,9].…”

Section: Introductionmentioning

confidence: 99%

“…The link between patients’ CYP2D6 genotype and plasma levels of tamoxifen and its metabolites has been established in population of European and Asian descent [10,11,12], but not in sub-Saharan populations. Studies also showed that CYP2D6 explains about 39–58% of the interpatient variability in endoxifen concentration [8] and residual variability is largely unexplained [7,12]. The extent to which CYP2D6 determines the wide interpatient variability of endoxifen under standard tamoxifen treatment is not well characterized in black African populations.…”

Section: Introductionmentioning

confidence: 99%

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CYP2D6 Genotype Predicts Plasma Concentrations of Tamoxifen Metabolites in Ethiopian Breast Cancer Patients

Ahmed

Makonnen

Fotoohi

et al. 2019

Cancers

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Tamoxifen displays wide inter-individual variability (IIV) in its pharmacokinetics and treatment outcome. Data on tamoxifen pharmacokinetics and pharmacogenetics from black African breast cancer patient populations is lacking. We investigated the pharmacokinetic and pharmacogenetic profile of tamoxifen and its major active metabolite, endoxifen, in Ethiopian breast cancer patients. A total of 81 female breast cancer patients on adjuvant tamoxifen therapy were enrolled. Tamoxifen (Tam) and its major metabolites, N-desmethyltamoxifen (NDM), 4-hydroxy-tamoxifen (4-HT), and (Z)-endoxifen (E) were quantified using LC-MS/MS. Genotyping for CYP2D6, CYP2C9, CYP2C19, CYP3A5, POR, and ABCB1 and UGT2B15 and copy number variation for CYP2D6 were done. The proportion of patients with low endoxifen level (<5.9 ng/mL) was 35.8% (median concentration 7.94 ng/mL). The allele frequency of CYP2D6 gene deletion (*5) and duplication (*1×N or *2×N) was 4.3% and 14.8%, respectively. Twenty-six percent of the patients carried duplicated or multiplicated CYP2D6 gene. An increase in CYP2D6 activity score was associated with increased endoxifen concentration and MRE/NDM (p < 0.001). The IIV in endoxifen concentration and MRE/NDM was 74.6% and 59%, respectively. CYP2D6 diplotype explained 28.2% and 44% of the variability in absolute endoxifen concentration and MRE/NDM, respectively. The explanatory power of CYP2D6 diplotype was improved among ABCB1c.4036G carriers (43% and 65.2%, respectively for endoxifen concentration and MRE/NDM) compared to A/A genotype. CYP2C9, CYP2C19, and CYP3A5 genotypes had no significant influence on endoxifen concentration or MRE/NDM. In conclusion, we report a high rate of low endoxifen level as well as large IIV in tamoxifen and its metabolite concentrations. CYP2D6 is significant predictor of plasma endoxifen level in a gene-dose dependent manner.

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“…[7][8][9] CYP2D6 is especially important for endoxifen formation and patients with impaired or no CYP2D6 activity have shown an increased risk for subtarget C SS,min ENDX . [8][9][10][11] Regarding a putative therapeutic threshold concentration, Madlensky et al reported that patients with C SS,min ENDX < 5.97 ng/mL had a 26% higher breast cancer recurrence rate compared with patients with C SS,min ENDX above this threshold (recurrence rates 16% vs. 10.1-14.7%). 9 This difference is similar to the reported 30% relative reduction in breast cancer recurrence rates, when postmenopausal patients receive aromatase inhibitors instead of tamoxifen.…”

Section: How Might This Change Clinical Pharma-cology or Translationamentioning

confidence: 99%

Obesity Alters Endoxifen Plasma Levels in Young Breast Cancer Patients: A Pharmacometric Simulation Approach

Mueller‐Schoell

Klopp-Schulze

Schroth

et al. 2020

Clin Pharma and Therapeutics

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Endoxifen is one of the most important metabolites of the prodrug tamoxifen. High interindividual variability in endoxifen steady‐state concentrations (CSS,min ENDX) is observed under tamoxifen standard dosing and patients with breast cancer who do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at a 26% higher recurrence risk compared with patients with endoxifen concentrations exceeding this value. In this investigation, 10 clinical tamoxifen studies were pooled (1,388 patients) to investigate influential factors on CSS,min ENDX using nonlinear mixed‐effects modeling. Age and body weight were found to significantly impact CSS,min ENDX in addition to CYP2D6 phenotype. Compared with postmenopausal patients, premenopausal patients had a 30% higher risk for subtarget CSS,min ENDX at tamoxifen 20 mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1–13.8‐fold higher risk for subtarget CSS,min ENDX compared with elderly low‐weight patients. Considering ever‐rising obesity rates and the clinical importance of tamoxifen for premenopausal patients, this subpopulation may benefit most from individualized tamoxifen dosing.

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Factors Affecting Tamoxifen Metabolism in Patients With Breast Cancer: Preliminary Results of the French PHACS Study

Cited by 17 publications

References 30 publications

Impairment of endoxifen formation in tamoxifen‐treated premenopausal breast cancer patients carrying reduced‐function CYP2D6 alleles

Impairment of endoxifen formation in tamoxifen‐treated premenopausal breast cancer patients carrying reduced‐function CYP2D6 alleles

CYP2D6 Genotype Predicts Plasma Concentrations of Tamoxifen Metabolites in Ethiopian Breast Cancer Patients

Obesity Alters Endoxifen Plasma Levels in Young Breast Cancer Patients: A Pharmacometric Simulation Approach

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