CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment

Yan Jin, Zeruesenay Desta, Vered Stearns, Bryan Ward, Herbert Ho, Kyung Hoon Lee, Todd Skaar, Anna Maria Storniolo, Lang Li, Adjei Araba, Rebecca Blanchard, Anne Nguyen, Lynda Ullmer, Jill Hayden, Suzanne Lemler, Richard M. Weinshilboum, James M. Rae, Daniel F. Hayes, David A. Flockhart

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Abstract

Background: The efficacy of tamoxifen therapy for the treatment of breast cancer varies widely among individuals. Plasma concentrations of the active tamoxifen metabolite endoxifen are associated with the cytochrome P450 (CYP) 2D6 genotype. We examined the effects of concomitant use of selective serotonin reuptake inhibitor antidepressants, which are CYP2D6 enzyme inhibitors commonly prescribed to treat hot flashes in women who take tamoxifen, and genotypes for genes that encode tamoxifen-metabolizing enzymes on plasma concentrations of tamoxifen and its metabolites. Methods: Eighty patients with newly diagnosed with breast cancer who were beginning tamoxifen therapy (20 mg/day orally), 24 of whom were taking CYP2D6 inhibitors, were genotyped for common alleles of the CYP2D6, CYP2C9, CYP3A5, and sulfotransferase (SULT) 1A1 genes. Plasma concentrations of tamoxifen and its metabolites were measured after 1 and 4 months of tamoxifen therapy. Differences in plasma concentrations of tamoxifen and its metabolites between genotype groups were analyzed by the Wilcoxon rank sum test All statistical tests were two-sided. Results: Among all women, plasma endoxifen concentrations after 4 months of tamoxifen therapy were statistically significantly lower in subjects with a CYP2D6 homozygous variant genotype (20.0 nM, 95% confidence interval [CI] = 11.1 to 28.9 nM) or a heterozygous genotype (43.1 nM, 95% CI = 33.3 to 52.9 nM) than in those with a homozygous wild-type genotype (78.0 nM, 95%CI = 65.9 to 90.1 nM) (both P = .003). Among subjects who carried a homozygous wild-type genotype, the mean plasma endoxifen concentration for those who were using CYP2D6 inhibitors was 58% lower than that for those who were not (38.6 nM versus 91.4 nM, difference = -52.8 nM, 95% CI = -86.1 to -19.5 nM, P =.0025). The plasma endoxifen concentration was slightly reduced in women taking venlafaxine, a weak inhibitor of CYP2D6, whereas the plasma endoxifen concentration was reduced substantially in subjects who took paroxetine (a potent inhibitor of CYP2D6). Genetic variations of CYP2C9, CYP3A5, or SULT1A1 had no statistically significant associations with plasma concentrations of tamoxifen or its metabolites. Conclusion: Interactions between CYP2D6 polymorphisms; and coadministered antidepressants and other drugs that are CYP2136 inhibitors may be associated with altered tamoxifen activity.

Original languageEnglish (US)
Pages (from-to)30-39
Number of pages10
JournalJournal of the National Cancer Institute
Volume97
Issue number1
DOIs
StatePublished - Jan 5 2005

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Cytochrome P-450 CYP2D6
Tamoxifen
Antidepressive Agents
Genotype
Breast Neoplasms
Therapeutics
Confidence Intervals
Cytochrome P-450 CYP3A
Nonparametric Statistics
Hot Flashes
Sulfotransferases
Paroxetine
Serotonin Uptake Inhibitors
Enzyme Inhibitors
Genes
Alleles

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. / Jin, Yan; Desta, Zeruesenay; Stearns, Vered; Ward, Bryan; Ho, Herbert; Lee, Kyung Hoon; Skaar, Todd; Storniolo, Anna Maria; Li, Lang; Araba, Adjei; Blanchard, Rebecca; Nguyen, Anne; Ullmer, Lynda; Hayden, Jill; Lemler, Suzanne; Weinshilboum, Richard M.; Rae, James M.; Hayes, Daniel F.; Flockhart, David A.

In: Journal of the National Cancer Institute, Vol. 97, No. 1, 05.01.2005, p. 30-39.

Research output: Contribution to journalArticle

Jin, Y, Desta, Z, Stearns, V, Ward, B, Ho, H, Lee, KH, Skaar, T, Storniolo, AM, Li, L, Araba, A, Blanchard, R, Nguyen, A, Ullmer, L, Hayden, J, Lemler, S, Weinshilboum, RM, Rae, JM, Hayes, DF & Flockhart, DA 2005, 'CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment', Journal of the National Cancer Institute, vol. 97, no. 1, pp. 30-39. https://doi.org/10.1093/jnci/dji005
Jin, Yan ; Desta, Zeruesenay ; Stearns, Vered ; Ward, Bryan ; Ho, Herbert ; Lee, Kyung Hoon ; Skaar, Todd ; Storniolo, Anna Maria ; Li, Lang ; Araba, Adjei ; Blanchard, Rebecca ; Nguyen, Anne ; Ullmer, Lynda ; Hayden, Jill ; Lemler, Suzanne ; Weinshilboum, Richard M. ; Rae, James M. ; Hayes, Daniel F. ; Flockhart, David A. / CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. In: Journal of the National Cancer Institute. 2005 ; Vol. 97, No. 1. pp. 30-39.
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abstract = "Background: The efficacy of tamoxifen therapy for the treatment of breast cancer varies widely among individuals. Plasma concentrations of the active tamoxifen metabolite endoxifen are associated with the cytochrome P450 (CYP) 2D6 genotype. We examined the effects of concomitant use of selective serotonin reuptake inhibitor antidepressants, which are CYP2D6 enzyme inhibitors commonly prescribed to treat hot flashes in women who take tamoxifen, and genotypes for genes that encode tamoxifen-metabolizing enzymes on plasma concentrations of tamoxifen and its metabolites. Methods: Eighty patients with newly diagnosed with breast cancer who were beginning tamoxifen therapy (20 mg/day orally), 24 of whom were taking CYP2D6 inhibitors, were genotyped for common alleles of the CYP2D6, CYP2C9, CYP3A5, and sulfotransferase (SULT) 1A1 genes. Plasma concentrations of tamoxifen and its metabolites were measured after 1 and 4 months of tamoxifen therapy. Differences in plasma concentrations of tamoxifen and its metabolites between genotype groups were analyzed by the Wilcoxon rank sum test All statistical tests were two-sided. Results: Among all women, plasma endoxifen concentrations after 4 months of tamoxifen therapy were statistically significantly lower in subjects with a CYP2D6 homozygous variant genotype (20.0 nM, 95{\%} confidence interval [CI] = 11.1 to 28.9 nM) or a heterozygous genotype (43.1 nM, 95{\%} CI = 33.3 to 52.9 nM) than in those with a homozygous wild-type genotype (78.0 nM, 95{\%}CI = 65.9 to 90.1 nM) (both P = .003). Among subjects who carried a homozygous wild-type genotype, the mean plasma endoxifen concentration for those who were using CYP2D6 inhibitors was 58{\%} lower than that for those who were not (38.6 nM versus 91.4 nM, difference = -52.8 nM, 95{\%} CI = -86.1 to -19.5 nM, P =.0025). The plasma endoxifen concentration was slightly reduced in women taking venlafaxine, a weak inhibitor of CYP2D6, whereas the plasma endoxifen concentration was reduced substantially in subjects who took paroxetine (a potent inhibitor of CYP2D6). Genetic variations of CYP2C9, CYP3A5, or SULT1A1 had no statistically significant associations with plasma concentrations of tamoxifen or its metabolites. Conclusion: Interactions between CYP2D6 polymorphisms; and coadministered antidepressants and other drugs that are CYP2136 inhibitors may be associated with altered tamoxifen activity.",
author = "Yan Jin and Zeruesenay Desta and Vered Stearns and Bryan Ward and Herbert Ho and Lee, {Kyung Hoon} and Todd Skaar and Storniolo, {Anna Maria} and Lang Li and Adjei Araba and Rebecca Blanchard and Anne Nguyen and Lynda Ullmer and Jill Hayden and Suzanne Lemler and Weinshilboum, {Richard M.} and Rae, {James M.} and Hayes, {Daniel F.} and Flockhart, {David A.}",
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T1 - CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment

AU - Jin, Yan

AU - Desta, Zeruesenay

AU - Stearns, Vered

AU - Ward, Bryan

AU - Ho, Herbert

AU - Lee, Kyung Hoon

AU - Skaar, Todd

AU - Storniolo, Anna Maria

AU - Li, Lang

AU - Araba, Adjei

AU - Blanchard, Rebecca

AU - Nguyen, Anne

AU - Ullmer, Lynda

AU - Hayden, Jill

AU - Lemler, Suzanne

AU - Weinshilboum, Richard M.

AU - Rae, James M.

AU - Hayes, Daniel F.

AU - Flockhart, David A.

PY - 2005/1/5

Y1 - 2005/1/5

N2 - Background: The efficacy of tamoxifen therapy for the treatment of breast cancer varies widely among individuals. Plasma concentrations of the active tamoxifen metabolite endoxifen are associated with the cytochrome P450 (CYP) 2D6 genotype. We examined the effects of concomitant use of selective serotonin reuptake inhibitor antidepressants, which are CYP2D6 enzyme inhibitors commonly prescribed to treat hot flashes in women who take tamoxifen, and genotypes for genes that encode tamoxifen-metabolizing enzymes on plasma concentrations of tamoxifen and its metabolites. Methods: Eighty patients with newly diagnosed with breast cancer who were beginning tamoxifen therapy (20 mg/day orally), 24 of whom were taking CYP2D6 inhibitors, were genotyped for common alleles of the CYP2D6, CYP2C9, CYP3A5, and sulfotransferase (SULT) 1A1 genes. Plasma concentrations of tamoxifen and its metabolites were measured after 1 and 4 months of tamoxifen therapy. Differences in plasma concentrations of tamoxifen and its metabolites between genotype groups were analyzed by the Wilcoxon rank sum test All statistical tests were two-sided. Results: Among all women, plasma endoxifen concentrations after 4 months of tamoxifen therapy were statistically significantly lower in subjects with a CYP2D6 homozygous variant genotype (20.0 nM, 95% confidence interval [CI] = 11.1 to 28.9 nM) or a heterozygous genotype (43.1 nM, 95% CI = 33.3 to 52.9 nM) than in those with a homozygous wild-type genotype (78.0 nM, 95%CI = 65.9 to 90.1 nM) (both P = .003). Among subjects who carried a homozygous wild-type genotype, the mean plasma endoxifen concentration for those who were using CYP2D6 inhibitors was 58% lower than that for those who were not (38.6 nM versus 91.4 nM, difference = -52.8 nM, 95% CI = -86.1 to -19.5 nM, P =.0025). The plasma endoxifen concentration was slightly reduced in women taking venlafaxine, a weak inhibitor of CYP2D6, whereas the plasma endoxifen concentration was reduced substantially in subjects who took paroxetine (a potent inhibitor of CYP2D6). Genetic variations of CYP2C9, CYP3A5, or SULT1A1 had no statistically significant associations with plasma concentrations of tamoxifen or its metabolites. Conclusion: Interactions between CYP2D6 polymorphisms; and coadministered antidepressants and other drugs that are CYP2136 inhibitors may be associated with altered tamoxifen activity.

AB - Background: The efficacy of tamoxifen therapy for the treatment of breast cancer varies widely among individuals. Plasma concentrations of the active tamoxifen metabolite endoxifen are associated with the cytochrome P450 (CYP) 2D6 genotype. We examined the effects of concomitant use of selective serotonin reuptake inhibitor antidepressants, which are CYP2D6 enzyme inhibitors commonly prescribed to treat hot flashes in women who take tamoxifen, and genotypes for genes that encode tamoxifen-metabolizing enzymes on plasma concentrations of tamoxifen and its metabolites. Methods: Eighty patients with newly diagnosed with breast cancer who were beginning tamoxifen therapy (20 mg/day orally), 24 of whom were taking CYP2D6 inhibitors, were genotyped for common alleles of the CYP2D6, CYP2C9, CYP3A5, and sulfotransferase (SULT) 1A1 genes. Plasma concentrations of tamoxifen and its metabolites were measured after 1 and 4 months of tamoxifen therapy. Differences in plasma concentrations of tamoxifen and its metabolites between genotype groups were analyzed by the Wilcoxon rank sum test All statistical tests were two-sided. Results: Among all women, plasma endoxifen concentrations after 4 months of tamoxifen therapy were statistically significantly lower in subjects with a CYP2D6 homozygous variant genotype (20.0 nM, 95% confidence interval [CI] = 11.1 to 28.9 nM) or a heterozygous genotype (43.1 nM, 95% CI = 33.3 to 52.9 nM) than in those with a homozygous wild-type genotype (78.0 nM, 95%CI = 65.9 to 90.1 nM) (both P = .003). Among subjects who carried a homozygous wild-type genotype, the mean plasma endoxifen concentration for those who were using CYP2D6 inhibitors was 58% lower than that for those who were not (38.6 nM versus 91.4 nM, difference = -52.8 nM, 95% CI = -86.1 to -19.5 nM, P =.0025). The plasma endoxifen concentration was slightly reduced in women taking venlafaxine, a weak inhibitor of CYP2D6, whereas the plasma endoxifen concentration was reduced substantially in subjects who took paroxetine (a potent inhibitor of CYP2D6). Genetic variations of CYP2C9, CYP3A5, or SULT1A1 had no statistically significant associations with plasma concentrations of tamoxifen or its metabolites. Conclusion: Interactions between CYP2D6 polymorphisms; and coadministered antidepressants and other drugs that are CYP2136 inhibitors may be associated with altered tamoxifen activity.

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