Comprehensive assessment of cytochromes P450 and transporter genetics with endoxifen concentration during tamoxifen treatment

Lauren A. Marcath, Allison M. Deal, Emily Van Wieren, William Danko, Christine M. Walko, Joseph G. Ibrahim, Karen E. Weck, David R. Jones, Zeruesenay Desta, Howard L. McLeod, Lisa A. Carey, William J. Irvin, Daniel L. Hertz

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Objectives Tamoxifen bioactivation to endoxifen is mediated primarily by CYP2D6; however, considerable variability remains unexplained. Our aim was to perform a comprehensive assessment of the effect of genetic variation in tamoxifen-relevant enzymes and transporters on steady-state endoxifen concentrations. Patients and methods Comprehensive genotyping of CYP enzymes and transporters was performed using the iPLEX ADME PGx Pro Panel in 302 tamoxifen-treated breast cancer patients. Predicted activity phenotype for 19 enzymes and transporters were analyzed for univariate association with endoxifen concentration, and then adjusted for CYP2D6 and clinical covariates. Results In univariate analysis, higher activity of CYP2C8 (regression β=0.22, P=0.020) and CYP2C9 (β=0.20, P=0.04), lower body weight (β=-0.014, P<0.0001), and endoxifen measurement during winter (each β< -0.39, P=0.002) were associated with higher endoxifen concentrations. After adjustment for the CYP2D6 diplotype, weight, and season, CYP2C9 remained significantly associated with higher concentrations (P=0.02), but only increased the overall model R2 by 1.3%. Conclusion Our results further support a minor contribution of CYP2C9 genetic variability toward steadystate endoxifen concentrations. Integration of clinician and genetic variables into individualized tamoxifen dosing algorithms would marginally improve their accuracy and potentially enhance tamoxifen treatment outcomes.

Original languageEnglish (US)
Pages (from-to)402-409
Number of pages8
JournalPharmacogenetics and Genomics
Volume27
Issue number11
DOIs
StatePublished - 2017

Fingerprint

Tamoxifen
Cytochrome P-450 Enzyme System
Cytochrome P-450 CYP2D6
Enzymes
Therapeutics
4-hydroxy-N-desmethyltamoxifen
Body Weight
Breast Neoplasms
Phenotype
Weights and Measures
Cytochrome P-450 CYP2C9

Keywords

  • CYP2C9
  • CYP2D6
  • Endoxifen
  • Pharmacogenomics
  • Season
  • Tamoxifen

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Marcath, L. A., Deal, A. M., Van Wieren, E., Danko, W., Walko, C. M., Ibrahim, J. G., ... Hertz, D. L. (2017). Comprehensive assessment of cytochromes P450 and transporter genetics with endoxifen concentration during tamoxifen treatment. Pharmacogenetics and Genomics, 27(11), 402-409. https://doi.org/10.1097/FPC.0000000000000311

Comprehensive assessment of cytochromes P450 and transporter genetics with endoxifen concentration during tamoxifen treatment. / Marcath, Lauren A.; Deal, Allison M.; Van Wieren, Emily; Danko, William; Walko, Christine M.; Ibrahim, Joseph G.; Weck, Karen E.; Jones, David R.; Desta, Zeruesenay; McLeod, Howard L.; Carey, Lisa A.; Irvin, William J.; Hertz, Daniel L.

In: Pharmacogenetics and Genomics, Vol. 27, No. 11, 2017, p. 402-409.

Research output: Contribution to journalArticle

Marcath, LA, Deal, AM, Van Wieren, E, Danko, W, Walko, CM, Ibrahim, JG, Weck, KE, Jones, DR, Desta, Z, McLeod, HL, Carey, LA, Irvin, WJ & Hertz, DL 2017, 'Comprehensive assessment of cytochromes P450 and transporter genetics with endoxifen concentration during tamoxifen treatment', Pharmacogenetics and Genomics, vol. 27, no. 11, pp. 402-409. https://doi.org/10.1097/FPC.0000000000000311
Marcath, Lauren A. ; Deal, Allison M. ; Van Wieren, Emily ; Danko, William ; Walko, Christine M. ; Ibrahim, Joseph G. ; Weck, Karen E. ; Jones, David R. ; Desta, Zeruesenay ; McLeod, Howard L. ; Carey, Lisa A. ; Irvin, William J. ; Hertz, Daniel L. / Comprehensive assessment of cytochromes P450 and transporter genetics with endoxifen concentration during tamoxifen treatment. In: Pharmacogenetics and Genomics. 2017 ; Vol. 27, No. 11. pp. 402-409.
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AU - Walko, Christine M.

AU - Ibrahim, Joseph G.

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AU - Jones, David R.

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N2 - Objectives Tamoxifen bioactivation to endoxifen is mediated primarily by CYP2D6; however, considerable variability remains unexplained. Our aim was to perform a comprehensive assessment of the effect of genetic variation in tamoxifen-relevant enzymes and transporters on steady-state endoxifen concentrations. Patients and methods Comprehensive genotyping of CYP enzymes and transporters was performed using the iPLEX ADME PGx Pro Panel in 302 tamoxifen-treated breast cancer patients. Predicted activity phenotype for 19 enzymes and transporters were analyzed for univariate association with endoxifen concentration, and then adjusted for CYP2D6 and clinical covariates. Results In univariate analysis, higher activity of CYP2C8 (regression β=0.22, P=0.020) and CYP2C9 (β=0.20, P=0.04), lower body weight (β=-0.014, P<0.0001), and endoxifen measurement during winter (each β< -0.39, P=0.002) were associated with higher endoxifen concentrations. After adjustment for the CYP2D6 diplotype, weight, and season, CYP2C9 remained significantly associated with higher concentrations (P=0.02), but only increased the overall model R2 by 1.3%. Conclusion Our results further support a minor contribution of CYP2C9 genetic variability toward steadystate endoxifen concentrations. Integration of clinician and genetic variables into individualized tamoxifen dosing algorithms would marginally improve their accuracy and potentially enhance tamoxifen treatment outcomes.

AB - Objectives Tamoxifen bioactivation to endoxifen is mediated primarily by CYP2D6; however, considerable variability remains unexplained. Our aim was to perform a comprehensive assessment of the effect of genetic variation in tamoxifen-relevant enzymes and transporters on steady-state endoxifen concentrations. Patients and methods Comprehensive genotyping of CYP enzymes and transporters was performed using the iPLEX ADME PGx Pro Panel in 302 tamoxifen-treated breast cancer patients. Predicted activity phenotype for 19 enzymes and transporters were analyzed for univariate association with endoxifen concentration, and then adjusted for CYP2D6 and clinical covariates. Results In univariate analysis, higher activity of CYP2C8 (regression β=0.22, P=0.020) and CYP2C9 (β=0.20, P=0.04), lower body weight (β=-0.014, P<0.0001), and endoxifen measurement during winter (each β< -0.39, P=0.002) were associated with higher endoxifen concentrations. After adjustment for the CYP2D6 diplotype, weight, and season, CYP2C9 remained significantly associated with higher concentrations (P=0.02), but only increased the overall model R2 by 1.3%. Conclusion Our results further support a minor contribution of CYP2C9 genetic variability toward steadystate endoxifen concentrations. Integration of clinician and genetic variables into individualized tamoxifen dosing algorithms would marginally improve their accuracy and potentially enhance tamoxifen treatment outcomes.

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