CYP2D6 genotype and adverse effects as indicators of plasma endoxifen in breast cancer patients taking tamoxifen

Bavanthi Balakrishnar, Alexander M. Menzies, Sayed Sahanawaz Ali, Shang Heng Yeap, Bo Gao, Chris Liddle, Sally Coulter, Pamela Provan, Val Gebski, Rina Hui, Richard Kefford, Nicholas Wilcken, Rosemary L. Balleine, Howard Gurney

Research output: Contribution to journalMeeting abstractResearchpeer-review

Abstract

Background: Tamoxifen is a prodrug. Its principal active metabolite endoxifen is a product of cytochrome P450 2D6 (CYP2D6) metabolism. The CYP2D6 gene is highly polymorphic with a number of relatively common reduced function alleles. The aim of this study was to determine whether plasma endoxifen levels were reflected by CYP2D6 genotype or adverse effects in individuals taking tamoxifen. Methods: Plasma endoxifen was measured by High Performance Liquid Chromatography / Mass Spectroscopy in 90 breast cancer patients taking 20mg tamoxifen per day. Ten CYP2D6 single nucleotide polymorphisms were assessed to designate four putative CYP2D6 functional categories: ultra-rapid (UM), extensive (EM), intermediate (IM) and poor (PM) metabolizers. CYP2D6 inhibitor use and adverse effects were documented. The study was part of an ongoing Australian trial of tamoxifen dose escalation. Results: There was marked variation in plasma endoxifen levels across the cohort (mean 27.6 nM, SD 14.3). Endoxifen levels were significantly associated with metabolizer categories (p<0.001, r= -0.44), but were not distinctive between categories. For example, in the EM category (n=46) endoxifen levels ranged from 3.8-72.2 nM (mean 32.6 nM) with levels in the lowest quartile (3.8-19.7 nM) substantially overlapping the PM category (n=11); 6.1-24.7 nM. Consistent with an impact of non-CYP2D6 genotype related factors on endoxifen levels, endoxifen was significantly lower in 18 patients taking CYP2D6 inhibitor medications (p=0.005). There was no association between endoxifen levels and vasomotor symptoms or other adverse effects of tamoxifen. Conclusions: Endoxifen levels were highly variable in patients taking standard dose tamoxifen, and not predicted by CYP2D6 genotype or adverse effects. Therapeutic monitoring of endoxifen levels may be a useful approach to assess tamoxifen activity.
LanguageEnglish
Pages550-550
Number of pages1
JournalJournal of Clinical Oncology
Volume30
Issue numberSupplement 15
Publication statusPublished - 20 May 2012
Externally publishedYes
Event48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) - Chicago, United States
Duration: 1 Jun 20126 Jun 2012

Cite this

Balakrishnar, B., Menzies, A. M., Ali, S. S., Yeap, S. H., Gao, B., Liddle, C., ... Gurney, H. (2012). CYP2D6 genotype and adverse effects as indicators of plasma endoxifen in breast cancer patients taking tamoxifen. Journal of Clinical Oncology, 30(Supplement 15), 550-550.
Balakrishnar, Bavanthi ; Menzies, Alexander M. ; Ali, Sayed Sahanawaz ; Yeap, Shang Heng ; Gao, Bo ; Liddle, Chris ; Coulter, Sally ; Provan, Pamela ; Gebski, Val ; Hui, Rina ; Kefford, Richard ; Wilcken, Nicholas ; Balleine, Rosemary L. ; Gurney, Howard. / CYP2D6 genotype and adverse effects as indicators of plasma endoxifen in breast cancer patients taking tamoxifen. In: Journal of Clinical Oncology. 2012 ; Vol. 30, No. Supplement 15. pp. 550-550.
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title = "CYP2D6 genotype and adverse effects as indicators of plasma endoxifen in breast cancer patients taking tamoxifen",
abstract = "Background: Tamoxifen is a prodrug. Its principal active metabolite endoxifen is a product of cytochrome P450 2D6 (CYP2D6) metabolism. The CYP2D6 gene is highly polymorphic with a number of relatively common reduced function alleles. The aim of this study was to determine whether plasma endoxifen levels were reflected by CYP2D6 genotype or adverse effects in individuals taking tamoxifen. Methods: Plasma endoxifen was measured by High Performance Liquid Chromatography / Mass Spectroscopy in 90 breast cancer patients taking 20mg tamoxifen per day. Ten CYP2D6 single nucleotide polymorphisms were assessed to designate four putative CYP2D6 functional categories: ultra-rapid (UM), extensive (EM), intermediate (IM) and poor (PM) metabolizers. CYP2D6 inhibitor use and adverse effects were documented. The study was part of an ongoing Australian trial of tamoxifen dose escalation. Results: There was marked variation in plasma endoxifen levels across the cohort (mean 27.6 nM, SD 14.3). Endoxifen levels were significantly associated with metabolizer categories (p<0.001, r= -0.44), but were not distinctive between categories. For example, in the EM category (n=46) endoxifen levels ranged from 3.8-72.2 nM (mean 32.6 nM) with levels in the lowest quartile (3.8-19.7 nM) substantially overlapping the PM category (n=11); 6.1-24.7 nM. Consistent with an impact of non-CYP2D6 genotype related factors on endoxifen levels, endoxifen was significantly lower in 18 patients taking CYP2D6 inhibitor medications (p=0.005). There was no association between endoxifen levels and vasomotor symptoms or other adverse effects of tamoxifen. Conclusions: Endoxifen levels were highly variable in patients taking standard dose tamoxifen, and not predicted by CYP2D6 genotype or adverse effects. Therapeutic monitoring of endoxifen levels may be a useful approach to assess tamoxifen activity.",
author = "Bavanthi Balakrishnar and Menzies, {Alexander M.} and Ali, {Sayed Sahanawaz} and Yeap, {Shang Heng} and Bo Gao and Chris Liddle and Sally Coulter and Pamela Provan and Val Gebski and Rina Hui and Richard Kefford and Nicholas Wilcken and Balleine, {Rosemary L.} and Howard Gurney",
year = "2012",
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Balakrishnar, B, Menzies, AM, Ali, SS, Yeap, SH, Gao, B, Liddle, C, Coulter, S, Provan, P, Gebski, V, Hui, R, Kefford, R, Wilcken, N, Balleine, RL & Gurney, H 2012, 'CYP2D6 genotype and adverse effects as indicators of plasma endoxifen in breast cancer patients taking tamoxifen', Journal of Clinical Oncology, vol. 30, no. Supplement 15, pp. 550-550.

CYP2D6 genotype and adverse effects as indicators of plasma endoxifen in breast cancer patients taking tamoxifen. / Balakrishnar, Bavanthi; Menzies, Alexander M.; Ali, Sayed Sahanawaz; Yeap, Shang Heng; Gao, Bo; Liddle, Chris; Coulter, Sally; Provan, Pamela; Gebski, Val; Hui, Rina; Kefford, Richard; Wilcken, Nicholas; Balleine, Rosemary L.; Gurney, Howard.

In: Journal of Clinical Oncology, Vol. 30, No. Supplement 15, 20.05.2012, p. 550-550.

Research output: Contribution to journalMeeting abstractResearchpeer-review

TY - JOUR

T1 - CYP2D6 genotype and adverse effects as indicators of plasma endoxifen in breast cancer patients taking tamoxifen

AU - Balakrishnar, Bavanthi

AU - Menzies, Alexander M.

AU - Ali, Sayed Sahanawaz

AU - Yeap, Shang Heng

AU - Gao, Bo

AU - Liddle, Chris

AU - Coulter, Sally

AU - Provan, Pamela

AU - Gebski, Val

AU - Hui, Rina

AU - Kefford, Richard

AU - Wilcken, Nicholas

AU - Balleine, Rosemary L.

AU - Gurney, Howard

PY - 2012/5/20

Y1 - 2012/5/20

N2 - Background: Tamoxifen is a prodrug. Its principal active metabolite endoxifen is a product of cytochrome P450 2D6 (CYP2D6) metabolism. The CYP2D6 gene is highly polymorphic with a number of relatively common reduced function alleles. The aim of this study was to determine whether plasma endoxifen levels were reflected by CYP2D6 genotype or adverse effects in individuals taking tamoxifen. Methods: Plasma endoxifen was measured by High Performance Liquid Chromatography / Mass Spectroscopy in 90 breast cancer patients taking 20mg tamoxifen per day. Ten CYP2D6 single nucleotide polymorphisms were assessed to designate four putative CYP2D6 functional categories: ultra-rapid (UM), extensive (EM), intermediate (IM) and poor (PM) metabolizers. CYP2D6 inhibitor use and adverse effects were documented. The study was part of an ongoing Australian trial of tamoxifen dose escalation. Results: There was marked variation in plasma endoxifen levels across the cohort (mean 27.6 nM, SD 14.3). Endoxifen levels were significantly associated with metabolizer categories (p<0.001, r= -0.44), but were not distinctive between categories. For example, in the EM category (n=46) endoxifen levels ranged from 3.8-72.2 nM (mean 32.6 nM) with levels in the lowest quartile (3.8-19.7 nM) substantially overlapping the PM category (n=11); 6.1-24.7 nM. Consistent with an impact of non-CYP2D6 genotype related factors on endoxifen levels, endoxifen was significantly lower in 18 patients taking CYP2D6 inhibitor medications (p=0.005). There was no association between endoxifen levels and vasomotor symptoms or other adverse effects of tamoxifen. Conclusions: Endoxifen levels were highly variable in patients taking standard dose tamoxifen, and not predicted by CYP2D6 genotype or adverse effects. Therapeutic monitoring of endoxifen levels may be a useful approach to assess tamoxifen activity.

AB - Background: Tamoxifen is a prodrug. Its principal active metabolite endoxifen is a product of cytochrome P450 2D6 (CYP2D6) metabolism. The CYP2D6 gene is highly polymorphic with a number of relatively common reduced function alleles. The aim of this study was to determine whether plasma endoxifen levels were reflected by CYP2D6 genotype or adverse effects in individuals taking tamoxifen. Methods: Plasma endoxifen was measured by High Performance Liquid Chromatography / Mass Spectroscopy in 90 breast cancer patients taking 20mg tamoxifen per day. Ten CYP2D6 single nucleotide polymorphisms were assessed to designate four putative CYP2D6 functional categories: ultra-rapid (UM), extensive (EM), intermediate (IM) and poor (PM) metabolizers. CYP2D6 inhibitor use and adverse effects were documented. The study was part of an ongoing Australian trial of tamoxifen dose escalation. Results: There was marked variation in plasma endoxifen levels across the cohort (mean 27.6 nM, SD 14.3). Endoxifen levels were significantly associated with metabolizer categories (p<0.001, r= -0.44), but were not distinctive between categories. For example, in the EM category (n=46) endoxifen levels ranged from 3.8-72.2 nM (mean 32.6 nM) with levels in the lowest quartile (3.8-19.7 nM) substantially overlapping the PM category (n=11); 6.1-24.7 nM. Consistent with an impact of non-CYP2D6 genotype related factors on endoxifen levels, endoxifen was significantly lower in 18 patients taking CYP2D6 inhibitor medications (p=0.005). There was no association between endoxifen levels and vasomotor symptoms or other adverse effects of tamoxifen. Conclusions: Endoxifen levels were highly variable in patients taking standard dose tamoxifen, and not predicted by CYP2D6 genotype or adverse effects. Therapeutic monitoring of endoxifen levels may be a useful approach to assess tamoxifen activity.

M3 - Meeting abstract

VL - 30

SP - 550

EP - 550

JO - Journal of Clinical Oncology

T2 - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 1527-7755

IS - Supplement 15

ER -

Balakrishnar B, Menzies AM, Ali SS, Yeap SH, Gao B, Liddle C et al. CYP2D6 genotype and adverse effects as indicators of plasma endoxifen in breast cancer patients taking tamoxifen. Journal of Clinical Oncology. 2012 May 20;30(Supplement 15):550-550.