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CYP2D6 genotype predicts tamoxifen discontinuation and drug response : a secondary analysis of the KARISMA trial

He, W. ; Eriksson, M. ; Eliasson, E. ; Grassmann, F. ; Bäcklund, M. ; Gabrielson, M. ; Hammarström, M. ; Margolin, S. ; Thorén, L. and Wengström, Y. , et al. (2021) In Annals of Oncology 32(10). p.1286-1293
Abstract

Background: Guidelines regarding whether tamoxifen should be prescribed based on women's cytochrome P450 2D6 (CYP2D6) genotypes are conflicting and have caused confusion. This study aims to investigate if CYP2D6 metabolizer status isa associated with tamoxifen-related endocrine symptoms, tamoxifen discontinuation, and mammographic density change. Patients and methods: We used data from 1440 healthy women who participated the KARISMA dose determination trial. Endocrine symptoms were measured using a modified Functional Assessment of Cancer Therapy – Endocrine Symptoms (FACT-ES) questionnaire. Change in mammographic density was measured and used as a proxy for tamoxifen response. Participants were genotyped and categorized as poor,... (More)

Background: Guidelines regarding whether tamoxifen should be prescribed based on women's cytochrome P450 2D6 (CYP2D6) genotypes are conflicting and have caused confusion. This study aims to investigate if CYP2D6 metabolizer status isa associated with tamoxifen-related endocrine symptoms, tamoxifen discontinuation, and mammographic density change. Patients and methods: We used data from 1440 healthy women who participated the KARISMA dose determination trial. Endocrine symptoms were measured using a modified Functional Assessment of Cancer Therapy – Endocrine Symptoms (FACT-ES) questionnaire. Change in mammographic density was measured and used as a proxy for tamoxifen response. Participants were genotyped and categorized as poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers. Results: The median endoxifen level per mg oral tamoxifen among poor, intermediate, normal and ultrarapid CYP2D6 metabolizers were 0.18 ng/ml, 0.38 ng/ml, 0.56 ng/ml and 0.67 ng/ml, respectively. Ultrarapid CYP2D6 metabolizers were more likely than other groups to report a clinically relevant change in cold sweats, hot flash, mood swings, being irritable, as well as the overall modified FACT-ES score, after taking tamoxifen. The 6-month tamoxifen discontinuation rates among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were 25.7%, 23.6%, 28.6%, and 44.4%, respectively. Among those who continued and finished the 6-month tamoxifen intervention, the mean change in dense area among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were −0.8 cm2, −4.5 cm2, −4.1 cm2, and −8.0 cm2 respectively. Conclusions: Poor CYP2D6 metabolizers are likely to experience an impaired response to tamoxifen, measured through mammographic density reduction. In contrast, ultrarapid CYP2D6 metabolizers are at risk for exaggerated response with pronounced adverse effects that may lead to treatment discontinuation.

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organization
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Contribution to journal
publication status
published
subject
keywords
breast cancer, CYP2D6 genotype, mammographic density, tamoxifen, treatment discontinuation
in
Annals of Oncology
volume
32
issue
10
pages
1286 - 1293
publisher
Oxford University Press
external identifiers
  • pmid:34284099
  • scopus:85112111245
ISSN
0923-7534
DOI
10.1016/j.annonc.2021.07.005
language
English
LU publication?
yes
id
38a3e785-12d6-41ad-b1af-b73db5991a44
date added to LUP
2021-09-03 09:59:44
date last changed
2025-02-09 15:34:29
@article{38a3e785-12d6-41ad-b1af-b73db5991a44,
  abstract     = {{<p>Background: Guidelines regarding whether tamoxifen should be prescribed based on women's cytochrome P450 2D6 (CYP2D6) genotypes are conflicting and have caused confusion. This study aims to investigate if CYP2D6 metabolizer status isa associated with tamoxifen-related endocrine symptoms, tamoxifen discontinuation, and mammographic density change. Patients and methods: We used data from 1440 healthy women who participated the KARISMA dose determination trial. Endocrine symptoms were measured using a modified Functional Assessment of Cancer Therapy – Endocrine Symptoms (FACT-ES) questionnaire. Change in mammographic density was measured and used as a proxy for tamoxifen response. Participants were genotyped and categorized as poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers. Results: The median endoxifen level per mg oral tamoxifen among poor, intermediate, normal and ultrarapid CYP2D6 metabolizers were 0.18 ng/ml, 0.38 ng/ml, 0.56 ng/ml and 0.67 ng/ml, respectively. Ultrarapid CYP2D6 metabolizers were more likely than other groups to report a clinically relevant change in cold sweats, hot flash, mood swings, being irritable, as well as the overall modified FACT-ES score, after taking tamoxifen. The 6-month tamoxifen discontinuation rates among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were 25.7%, 23.6%, 28.6%, and 44.4%, respectively. Among those who continued and finished the 6-month tamoxifen intervention, the mean change in dense area among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were −0.8 cm<sup>2</sup>, −4.5 cm<sup>2</sup>, −4.1 cm<sup>2</sup>, and −8.0 cm<sup>2</sup> respectively. Conclusions: Poor CYP2D6 metabolizers are likely to experience an impaired response to tamoxifen, measured through mammographic density reduction. In contrast, ultrarapid CYP2D6 metabolizers are at risk for exaggerated response with pronounced adverse effects that may lead to treatment discontinuation.</p>}},
  author       = {{He, W. and Eriksson, M. and Eliasson, E. and Grassmann, F. and Bäcklund, M. and Gabrielson, M. and Hammarström, M. and Margolin, S. and Thorén, L. and Wengström, Y. and Borgquist, S. and Hall, P. and Czene, K.}},
  issn         = {{0923-7534}},
  keywords     = {{breast cancer; CYP2D6 genotype; mammographic density; tamoxifen; treatment discontinuation}},
  language     = {{eng}},
  number       = {{10}},
  pages        = {{1286--1293}},
  publisher    = {{Oxford University Press}},
  series       = {{Annals of Oncology}},
  title        = {{CYP2D6 genotype predicts tamoxifen discontinuation and drug response : a secondary analysis of the KARISMA trial}},
  url          = {{http://dx.doi.org/10.1016/j.annonc.2021.07.005}},
  doi          = {{10.1016/j.annonc.2021.07.005}},
  volume       = {{32}},
  year         = {{2021}},
}