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

W. He; M. Eriksson; E. Eliasson; F. Grassmann; M. Bäcklund; M. Gabrielson; M. Hammarström; S. Margolin; L. Thorén; Y. Wengström; S. Borgquist; P. Hall; K. Czene

doi:10.1016/j.annonc.2021.07.005

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

W. He, M. Eriksson, E. Eliasson, F. Grassmann, M. Bäcklund, M. Gabrielson, M. Hammarström, S. Margolin, L. Thorén, Y. Wengström, S. Borgquist, P. Hall^*, K. Czene

^*Corresponding author for this work

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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 is 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.

Original language	English
Pages (from-to)	1286-1293
Number of pages	8
Journal	Annals of Oncology
Volume	32
Issue number	10
Early online date	18 Jul 2021
DOIs	https://doi.org/10.1016/j.annonc.2021.07.005
Publication status	Published - 1 Oct 2021

Bibliographical note

Funding Information:
This work was supported by Märit and Hans Rausing's Initiative Against Breast Cancer (no grant number); the Kamprad Foundation [grant number: 20150052 ]; and Stockholm County Council [grant number: 4-2645/2015 ]; the Swedish Research Council [grant number 2018-02547 ]; the Swedish Cancer Society [grant number 19 0266 ]; and Swedish Research Council for Health, Working Life and Welfare (FORTE) [grant number 2016-00081 , 2018-00877 ]. WH is supported by Zhejiang University through ‘Hundred Talents Program’ (no grant number). The funding source had no role in study design, collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to approve publication of the finished manuscript.

Keywords

breast cancer
CYP2D6 genotype
mammographic density
tamoxifen
treatment discontinuation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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He, W., Eriksson, M., Eliasson, E., Grassmann, F., Bäcklund, M., Gabrielson, M., Hammarström, M., Margolin, S., Thorén, L., Wengström, Y., Borgquist, S., Hall, P., & Czene, K. (2021). CYP2D6 genotype predicts tamoxifen discontinuation and drug response: a secondary analysis of the KARISMA trial. Annals of Oncology, 32(10), 1286-1293. https://doi.org/10.1016/j.annonc.2021.07.005

He, W, Eriksson, M, Eliasson, E, Grassmann, F, Bäcklund, M, Gabrielson, M, Hammarström, M, Margolin, S, Thorén, L, Wengström, Y, Borgquist, S, Hall, P & Czene, K 2021, 'CYP2D6 genotype predicts tamoxifen discontinuation and drug response: a secondary analysis of the KARISMA trial', Annals of Oncology, vol. 32, no. 10, pp. 1286-1293. https://doi.org/10.1016/j.annonc.2021.07.005

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

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 is 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.",

keywords = "breast cancer, CYP2D6 genotype, mammographic density, tamoxifen, treatment discontinuation",

author = "W. He and M. Eriksson and E. Eliasson and F. Grassmann and M. B{\"a}cklund and M. Gabrielson and M. Hammarstr{\"o}m and S. Margolin and L. Thor{\'e}n and Y. Wengstr{\"o}m and S. Borgquist and P. Hall and K. Czene",

note = "Funding Information: This work was supported by M{\"a}rit and Hans Rausing's Initiative Against Breast Cancer (no grant number); the Kamprad Foundation [grant number: 20150052 ]; and Stockholm County Council [grant number: 4-2645/2015 ]; the Swedish Research Council [grant number 2018-02547 ]; the Swedish Cancer Society [grant number 19 0266 ]; and Swedish Research Council for Health, Working Life and Welfare (FORTE) [grant number 2016-00081 , 2018-00877 ]. WH is supported by Zhejiang University through {\textquoteleft}Hundred Talents Program{\textquoteright} (no grant number). The funding source had no role in study design, collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to approve publication of the finished manuscript. ",

year = "2021",

month = oct,

day = "1",

doi = "10.1016/j.annonc.2021.07.005",

language = "English",

volume = "32",

pages = "1286--1293",

journal = "Annals of Oncology",

issn = "0923-7534",

publisher = "Oxford University Press",

number = "10",

}

TY - JOUR

T1 - CYP2D6 genotype predicts tamoxifen discontinuation and drug response

T2 - a secondary analysis of the KARISMA trial

AU - He, W.

AU - Eriksson, M.

AU - Eliasson, E.

AU - Grassmann, F.

AU - Bäcklund, M.

AU - Gabrielson, M.

AU - Hammarström, M.

AU - Margolin, S.

AU - Thorén, L.

AU - Wengström, Y.

AU - Borgquist, S.

AU - Hall, P.

AU - Czene, K.

N1 - Funding Information: This work was supported by Märit and Hans Rausing's Initiative Against Breast Cancer (no grant number); the Kamprad Foundation [grant number: 20150052 ]; and Stockholm County Council [grant number: 4-2645/2015 ]; the Swedish Research Council [grant number 2018-02547 ]; the Swedish Cancer Society [grant number 19 0266 ]; and Swedish Research Council for Health, Working Life and Welfare (FORTE) [grant number 2016-00081 , 2018-00877 ]. WH is supported by Zhejiang University through ‘Hundred Talents Program’ (no grant number). The funding source had no role in study design, collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to approve publication of the finished manuscript.

PY - 2021/10/1

Y1 - 2021/10/1

N2 - 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 is 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.

AB - 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 is 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.

KW - breast cancer

KW - CYP2D6 genotype

KW - mammographic density

KW - tamoxifen

KW - treatment discontinuation

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DO - 10.1016/j.annonc.2021.07.005

M3 - Article

C2 - 34284099

AN - SCOPUS:85112111245

SN - 0923-7534

VL - 32

SP - 1286

EP - 1293

JO - Annals of Oncology

JF - Annals of Oncology

IS - 10

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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