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

Antineoplastic Agents, Hormonal / therapeutic use Breast Neoplasms / drug therapy Cytochrome P-450 CYP2D6 / genetics Female Genotype Humans Pharmaceutical Preparations Tamoxifen
CYP2D6 genotype breast cancer mammographic density tamoxifen treatment discontinuation

Journal

Annals of oncology : official journal of the European Society for Medical Oncology
ISSN: 1569-8041
Titre abrégé: Ann Oncol
Pays: England
ID NLM: 9007735

Informations de publication

Date de publication:
10 2021
Historique:
received: 06 04 2021
revised: 17 06 2021
accepted: 13 07 2021
pubmed: 21 7 2021
medline: 29 10 2021
entrez: 20 7 2021
Statut: ppublish

Résumé

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. 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. 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 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.

Sections du résumé

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 cm
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.

Identifiants

DOI: 10.1016/j.annonc.2021.07.005 PMID: 34284099
pubmed: 34284099
pii: S0923-7534(21)02183-9
doi: 10.1016/j.annonc.2021.07.005
pii:
doi:

Substances chimiques

Antineoplastic Agents, Hormonal 0
Pharmaceutical Preparations 0
Tamoxifen 094ZI81Y45
Cytochrome P-450 CYP2D6 EC 1.14.14.1

Types de publication

Journal Article Randomized Controlled Trial Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1286-1293

Informations de copyright

Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Disclosure The authors have declared no conflicts of interest.

Auteurs

W He (W)

Chronic Disease Research Institute, The Children's Hospital, and National Clinical Research Center for Child Health, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Department of Nutrition and Food Hygiene, School of Public Health, Zhejiang University, Hangzhou, Zhejiang, China; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

M Eriksson (M)

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

E Eliasson (E)

Department of Laboratory Medicine, Clinical Pharmacology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.

F Grassmann (F)

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.

M Bäcklund (M)

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

M Gabrielson (M)

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

M Hammarström (M)

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

S Margolin (S)

Department of Oncology, South General Hospital, Stockholm, Sweden; Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.

L Thorén (L)

Department of Oncology, South General Hospital, Stockholm, Sweden; Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.

Y Wengström (Y)

Department of Neurobiology, Care Science and Society, Division of Nursing and Theme Cancer, Karolinska University Hospital, Stockholm, Sweden.

S Borgquist (S)

Department of Oncology, Aarhus University Hospital and Aarhus University, Aarhus, Denmark; Department of Clinical Sciences Lund, Oncology, Lund University and Skåne University Hospital, Lund, Sweden.

P Hall (P)

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Oncology, South General Hospital, Stockholm, Sweden. Electronic address: per.hall@ki.se.

K Czene (K)

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

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Classifications MeSH

questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Antinéoplasiques hormonaux › CYP2D6 genotype predicts tamoxifen...
questionsmedicales.fr › Maladies de la peau et du tissu conjonctif › Maladies de la peau › Maladies du sein › Tumeurs du sein › CYP2D6 genotype predicts tamoxifen...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Hémoprotéines › Cytochromes › Cytochrome P-450 enzyme system › Famille-2 de cytochromes P450 › Cytochrome P-450 CYP2D6 › CYP2D6 genotype predicts tamoxifen...
questionsmedicales.fr › Phénomènes génétiques › Génotype › CYP2D6 genotype predicts tamoxifen...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › CYP2D6 genotype predicts tamoxifen...
questionsmedicales.fr › Préparations pharmaceutiques › CYP2D6 genotype predicts tamoxifen...
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures cycliques › Hydrocarbures aromatiques › Dérivés du benzène › Composés benzylidéniques › Stilbènes › Tamoxifène › CYP2D6 genotype predicts tamoxifen...