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

Ann Oncol. 2021 Oct;32(10):1286-1293. doi: 10.1016/j.annonc.2021.07.005. Epub 2021 Jul 18.

Authors

W He¹, M Eriksson², E Eliasson³, F Grassmann⁴, M Bäcklund², M Gabrielson², M Hammarström², S Margolin⁵, L Thorén⁵, Y Wengström⁶, S Borgquist⁷, P Hall⁸, K Czene²

Affiliations

¹ 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.
² Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
³ Department of Laboratory Medicine, Clinical Pharmacology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
⁵ Department of Oncology, South General Hospital, Stockholm, Sweden; Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
⁶ Department of Neurobiology, Care Science and Society, Division of Nursing and Theme Cancer, Karolinska University Hospital, Stockholm, Sweden.
⁷ 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.
⁸ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Oncology, South General Hospital, Stockholm, Sweden. Electronic address: per.hall@ki.se.

PMID: 34284099
DOI: 10.1016/j.annonc.2021.07.005

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: CYP2D6 genotype; breast cancer; mammographic density; tamoxifen; treatment discontinuation.

Publication types

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

MeSH terms

Antineoplastic Agents, Hormonal / therapeutic use
Breast Neoplasms* / drug therapy
Breast Neoplasms* / genetics
Cytochrome P-450 CYP2D6 / genetics
Female
Genotype
Humans
Pharmaceutical Preparations*
Tamoxifen

Substances

Antineoplastic Agents, Hormonal
Pharmaceutical Preparations
Tamoxifen
Cytochrome P-450 CYP2D6