Genetic variants in tamoxifen metabolism and early treatment discontinuation among premenopausal breast cancer patients.

IF 3 3区医学 Q2 ONCOLOGY

Breast Cancer Research and Treatment Pub Date : 2025-05-14 DOI:10.1007/s10549-025-07719-1

Kirsten M Woolpert, Thomas P Ahern, James W Baurley, Maret L Maliniak, Per Damkier, Anders Kjærsgaard, Lindsay J Collin, Stephen Hamilton-Dutoit, Trine Tramm, Bent Ejlertsen, Henrik T Sørensen, Timothy L Lash, Deirdre P Cronin-Fenton

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引用次数: 0

Abstract

Purpose: Premenopausal, estrogen receptor (ER)-positive breast cancer patients should receive tamoxifen for at least 5 years, but many prematurely discontinue. Activation, transport, and deactivation of tamoxifen and its metabolites are controlled by proteins encoded by genes with functional variations. We examined the impact of genetic polymorphisms in the tamoxifen pathway on early treatment discontinuation.

Methods: We included premenopausal women diagnosed with ER-positive breast cancer (2002-2011) in Denmark who initiated tamoxifen. We genotyped 26 genetic variants in 15 enzymes involved in tamoxifen metabolism. Early discontinuation was defined as tamoxifen use for < 5 years. We estimated individual and combined effects of genetic variants using a Bayesian pathway approach. We report Bayes Factors (BF), wherein values > 1 indicate support of an effect of the genetic pathway on discontinuation (compared with no effect).

Results: Among 3,729 patients, 536 (14%) discontinued tamoxifen within 5 years. Genetic variants involved in tamoxifen activation impacted early discontinuation (BF = 7.5), in a manner driven almost entirely by CYP2D6 activity (BF = 22.6). Several variants in CYP2D6 and transporter genes synergistically increased the hazard of early discontinuation (e.g., CYP2D6*2 and ABCC2; BF = 138).

Conclusions: Variants in enzymes responsible for activating tamoxifen metabolites-particularly within CYP2D6-influence early tamoxifen discontinuation. CYP2D6 variants synergistically interact with transporter gene variants, namely ABCC2, to further raise the risk of discontinuation.

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绝经前乳腺癌患者他莫昔芬代谢和早期停药的遗传变异。

目的：绝经前，雌激素受体（ER）阳性乳腺癌患者应接受他莫昔芬治疗至少5年，但许多患者过早停药。他莫昔芬及其代谢产物的激活、转运和失活是由具有功能变异的基因编码的蛋白质控制的。我们研究了他莫昔芬通路遗传多态性对早期停药的影响。方法：我们纳入了丹麦诊断为er阳性乳腺癌的绝经前妇女（2002-2011），她们开始服用他莫昔芬。我们对参与他莫昔芬代谢的15种酶的26种遗传变异进行了基因分型。早期停药被定义为使用他莫昔芬1次表明支持遗传途径对停药的影响（与无影响相比）。结果：在3729例患者中，536例（14%）在5年内停用他莫昔芬。涉及他莫昔芬激活的遗传变异影响早期停药（BF = 7.5），其方式几乎完全由CYP2D6活性驱动（BF = 22.6）。CYP2D6和转运基因的几种变异协同增加了早期停药的危险(例如，CYP2D6*2和ABCC2；bf = 138)。结论：负责激活他莫昔芬代谢物的酶的变异-特别是cyp2d6 -影响他莫昔芬的早期停药。CYP2D6变异与转运基因变异ABCC2协同作用，进一步增加停药风险。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Breast Cancer Research and Treatment 医学-肿瘤学

CiteScore

6.80

自引率

2.60%

发文量

342

审稿时长

1 months

期刊介绍： Breast Cancer Research and Treatment provides the surgeon, radiotherapist, medical oncologist, endocrinologist, epidemiologist, immunologist or cell biologist investigating problems in breast cancer a single forum for communication. The journal creates a "market place" for breast cancer topics which cuts across all the usual lines of disciplines, providing a site for presenting pertinent investigations, and for discussing critical questions relevant to the entire field. It seeks to develop a new focus and new perspectives for all those concerned with breast cancer.