Drug Interactions With Tamoxifen and Treatment Effectiveness in Premenopausal Breast Cancer Patients: A Bayesian Joint Modeling Approach.

IF 2.4 4区医学 Q3 PHARMACOLOGY & PHARMACY

Pharmacoepidemiology and Drug Safety Pub Date : 2025-05-01 DOI:10.1002/pds.70157

Kirsten M Woolpert, Deirdre P Cronin-Fenton, Per Damkier, Anders Kjærsgaard, Stephen Hamilton-Dutoit, Bent Ejlertsen, Richard F MacLehose, Peer Christiansen, Rebecca A Silliman, Timothy L Lash, Thomas P Ahern, Lindsay J Collin

{"title":"Drug Interactions With Tamoxifen and Treatment Effectiveness in Premenopausal Breast Cancer Patients: A Bayesian Joint Modeling Approach.","authors":"Kirsten M Woolpert, Deirdre P Cronin-Fenton, Per Damkier, Anders Kjærsgaard, Stephen Hamilton-Dutoit, Bent Ejlertsen, Richard F MacLehose, Peer Christiansen, Rebecca A Silliman, Timothy L Lash, Thomas P Ahern, Lindsay J Collin","doi":"10.1002/pds.70157","DOIUrl":null,"url":null,"abstract":"Purpose: Tamoxifen is guideline treatment for premenopausal women with estrogen receptor-positive (ER+) breast cancer. Therapeutic efficacy relies partly on tamoxifen biotransformation by CYP2D6, CYP2C19, and CYP3A4 enzymes. We conducted a cohort study to evaluate whether concomitant prescription of drugs that inhibit these enzymes impacted breast cancer recurrence.Methods: We enrolled 4493 premenopausal women with stage I-III ER+ breast cancer (2002-2011) treated with tamoxifen. We defined time-varying CYP-inhibiting drug exposures as the proportion of overlapping days during the tamoxifen treatment period. We estimated associations of concomitant medication use with recurrence using: (1) Bayesian joint modeling (hazard ratio [HR] and 95% credible intervals [95% CrI]), (2) traditional Cox regression (HR and 95% confidence intervals [95% CI]).Results: During tamoxifen therapy, 13% of the cohort used strong CYP2D6 inhibitors, 31% weak CYP2D6 inhibitors, 37% CYP2C19 inhibitors, and 12% CYP3A4/5 inhibitors. Bayesian joint models showed that women with ≥ 50% overlap between tamoxifen and CYP2D6 inhibitors had increased recurrence risk compared with 0% overlap (HR: 1.24, 95% CrI: 0.96, 1.58). No recurrence association was seen for CYP2C19 inhibitors (≥ 50% vs. 0%, HR = 1.0, 95% CrI: 0.69, 1.40), but traditional Cox models yielded positive associations for CYP2C19 overlap (≥ 50% vs. 0%, HR = 1.45, 95% CI: 1.07, 1.96). With Bayesian joint models, we observed no association between ≥ 50% versus 0% overlap with CYP3A4/5 inhibitors (HR: 0.84, 95% CrI: 0.32, 1.93).Conclusions: With Bayesian joint modeling, we saw a slight increase in recurrence among CYP2D6-inhibitor users, but no increase among CYP2C19- or CYP3A4-inhibitor users. Results from Cox regression models were less plausible.","PeriodicalId":19782,"journal":{"name":"Pharmacoepidemiology and Drug Safety","volume":"34 5","pages":"e70157"},"PeriodicalIF":2.4000,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12076038/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmacoepidemiology and Drug Safety","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/pds.70157","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}

引用次数: 0

Abstract

Purpose: Tamoxifen is guideline treatment for premenopausal women with estrogen receptor-positive (ER+) breast cancer. Therapeutic efficacy relies partly on tamoxifen biotransformation by CYP2D6, CYP2C19, and CYP3A4 enzymes. We conducted a cohort study to evaluate whether concomitant prescription of drugs that inhibit these enzymes impacted breast cancer recurrence.

Methods: We enrolled 4493 premenopausal women with stage I-III ER+ breast cancer (2002-2011) treated with tamoxifen. We defined time-varying CYP-inhibiting drug exposures as the proportion of overlapping days during the tamoxifen treatment period. We estimated associations of concomitant medication use with recurrence using: (1) Bayesian joint modeling (hazard ratio [HR] and 95% credible intervals [95% CrI]), (2) traditional Cox regression (HR and 95% confidence intervals [95% CI]).

Results: During tamoxifen therapy, 13% of the cohort used strong CYP2D6 inhibitors, 31% weak CYP2D6 inhibitors, 37% CYP2C19 inhibitors, and 12% CYP3A4/5 inhibitors. Bayesian joint models showed that women with ≥ 50% overlap between tamoxifen and CYP2D6 inhibitors had increased recurrence risk compared with 0% overlap (HR: 1.24, 95% CrI: 0.96, 1.58). No recurrence association was seen for CYP2C19 inhibitors (≥ 50% vs. 0%, HR = 1.0, 95% CrI: 0.69, 1.40), but traditional Cox models yielded positive associations for CYP2C19 overlap (≥ 50% vs. 0%, HR = 1.45, 95% CI: 1.07, 1.96). With Bayesian joint models, we observed no association between ≥ 50% versus 0% overlap with CYP3A4/5 inhibitors (HR: 0.84, 95% CrI: 0.32, 1.93).

Conclusions: With Bayesian joint modeling, we saw a slight increase in recurrence among CYP2D6-inhibitor users, but no increase among CYP2C19- or CYP3A4-inhibitor users. Results from Cox regression models were less plausible.

查看原文本刊更多论文

绝经前乳腺癌患者与他莫昔芬的药物相互作用及治疗效果：贝叶斯联合建模方法。

目的：他莫昔芬是绝经前雌激素受体阳性（ER+）乳腺癌的指导治疗。治疗效果部分依赖于他莫昔芬通过CYP2D6、CYP2C19和CYP3A4酶的生物转化。我们进行了一项队列研究，以评估同时服用抑制这些酶的药物是否会影响乳腺癌的复发。方法：我们招募了4493名接受他莫昔芬治疗的绝经前I-III期ER+乳腺癌妇女（2002-2011）。我们将时变cypp抑制药物暴露定义为他莫昔芬治疗期间重叠天数的比例。我们使用贝叶斯联合建模（风险比[HR]和95%可信区间[95% CrI]），(2)传统Cox回归（风险比[HR]和95%可信区间[95% CI]）来估计伴随用药与复发的关系。结果：在他莫昔芬治疗期间，13%的队列患者使用强CYP2D6抑制剂，31%的患者使用弱CYP2D6抑制剂，37%的患者使用CYP2C19抑制剂，12%的患者使用CYP3A4/5抑制剂。贝叶斯联合模型显示，他莫昔芬与CYP2D6抑制剂重叠≥50%的女性与重叠0%的女性相比，复发风险增加（HR: 1.24, 95% CrI: 0.96, 1.58）。CYP2C19抑制剂与复发无相关性（≥50% vs 0%, HR = 1.0, 95% CrI: 0.69, 1.40），但传统Cox模型显示CYP2C19重叠与复发呈正相关（≥50% vs 0%, HR = 1.45, 95% CI: 1.07, 1.96）。通过贝叶斯联合模型，我们观察到CYP3A4/5抑制剂重叠≥50%和0%之间没有关联（HR: 0.84, 95% CrI: 0.32, 1.93）。结论：通过贝叶斯联合建模，我们发现cyp2d6抑制剂使用者的复发率略有增加，但CYP2C19-或cyp3a4抑制剂使用者的复发率没有增加。Cox回归模型的结果不太可信。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Pharmacoepidemiology and Drug Safety 医学-药学

CiteScore

4.80

自引率

7.70%

发文量

173

审稿时长

3 months

期刊介绍： The aim of Pharmacoepidemiology and Drug Safety is to provide an international forum for the communication and evaluation of data, methods and opinion in the discipline of pharmacoepidemiology. The Journal publishes peer-reviewed reports of original research, invited reviews and a variety of guest editorials and commentaries embracing scientific, medical, statistical, legal and economic aspects of pharmacoepidemiology and post-marketing surveillance of drug safety. Appropriate material in these categories may also be considered for publication as a Brief Report. Particular areas of interest include: design, analysis, results, and interpretation of studies looking at the benefit or safety of specific pharmaceuticals, biologics, or medical devices, including studies in pharmacovigilance, postmarketing surveillance, pharmacoeconomics, patient safety, molecular pharmacoepidemiology, or any other study within the broad field of pharmacoepidemiology; comparative effectiveness research relating to pharmaceuticals, biologics, and medical devices. Comparative effectiveness research is the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition, as these methods are truly used in the real world; methodologic contributions of relevance to pharmacoepidemiology, whether original contributions, reviews of existing methods, or tutorials for how to apply the methods of pharmacoepidemiology; assessments of harm versus benefit in drug therapy; patterns of drug utilization; relationships between pharmacoepidemiology and the formulation and interpretation of regulatory guidelines; evaluations of risk management plans and programmes relating to pharmaceuticals, biologics and medical devices.