已经报道了HR+/HER2-乳腺癌转移患者对细胞周期蛋白依赖激酶4和6抑制剂（CDKi）帕博西尼布、利博西尼布和阿贝马西布的治疗反应存在广泛的个体间变异。本研究探讨了230名患者ADME基因中的遗传多态性（负责药物吸收、分布、代谢和消除）对CDKi的安全性影响。选定的终点包括首个治疗周期第14天的3/4级脓毒症、早期剂量限制性毒性（DLT）以及最初三个周期内的剂量降低。我们的分析结果显示，在CYP3A4、CYP3A5、ABCB1和ABCG2基因的多态性和这些终点之间存在关联。同时还研究了它们对CDKi血浆浓度（Ctrough）的影响。具体而言，ABCB1 c.1236C>T和c.2677C>T的多态性与首个治疗周期第14天的3/4级脓毒症显著相关（OR为3.94，95% CI为1.32-11.75；p值为0.014；OR为3.32，95% CI为1.12-9.85；p值为0.030）。此外，ABCB1 c.3435C>T与早期DLTs和剂量降低的风险增加（OR为3.28，95% CI为1.22-8.84，p值为0.019；OR为2.60，95% CI为1.20-5.60，p值为0.015）。CYP3A4*22等位基因的携带者在单变量分析中也表现出较高的早期DLTs风险（OR为3.10，95% CI为1.01-9.56，p值为0.049）。此外，ABCB1 1236T-3435T-2677T（A）变异单倍型的个体与第14天的3/4级脓毒症有显著关联（OR为3.36，95% CI为1.20-9.41；p值为0.021），在单变量分析中与早期DLTs也有关联（OR为3.08，95% CI为1.19-7.95；p值为0.020）。ABCB1 T-T-T（A）单倍型的同型载体趋向于具有较高的利博西尼布Ctrough均值（934.0 ng/mL vs. 752.0 ng/mL和668.0 ng/mL）。尽管初步，这些发现为药代遗传标志物在CDKi安全性评估中的作用提供了有希望的见解，有望有助于解决CDKi反应的个体间变异。版权所有 © 2023 Elsevier Masson SAS出版。

A wide interindividual variability in therapeutic response to cyclin-dependent kinases 4 and 6 inhibitors (CDKis) palbociclib, ribociclib and abemaciclib, among patients with HR+/HER2- metastatic breast cancer has been reported. This study explored the impact of genetic polymorphisms in ADME genes (responsible for drug absorption, distribution, metabolism, and elimination) on CDKis safety profiles in 230 patients. Selected endpoints include grade 3/4 neutropenia at day 14 of the first treatment cycle, early dose-limiting toxicities (DLTs), and dose reductions within the initial three cycles. Our analysis revealed associations between these endpoints and polymorphisms in CYP3A4, CYP3A5, ABCB1, and ABCG2 genes. Their impact on CDKis plasma concentrations (Ctrough) was also examined. Specifically, ABCB1 c.1236C>T and c.2677C>T polymorphisms correlated significantly with grade 3/4 neutropenia at day 14 (OR 3.94, 95% CI 1.32-11.75; p = 0.014 and OR 3.32, 95% CI 1.12-9.85; p = 0.030). Additionally, ABCB1 c.3435C>T was associated with an elevated risk of early DLTs and dose reductions (OR 3.28, 95% CI 1.22-8.84, p = 0.019; OR 2.60, 95% CI 1.20-5.60, p = 0.015). Carriers of the CYP3A4*22 allele also demonstrated in univariate a higher risk of early DLTs (OR 3.10, 95% CI 1.01-9.56, p = 0.049). Furthermore, individuals with the ABCB1 1236T-3435T-2677T(A) variant haplotype exhibited significant associations with grade 3/4 neutropenia at day 14 (OR 3.36, 95% CI 1.20-9.41; p = 0.021) and early DLTs in univariate (OR 3.08, 95% CI 1.19-7.95; p = 0.020). Homozygous carriers of the ABCB1 T-T-T(A) haplotype tended to have a higher mean ribociclib Ctrough (934.0 ng/mL vs. 752.0 ng/mL and 668.0 ng/mL). Regardless preliminary, these findings offer promising insights into the role of pharmacogenetic markers in CDKis safety profiles, potentially contributing to address the interindividual variability in CDKis responses.Copyright © 2023. Published by Elsevier Masson SAS.