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Effect of genetic polymorphisms in CYP3A4, CYP3A5, and m-TOR on everolimus blood exposure and clinical outcomes in cancer patients


Genetic variations in CYP3A4, CYP3A5, and m-TOR could contribute to interpatient variability regarding m-TOR inhibitors pharmacokinetics or cellular effects. The purpose of this study was to evaluate the influence of selected candidate variations in these genes on everolimus pharmacokinetics, efficacy, and toxicity in cancer patients. Thirty-four patients receiving everolimus for breast (n = 22) or renal (n = 10) cancers, or neuroendocrine tumors of pancreatic origin (n = 2) were included in the study. Six variants in genes related to everolimus pharmacokinetics (CYP3A4*22 and CYP3A5*3) or pharmacodynamics (m-TOR rs2295079, rs2295080, rs2024627 and rs1057079) were genotyped. Associations with trough concentrations (C0), dose reductions, or treatment interruptions due to toxicity and progression-free survival were investigated using generalized estimating equations and Cox models. CYP3A5 nonexpressers had significantly higher C0 as compared with expressers (βGG vs AG = + 6.32 ± 2.22 ng/mL, p = 0.004). m-TOR rs2024627 was significantly associated with an increased risk of cancer progression studied alone or as part of an haplotype (T vs C: HR = 2.60, 95% CI [1.16–5.80], p = 0.020; CTCG vs other haplotypes HR = 2.29, 95% CI [1.06–4.95], p = 0.035, respectively). This study showed that CYP3A5 expression impacts everolimus pharmacokinetics in cancer patients and identified a genetic variation in m-TOR associated with the risk of cancer progression.

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Fig. 1: Boxplots representing EVR troguh variations as function of CYP3A4*22 and CYP3A5*3 genotypes studied independantly or conjointly as metabolic status.
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We are grateful to K. Poole for manuscript editing.

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Correspondence to Jean-Baptiste Woillard.

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SF receives funding from Novartis, Pfizer, Sanofi, BMS, Jansen, and Amgen; the other authors have no conflict of interest to declare.

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Bonnet, S., Falkowski, S., Deppenweiler, M. et al. Effect of genetic polymorphisms in CYP3A4, CYP3A5, and m-TOR on everolimus blood exposure and clinical outcomes in cancer patients. Pharmacogenomics J 20, 647–654 (2020).

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