Beuselinck Benoit, Lambrechts Diether, Van Brussel Thomas, Wolter Pascal, Cardinaels Nina, Joniau Steven, Lerut Evelyne, Karadimou Alexandra, Couchy Gabrielle, Sebe Philippe, Ravaud Alain, Zerbib Marc, Caty Armelle, Paridaens Robert, Schöffski Patrick, Verkarre Virginie, Berger Julien, Patard Jean-Jacques, Zucman-Rossi Jessica, Oudard Stéphane
Department of General Medical Oncology and Laboratory for Experimental Oncology, University Hospitals Leuven, Leuven Cancer Institute , KU Leuven, Leuven , Belgium.
Acta Oncol. 2014 Oct;53(10):1413-22. doi: 10.3109/0284186X.2014.918276. Epub 2014 May 30.
There is growing evidence that sunitinib plasma levels have an impact on treatment outcome in patients with metastatic renal cell carcinoma (mRCC). We studied the impact of single nucleotide polymorphisms (SNPs) in genes involved in sunitinib pharmacokinetics, and additionally, sunitinib pharmacodynamics on dose reductions of the tyrosine kinase inhibitor.
We retrospectively analyzed germ-line DNA retrieved from mRCC patients receiving sunitinib as first-line therapy. We genotyped 11 key SNPs, respectively, in ABCB1, NR1/2, NR1/3 and CYP3A5, involved in sunitinib pharmacokinetics as well as VEGFR1 and VEGFR3, which have been suggested as regulators of sunitinib pharmacodynamics. Association between these SNPs and time-to-dose-reduction (TTDR) was studied by Cox regression.
We identified 96 patients who were treated with sunitinib and from whom germ-line DNA and data on dose reductions were available. We observed an increased TTDR in patients carrying the TT-genotype in ABCB1 rs1125803 compared to patients with CC- or CT-genotypes (19 vs. 7 cycles; p = 0.031 on univariate analysis and p = 0.012 on multivariate analysis) and an increased TTDR in patients carrying the TT/TA-variant in ABCB1 rs2032582 compared to patients with the GG- or GT/GA-variant (19 vs. 7 cycles; p = 0.046 on univariate analysis and p = 0.024 on multivariate analysis).
mRCC patients carrying the rs1128503 TT-variant or the TT/TA-variant in rs2032582 in ABCB1, which encodes for an efflux pump, do require less dose reductions due to adverse events compared to patients with the wild type or heterozygote variants in these genes.
越来越多的证据表明，舒尼替尼的血浆水平会影响转移性肾细胞癌（mRCC）患者的治疗结果。我们研究了参与舒尼替尼药代动力学的基因中的单核苷酸多态性（SNP）的影响，此外，还研究了舒尼替尼药效学对酪氨酸激酶抑制剂剂量减少的影响。
我们回顾性分析了接受舒尼替尼一线治疗的mRCC患者的生殖系DNA。我们分别对参与舒尼替尼药代动力学的ABCB1、NR1/2、NR1/3和CYP3A5以及被认为是舒尼替尼药效学调节剂的VEGFR1和VEGFR3中的11个关键SNP进行了基因分型。通过Cox回归研究这些SNP与剂量减少时间（TTDR）之间的关联。
我们确定了96例接受舒尼替尼治疗的患者，他们的生殖系DNA和剂量减少数据可用。我们观察到，与CC或CT基因型患者相比，ABCB1 rs1125803携带TT基因型的患者TTDR增加（19个周期对7个周期；单变量分析p = 0.031，多变量分析p = 0.012），与GG或GT/GA变体患者相比，ABCB1 rs2032582携带TT/TA变体的患者TTDR增加（19个周期对7个周期；单变量分析p = 0.046，多变量分析p = 0.024）。
与这些基因中野生型或杂合子变体的患者相比，ABCB1中编码外排泵的rs1128503 TT变体或rs2032582中的TT/TA变体的mRCC患者由于不良事件而需要减少剂量的情况较少。
