Priyadarshini Rekha, Raj Gerard Marshall, Sundaram Rajan, Kayal Smita, Ramesh Ananthakrishnan, Shewade Deepak Gopal
Department of Pharmacology, Indira Gandhi Medical College & Research Institute (IGMC & RI), Puducherry, 605009, India.
Department of Pharmacology, Sri Venkateshwaraa Medical College Hospital and Research Centre (SVMCH & RC), Puducherry, 605102, India.
Breast Cancer. 2021 Mar;28(2):414-423. doi: 10.1007/s12282-020-01177-x. Epub 2020 Oct 30.
Genetic factors could be attributed to the variability in docetaxel plasma levels and its subsequent therapeutic response. The objectives of this study were to assess the effect of ABCB1 gene polymorphisms [SNPs rs1045642 (C3435T) and rs1128503 (C1236T)] on docetaxel plasma levels and also to analyze the influence of docetaxel plasma levels on tumour response in the ethnically distinct South Indian population.
104 locally advanced breast cancer (LABC) patients on docetaxel-based neo-adjuvant chemotherapy (NACT) were included. The plasma docetaxel levels were estimated using the validated reverse phase liquid chromatography with mass spectrometry (LC-MS/MS). DNA was extracted (phenol-chloroform extraction method) and the real-time PCR system using validated TaqMan® SNP genotyping assay method was used for genotyping. Tumour response was assessed by RECIST criteria based on the MRI images.
Patients with "CT/TT" genotype of the SNP C1236T had a C/C ratio of 1.6 times higher than those with "CC" genotype (13.5 ± 6.5 vs 8.3 ± 3.1, p = 0.002). Though not significant, patients with "CT/TT" genotype had greater initial plasma concentration (C) and area under the plasma concentration-time curve (AUC). Conversely, the SNP C3435T was not associated with the plasma docetaxel levels. Furthermore, the C and normalized C were found to be higher in tumour responders compared to non-responders (p < 0.05).
The plasma levels of docetaxel were significantly influenced by the SNP C1236T of ABCB1 gene coding for the MDR1 transporter (P-glycoprotein). The plasma levels of docetaxel were also found to influence its therapeutic effect.
遗传因素可能导致多西他赛血浆水平的变异性及其后续治疗反应。本研究的目的是评估ABCB1基因多态性[单核苷酸多态性（SNP）rs1045642（C3435T）和rs1128503（C1236T）]对多西他赛血浆水平的影响，并分析多西他赛血浆水平对不同种族的南印度人群肿瘤反应的影响。
纳入104例接受以多西他赛为基础的新辅助化疗（NACT）的局部晚期乳腺癌（LABC）患者。采用经过验证的反相液相色谱-质谱联用（LC-MS/MS）法测定血浆多西他赛水平。提取DNA（酚-氯仿提取法），并使用经过验证的TaqMan®SNP基因分型检测方法的实时PCR系统进行基因分型。根据MRI图像，采用RECIST标准评估肿瘤反应。
SNP C1236T的“CT/TT”基因型患者的C/C比值比“CC”基因型患者高1.6倍（13.5±6.5对8.3±3.1，p = 0.002）。虽然不显著，但“CT/TT ”基因型患者的初始血浆浓度（C）和血浆浓度-时间曲线下面积（AUC）更高。相反，SNP C3435T与血浆多西他赛水平无关。此外，与无反应者相比，肿瘤反应者的C和标准化C更高（p < 0.05）。
编码多药耐药蛋白1转运体（P-糖蛋白）的ABCB1基因的SNP C1236T对多西他赛的血浆水平有显著影响。还发现多西他赛的血浆水平会影响其治疗效果。
