Priyadarshini Rekha, Raj Gerard Marshall, Kayal Smita, Ramesh Ananthakrishnan, Shewade Deepak Gopal
Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.
Department of Pharmacology, Sri Venkateshwaraa Medical College Hospital and Research Centre (SVMCH & RC), Puducherry, India.
J Clin Pharm Ther. 2019 Apr;44(2):188-196. doi: 10.1111/jcpt.12797. Epub 2019 Jan 13.
Variable response to docetaxel-based neo-adjuvant chemotherapy (NACT) in breast cancer patients had been reported. Genetic polymorphisms in the ABCB1 gene coding for the efflux transporter MDR1 (P-glycoprotein, P-gp) could result in altered tumour response. Hence, this study was proposed to assess the effect of single nucleotide polymorphisms (SNPs) of ABCB1 gene on tumour response in locally advanced breast cancer patients (LABC) of South India who have a distinct genetic makeup.
Out of 162 LABC patients recruited, 129 patients were included for the final analysis. DNA was extracted by "phenol-chloroform extraction method" from the WBCs, and genotyping for SNPs rs1045642 (C3435T) and rs1128503 (C1236T) in ABCB1 gene was performed with real-time PCR system using validated TaqMan SNP genotyping assay method. Tumour response was assessed by RECIST criteria based on the MRIs taken before and after completion of four cycles of docetaxel therapy.
A total of 102 (79.1%) patients were found to be responders and 27 (20.9%) patients were found to be non-responders to docetaxel therapy. Patients with "CT/TT" genotypes (response rate: 83.3%) of ABCB1 (C1236T) gene showed better tumour response than those with "CC" genotype (response rate: 16.6%) [OR = 2.94 (CI: 1.15-7.52); P = 0.03]. However, on performing binary logistic regression, neither the studied SNPs nor the non-genetic factors like age, BMI, postmenopausal status, laterality of the tumour, ER status, PR status and Her-2/neu status were found to be associated with tumour response to docetaxel (P > 0.05).
The tumour response to docetaxel was significantly influenced by the SNP C1236T of ABCB1 gene coding for the P-gp. However, when adjusted for other non-genetic factors, neither of the ABCB1 variants were found to be associated with tumour response to docetaxel-based NACT in LABC patients of South India.
已有报道称乳腺癌患者对基于多西他赛的新辅助化疗（NACT）存在不同反应。编码外排转运蛋白MDR1（P-糖蛋白，P-gp）的ABCB1基因中的基因多态性可能导致肿瘤反应改变。因此，本研究旨在评估ABCB1基因单核苷酸多态性（SNP）对印度南部具有独特基因构成的局部晚期乳腺癌（LABC）患者肿瘤反应的影响。
在招募的162例LABC患者中，129例患者纳入最终分析。采用“酚-氯仿提取法”从白细胞中提取DNA，并使用经过验证的TaqMan SNP基因分型检测方法，通过实时PCR系统对ABCB1基因中的SNP rs1045642（C3435T）和rs1128503（C1236T）进行基因分型。根据多西他赛治疗四个周期前后的MRI检查，采用RECIST标准评估肿瘤反应。
共发现102例（79.1%）患者对多西他赛治疗有反应，27例（20.9%）患者无反应。ABCB1（C1236T）基因“CT/TT”基因型患者（反应率：83.3%）的肿瘤反应优于“CC”基因型患者（反应率：16.6%）[OR = 2.94（CI：1.15 - 7.52）；P = 0.03]。然而，进行二元逻辑回归分析时，所研究的SNP以及年龄、BMI、绝经后状态、肿瘤侧别、ER状态、PR状态和Her-2/neu状态等非遗传因素均未发现与多西他赛的肿瘤反应相关（P > 0.05）。
编码P-gp的ABCB1基因的SNP C1236T对多西他赛的肿瘤反应有显著影响。然而，在对其他非遗传因素进行校正后，在印度南部LABC患者中，未发现ABCB1的任何变体与基于多西他赛的NACT的肿瘤反应相关。
