288P - Effect of ABCB1 gene polymorphisms C3435T and C1236T on tumour response and plasma levels of docetaxel in locally-advanced breast cancer patients of South India receiving neo-adjuvant chemotherapy

Abstract

Variable response to docetaxel, which is given in locally-advanced breast cancer (LABC) patients as a part of neo-adjuvant chemotherapy (NACT), had been reported. This altered response could be due to polymorphisms in the gene (ABCB1) coding for the efflux transporter ABCB1 (MDR1). Objectives: · To evaluate the effect of single nucleotide polymorphisms (SNPs) C3435T (rs1045642) and C1236T (rs1128503) in ABCB1 gene on the tumor response in LABC patients of South India receiving docetaxel as NACT. · To determine the effect of these SNPs on plasma levels of docetaxel. Tumour response to docetaxel was evaluated in 129 LABC patients, out of which plasma levels of docetaxel were estimated in 74. Blood samples were collected at the end of infusion and 1 hour later. DNA was extracted by ‘phenol-chloroform extraction method’ from the leucocytes. Genotyping was performed with RT-PCR System. Tumor response was assessed by RECIST criteria. Plasma levels of docetaxel were estimated by LCMS/MS. Patients with “CT/TT” genotypes (response rate: 66%) of ABCB1 gene (C1236T) showed better tumor response than those with “CC” genotype (response rate: 13%) [OR = 2.94 (CI: 1.15 - 7.52); p = 0.032]. The superior response in “CT/TT” genotypes can be attributed to the presence of “T” allele causing altered function of ABCB1 gene coding for MDR1 transporter. Plasma levels of docetaxel were also in line with the tumor response in “CT/TT” genotypes of ABCB1 gene (C1236T). Mean of the plasma concentration ratios (C0/C1) of docetaxel in “CT/TT” genotypes (13.49 ± 6.48 ng/mL) were significantly higher than those of the “CC” genotype (8.19 ± 3.10 ng/mL) [p = 0.003]. In contrast, the genotypes of C3435T in ABCB1 gene were not found to significantly influence the tumor response or the plasma levels of docetaxel. These results suggest that ABCB1 C1236T polymorphism could significantly influence the treatment response to docetaxel and the plasma levels of docetaxel. Hence, our study emphasizes the importance of ABCB1 genotyping for individualization of docetaxel pharmacotherapy in breast cancer patients.