Background: 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.
Methods: 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.
Results: Patients with "CT/TT" genotype of the SNP C1236T had a C0/Ct 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 (C0) and area under the plasma concentration-time curve (AUC0-t). Conversely, the SNP C3435T was not associated with the plasma docetaxel levels. Furthermore, the C0 and normalized C0 were found to be higher in tumour responders compared to non-responders (p < 0.05).
Conclusions: 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.
Keywords: ATP-binding cassette family B member 1 (ABCB1); Area under the plasma concentration–time curve (AUC); Docetaxel; Locally-advanced breast cancer; Neo-adjuvant chemotherapy.