Polymorphisms in ABCB1 and CYP19A1 genes affect anastrozole plasma concentrations and clinical outcomes in postmenopausal breast cancer patients.

Abstract

Anastrozole, an aromatase inhibitor widely used in breast cancer, has recently been indicated to be a P-glycoprotein (ABCB1) substrate. We have aimed to determine whether ABCB1 single-nucleotide polymorphisms (SNPs) can affect anastrozole plasma concentrations in these patients. In addition, we assessed the impact of SNPs in CYP19A1 and TCL1A on the development of arthralgia and cancer recurrence in our series. This study included 110 postmenopausal women with hormone receptor-positive breast cancer. Anastrozole plasma levels were determined by a liquid chromatography-electrospray ionization-quadrupole-time-of-flight mass spectrometry system. Patients were genotyped for SNPs in the ABCB1, TCL1A and CYP19A1 genes to search for associations with pharmacokinetic and pharmacodynamics parameters using logistic regression models. Anastrozole concentrations showed an almost nine-fold interindividual variability (mean 26.95±11.91ngml-1 ). The ABCB1 2677-TT genotype was associated with higher plasma levels (32.22±12.82 vs. 25.86±11.56ngml-1 for GG/GT subjects; 95% confidence interval: -12.3 to -0.40), whilst the 3435-TT genotype showed a protective effect on the risk of arthralgia (odds ratio =0.32 [0.11-0.89]; P=0.029). The CYP19A1 rs1008805 GG genotype was strongly and inversely associated with arthralgia (odds ratio=0.24 [0.09-0.65], P=0.004); however, SNPs near the TCL1A gene were not linked to this adverse effect. None of the patients who had cancer recurrence harboured the CYP19A1 rs727479 AA genotype, which, in contrast, was present in 38% of patients who did not relapse (P for trend=0.031). Our findings indicate that variability in anastrozole plasma levels may be attributable to the status of the ABCB1 gene locus. Furthermore, genetic variants in CYP19A1 were associated with arthralgia and cancer recurrence in our patients.