Effect of MRP2 and MRP3 Polymorphisms on Anastrozole Glucuronidation and MRP2 and MRP3 Gene Expression in Normal Liver Samples

Edavana, Vineetha Koroth; Penney, Rosalind B.; Yao-Borengasser, Aiwei; Starlard‐Davenport, Athena; Dhakal, Ishwori; Kadlubar, Susan

doi:10.16966/2381-3318.112

Cited by 6 publications

(1 citation statement)

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“…In any case, the fact that the precise link between anastrozole levels and the onset of musculoskeletal symptoms is yet to be elucidated makes these results hard to interpret. By contrast, the consequences of an altered ABCB1 Table 3 Association of TCL1A, ABCB1 and CYP19A1 polymorphisms with the onset of arthralgia in postmenopausal, hormone-receptor positive breast cancer patients [32], the main elimination pathway for this drug [33].…”

Section: Discussionmentioning

confidence: 99%

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

Gervasini

Jara

Olier

et al. 2016

Brit J Clinical Pharma

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Keywords anastrozole, arthralgia, breast cancer, single nucleotide polymorphisms AIMSAnastrozole, 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. METHODSThis 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. RESULTSAnastrozole concentrations showed an almost nine-fold interindividual variability (mean 26.95 ± 11.91 ng ml À1 ). The ABCB1 2677-TT genotype was associated with higher plasma levels (32.22 ± 12.82 vs. 25.86 ± 11.56 ng ml À1 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). CONCLUSIONOur 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. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2017) 83 562-571 562

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Section: Discussionmentioning

confidence: 99%

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

Gervasini

Jara

Olier

et al. 2016

Brit J Clinical Pharma

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Regression and Genomic Analyses on the Association Between Dose-Normalized Mycophenolic Acid Exposure and Absolute Neutrophil Count in Steroid-Free, De Novo Kidney Transplant Recipients

et al. 2018

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Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients

et al. 2018

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The differences in patients’ response to the same medication, toxicity included, are one of the major problems in breast cancer treatment. Chemotherapy toxicity makes a significant clinical problem due to decreased quality of life, prolongation of treatment and reinforcement of negative emotions associated with therapy.In this study we evaluated the genetic and clinical risk factors of FAC chemotherapy-related toxicities in the group of 324 breast cancer patients. Selected genes and their polymorphisms were involved in FAC drugs transport (ABCB1, ABCC2, ABCG2,SLC22A16), metabolism (ALDH3A1, CBR1, CYP1B1, CYP2C19, DPYD, GSTM1, GSTP1, GSTT1, MTHFR,TYMS), DNA damage recognition, repair and cell cycle control (ATM, ERCC1, ERCC2, TP53, XRCC1).The multifactorial risk models that combine genetic risk modifiers and clinical characteristics were constructed for 12 toxic symptoms. The majority of toxicities was dependent on the modifications in components of more than one pathway of FAC drugs, while the impact level of clinical factors was comparable to the genetic ones. For the carriers of multiple high risk factors the chance of developing given symptom was significantly elevated which proved the factor-dosage effect. We found the strongest associations between concurrent presence of clinical factors - overall and recurrent anemia, nephrotoxicity and early nausea and genetic polymorphisms in genes responsible for DNA repair, drugs metabolism and transport pathways. These results indicate the possibility of selection of the patients with expected high tolerance to FAC treatment and consequently with high chance of chemotherapy completion without the dose reduction, treatment delays and decline in the quality of life.

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Effect of MRP2 and MRP3 Polymorphisms on Anastrozole Glucuronidation and MRP2 and MRP3 Gene Expression in Normal Liver Samples

Cited by 6 publications

References 43 publications

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

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

Regression and Genomic Analyses on the Association Between Dose-Normalized Mycophenolic Acid Exposure and Absolute Neutrophil Count in Steroid-Free, De Novo Kidney Transplant Recipients

Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients

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