Polymorphisms in SLCO1B3 and NR1I2 as genetic determinants of hematotoxicity of carboplatin and paclitaxel combination

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From: Pharmacogenomics(Vol. 16, Issue 13)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 6,973 words
Lexile Measure: 1530L

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Author(s): Litaty Céphanoée Mbatchi aff1 aff2 aff3 , Antonin Schmitt aff4 , Fabienne Thomas aff4 , Yoann Cazaubon aff3 , Jacques Robert aff5 , Serge Lumbroso aff1 , Jean-Paul Brouillet aff1 aff2 , Philippe Pourquier aff2 , Etienne Chatelut aff4 , Jean-Christophe Boyer aff1 , Alexandre Evrard [*] aff1 aff2 aff3

Keywords:

carboplatin; drug metabolism; hematotoxicity; paclitaxel; pregnane X receptor; PXR; SLCO1B3; SNP

Background

The combination of carboplatin and paclitaxel is one of the main chemotherapy protocols used to treat ovarian and uterine cancers [1,2 ] and lung cancer [3 ]. Both drugs exhibit myelotoxicity as a major side effect [4,5 ]. In a previous study, pharmacokinetics of carboplatin and absolute counts of neutrophils and platelets were used to build pharmacokinetic and pharmacodynamic (PK-PD) models in order to assess the patients' sensitivity to carboplatin hematotoxicity [6 ]. Various demographic and biological data were taken into account in these models, but concomitant treatment was the most relevant covariate. Thus, the combination of carboplatin with paclitaxel is associated with a reduced sensitivity to thrombocytopenia, whereas neutropenia was dramatically increased as compared with carboplatin alone. The influence of two SNPs of GSTP1 (rs1695, rs1138272) and two in ERCC1 (rs11615, rs3212986) was studied, but no association was observed between these polymorphisms and interpatient variability in hematological sensitivity to carboplatin-based regimen. The purpose of the present ancillary study was to widen the pharmacogenetic aspect of the analysis using a candidate gene approach. Among the initial cohort, 201 patients who received a combination of carboplatin and paclitaxel were studied.

Changes in PK and PD processes can both explain the variability of toxic events. Carboplatin toxicity depends on its PKs, especially its renal elimination, as well as on the ability of healthy cells to handle DNA damage and to ensure drug efflux. Thus, in accordance with the pathways described in pharmGKB database [41 ], candidate SNPs in XRCC1, ERCC2, ERCC4, ERCC6, XPA and MLH1 genes (encoding DNA damage recognition and repair proteins) and in the ABCC2 transporter gene were selected for the study. Conversely to carboplatin, paclitaxel exhibits an extensive hepatic metabolism involving phase I enzymes (CYP1B1, CYP3A4, CYP3A5, CYP2C8) and transporters (SLCO1B3, ABCB1, ABCC1, ABCC2) [7,8 ]. SNPs from the nuclear receptors CAR (NR1I3 ) and PXR (NR1I2 ) were also selected because of the crucial role of these genes as ligand-dependent transcription factors regulating the expression of many drug-metabolizing enzymes and transporters [9 ]. The functional impact of these SNPs on the expression of CAR and PXR as well as on their target genes and their ligand-mediated induction was already demonstrated in vitro [10 ]. This is of particular interest since paclitaxel is a ligand of PXR [ 11 ]. Links between NR1I2 and NR1I3 SNPs and the pharmacogenetics of other anticancer drugs were also evidenced, including the PKs of doxorubicin [12 ]; the objective response rate to pazopanib [13 ]; the progression-free survival and risk of neutropenia following sunitinib treatment [14,15 ]; the reduction in nadir hemoglobin, platelets and/or neutrophils from baseline in Chinese patients treated with docetaxel [16 ].

To determine the potential relationship between...

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Gale Document Number: GALE|A428515779