The influence of single-nucleotide polymorphisms on overall survival and toxicity in cabazitaxel-treated patients with metastatic castration-resistant prostate cancer

Abstract

Purpose Cabazitaxel, used in patients with metastatic castration-resistant prostate cancer (mCRPC), is associated with adverse events which may require dose reductions or discontinuation of treatment. We investigated the potential association of single-nucleotide polymorphisms (SNPs) in genes encoding drug transporters and drug-metabolizing enzymes with cabazitaxel toxicity, overall survival (OS) and pharmacokinetics (PK). Methods A total of 128 cabazitaxel-treated mCRPC patients, of whom prospectively collected data on toxicity and OS were available and 24 mCRPC patients with available cabazitaxel PK measurements, were genotyped using genomic DNA obtained from EDTA blood. The SLCO1B1 (388A > G; *1B; rs2306283 and 521 T > C; *5; rs4149056 and haplotype SLCO1B1*15), SLCO1B3 (334 T > G; rs4149117), CYP3A4 (*22; rs35599367), CYP3A5 (*3; rs776746), ABCB1 (3435C > T; rs1045642), and TUBB1 (57 + 87A > C; rs463312) SNPs were tested for their association with clinical and PK parameters by univariate/ multivariate logistic regression, log-rank test, or Kruskal-Wallis test. Results The SLCO1B1*15 haplotype was significantly associated with a lower incidence of leukopenia and neutropenia (p = 0.020 and p = 0.028, respectively). Patients harboring a homozygous variant for SLCO1B1*1B experienced higher rate ≥ grade 3 (p = 0.042). None of the SNPs were associated with pharmacokinetics or OS. Conclusions In this study, SLCO1B1 (SLCO1B1*15 and SLCO1B1*1B) was associated with cabazitaxel-induced adverse events in mCRPC patients. As the associations were opposite to previous studies in other drugs and contradicted an underlying pharmacokinetic rationale, these findings are likely to be false-positive and would ideally be validated with even larger (pharmacokinetic) cohorts.

The SNPs rs429358 and rs7412 of APOE gene are association with cerebral infarction but not SNPs rs2306283 and rs4149056 of SLCO1B1 gene in southern Chinese Hakka population

“…These two SNPs can be combined to produce four different haplotypes: *1a (388A-521 T), *1b (388G-521 T), *5 (388A-521C) and *15 (388G-521C) [15][16][17]. Most studies to date on SLCO1B1 have focused on the effect of SLCO1B1 polymorphisms on the pharmacokinetics, efficacy and side effects of oral hypoglycemic agents, statins, and antitumor agents [18,19].…”

Long-Term Prostate-Specific Antigen Response on a Low-Dose Cabazitaxel Regimen for Metastatic Castration-Resistant Prostate Cancer: A Case Report

“…Although the mechanisms responsible for the long-term response and severe thrombocytopenia in our patient are unknown, the pharmacokinetics of cabazitaxel may be relevant. Cabazitaxel is a substrate of the transmembrane transporters P-glycoprotein (encoded by the gene ABCB1 ), OATP1B1 ( SLCO1B1 ) and OATP1B3 ( SLCO1B3 ) and is mainly metabolized by isoenzymes CYP3A4/5 and to a lesser extent by CYP2C8 in the liver [ 17 – 19 ]. Some single-nucleotide polymorphisms in these genes are known to affect the pharmacokinetics of cabazitaxel and are associated with the incidence of grade 3–4 toxicity, although their impact on therapeutic efficacy for CRPC has not been established [ 19 ].…”

“…Cabazitaxel is a substrate of the transmembrane transporters P-glycoprotein (encoded by the gene ABCB1 ), OATP1B1 ( SLCO1B1 ) and OATP1B3 ( SLCO1B3 ) and is mainly metabolized by isoenzymes CYP3A4/5 and to a lesser extent by CYP2C8 in the liver [ 17 – 19 ]. Some single-nucleotide polymorphisms in these genes are known to affect the pharmacokinetics of cabazitaxel and are associated with the incidence of grade 3–4 toxicity, although their impact on therapeutic efficacy for CRPC has not been established [ 19 ]. In the present case, no drugs affecting the pharmacokinetics of cabazitaxel, such as inhibitors of CYP3A or OATP1B, were administered during treatment.…”

The SNPs rs429358 and rs7412 of APOE gene are association with cerebral infarction but not SNPs rs2306283 and rs4149056 of SLCO1B1 gene in southern Chinese Hakka population

“…These two SNPs can be combined to produce four different haplotypes: *1a (388A-521T), *1b (388G-521T), *5 (388A-521C) and *15 (388G-521C) [15][16][17]. Most studies to date on SLCO1B1 have focused on the effect of SLCO1B1 polymorphisms on the pharmacokinetics, e cacy and side effects of oral hypoglycemic agents, statins, and antitumor agents [18,19].…”