Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

Abstract

Neurotoxicity is one of the most relevant dose-limiting toxicities of the anticancer drug paclitaxel. It exhibits substantial interindividual variability of unknown molecular basis, and represents one of the major challenges for the improvement of paclitaxel therapy. The extensive variability in paclitaxel clearance and metabolism lead us to investigate the association between polymorphisms in paclitaxel elimination pathway and neurotoxicity. We selected 13 relevant polymorphisms in genes encoding paclitaxel metabolizing enzymes (CYP2C8, CYP3A4 and CYP3A5) and transporters (organic anion transporting polypeptide (OATP) 1B1, OATP1B3 and P-glycoprotein) and genotyped them in 118 Spanish cancer patients treated with paclitaxel. After adjusting for age and treatment schedule, CYP2C8 Haplotype C and CYP3A5*3 were associated with protection (hazard ratio (HR) (per allele) ¼ 0.55; 95% confidence interval (CI) ¼ 0.34-0.89; P ¼ 0.014 and HR (per allele) ¼ 0.51; 95%CI ¼ 0.30-0.86; and P ¼ 0.012, respectively) and CYP2C8*3 with increased risk (HR (per allele) ¼ 1.72; 95%CI ¼ 1.05-2.82; and P ¼ 0.032). In each case, the allele causing increased paclitaxel metabolism was associated with increased neurotoxicity, suggesting an important role for metabolism and hydroxylated paclitaxel metabolites. We estimated the HR per paclitaxel-metabolism increasing allele carried across the three polymorphisms to be HR ¼ 1.64 (95% CI ¼ 1.26-2.14; P ¼ 0.0003). The results for P-glycoprotein were inconclusive, and no associations were observed for the other genes studied. The incorporation of this genetic data in treatment selection could help to reduce neurotoxicity events, thereby individualizing paclitaxel pharmacotherapy. These results warrant validation in independent series.

Retrospective study of the impact of pharmacogenetic variants on paclitaxel toxicity and survival in patients with ovarian cancer

“…While this study included far more patients than our study and other previous studies it also raised a debate concerning power and the interpretation of P-values [32][33][34]. Our results however, do agree with the conclusions made by Marsh et al; but are again contrasted by a very recent paper by Leskelä et al [35] who demonstrates an association between CYP2C8*3 and CYP3A5 in a mixed retrospective/prospective study.…”

Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy

“…Although the main goal of this study was to identify neuropathy associated lowfrequency coding variants, we also found two common polymorphisms associated with the neuropathy: CYP2C8 rs1058930 (CYP2C8*4), for which previous studies have found contradictory results (9,14), and PRX rs268674, which was associated with neuropathy risk here for the first time. Further studies should evaluate the relevance of these results.…”

“…Patients with no or low neuropathy (grade 0/1) were censored at total administered cumulative dose. We also evaluated the association using univariate and multivariable Cox regression analysis (14).…”

“…CYP2C8*3 (12)(13)(14), CYP3A4*22 (7), TUBB2A rs909964 and rs909965 (8,9)) influence neuropathy risk, while genome wide genotyping has uncovered novel genes (10,11). A GWAS by our group (11) suggested that the EPHA gene family, which plays a key role in the development of nervous system and in nerve injury repair (15)(16)(17), was a key player for paclitaxel neuropathy susceptibility.…”

Replication of Genetic Polymorphisms Reported to Be Associated with Taxane-Related Sensory Neuropathy in Patients with Early Breast Cancer Treated with Paclitaxel

“…2, 11, and [16][17][18][19][20][21][22][23][24][25][26][27][28][29]. Any studies investigating genetic variations only associated with pharmacokinetic, outcome, or taxane resistance endpoints but not sensory peripheral neuropathy/neurotoxicity were excluded.…”