CYP2C8*3 was significantly associated with increased risks of severe (grades 3-4) neutropenia (OR<sub>adjusted</sub> 2.11; 95% CI 1.24-3.6; dominant model) and severe thrombocytopenia (OR<sub>adjusted</sub> 4.93; 95% CI 1.69-14.35; recessive model), whereas ABCB1 variant genotypes (OR<sub>adjusted</sub> 2.13; 95% CI 1.32-3.42), in association with CYP2C8*3 wild type (GG) (OR<sub>adjusted</sub> 1.93; 95% CI 1.17-3.19), were predictive of severe fatigue.
These results suggest that genetic variation in ABCC1 and ABCB1 may contribute to irinotecan-induced neutropenia by altering expression of transporters involved in irinotecan metabolite disposition.
Associations were found between toxicities and gene variants (P<0.05), including neutropenia with ABCB1 (rs1045642) and SLC0B3 (rs4149117 and rs7311358); and diarrhoea with CYP2C9 (rs1057910), CYP2C19 (rs3758581), UGT1A6 (rs4124874) and SLC22A1 (rs72552763).
Meta-analysis showed an decreased risk of irinotecan-induced neutropenia in patients expressing ABCB1 2677G>T/G (odds ratio [OR]: 0.24; 95% CI: 0.1-0.59; p = 0.002) but increased risk for ABCC2 3972T>T (OR: 1.67; 95% CI: 1.01-2.74; p = 0.04).
On evaluating higher order gene-gene interaction models by MDR analysis, CYP3A5*3; ABCB11236C>T and ABCB1 2677G>T/A; ABCB1 3435C>T and CYP1B1*3 showed significant association with treatment response, grade 2-4 anemia and dose delay/reduction due to neutropenia (P=0.024, P=0.004, P=0.026), respectively.
In addition, a statistically significant association was found among neutropenia (absolute neutrophil count<500) and variant allele carriers of ABCB1 rs1045642 (OR=5.174; 95% CI: 1.674; 15.989) and ABCB1 rs1128503 (OR=3.364; 95% CI: 1.257; 9.004), respectively.
In addition, a statistically significant association was found among neutropenia (absolute neutrophil count<500) and variant allele carriers of ABCB1rs1045642 (OR=5.174; 95% CI: 1.674; 15.989) and ABCB1rs1128503 (OR=3.364; 95% CI: 1.257; 9.004), respectively.
CYP2C8*3 and the ABCB1 SNPs C1236T, G2677T/A, and C3435T were not statistically significantly correlated to overall survival, sensoric neuropathy, and neutropenia in 119 patients treated for ovarian cancer with paclitaxel/carboplatin.
PG analysis showed that ABCB1 (C3435T)T/T (membrane transport) was associated with IP-related diarrhea; UGT1A1 (G-3156A)A/A (drug metabolism) was associated with IP-related neutropenia.
Polymorphisms that are associated with ABCB1 expression and function may be linked to treatment efficacy and the development of neutropenia and neurotoxicity in patients with androgen-independent prostate cancer receiving docetaxel.
Since one SNP in ABCB1, four SNPs in ABCC2, four SNPs in SLCO1B3, and one SNP in NR1I2 showed a possible association with the grade 3 leukopenia/neutropenia (P-value of <0.05), we further examined these 10 SNPs using 29 additionally obtained patients, 11 patients with grade 3/4 leukopenia/neutropenia, and 18 with no toxicity.
This pilot study suggests that paclitaxel-induced neuropathy and neutropenia might be linked to inherited variants of ABCB1 through a mechanism that is unrelated to altered plasma pharmacokinetics.
This pilot study suggests that paclitaxel-induced neuropathy and neutropenia might be linked to inherited variants of ABCB1 through a mechanism that is unrelated to altered plasma pharmacokinetics.