Genetic Variations of Drug Transporters Can Influence on Drug Response in Patients Treated with Docetaxel Chemotherapy

Abstract

PurposeDose-limiting toxicities of docetaxel are widely considered to be neutropenia, anemia, skin toxicity, and nausea. One of the factors that limit the use of docetaxel is its unpredictability of inter-individual variation in toxicity.Materials and MethodsIn order to identify the genetic factors that affect the risk of docetaxel-induced toxicities, we recruited patients who received docetaxel chemotherapy. We genotyped 92 patients with single-nucleotide polymorphisms (SNPs) in 5 genes: CYP3A4 (CYP3A4*1B, CYP3A4*18, and CYP3A4*3), CYP3A5 (CYP3A5*2 and CYP3A5*3), ABCB1 (C1236T, G2677G/T, and C3435T), SLCO1B3 (rs11045585), and ABCC2 (rs12762549).ResultsOut of 92 patients, 70 had grade 3 or 4 neutropenia; 4 had grade 1 or 2; and 18 had no toxicity (76.1%, 4.3%, and 19.6%, respectively). The findings of the SNP analysis showed that patients with TT genotype of ABCB1 3435C>T polymorphism showed significantly higher risk of neutropenia and anemia (p=0.029 and p=0.044, respectively). There were significant associations between docetaxel-induced leucopenia and 2677G/T of ABCB1 and rs12762549 of ABCC2 (p=0.025 and p=0.028, respectively). In a multivariate analysis, we observed that patients carrying 2677G>T in ABCB1might be associated with higher risk of chemo-resistance when treated with docetaxel (odds ratio [OR], 6.48; confidence interval, 1.92 to 21.94; p=0.003). In a subgroup analysis of non-small cell lung cancer patients, a significant association of tumor response with G2677T/A (OR, 4.54) in ABCB1 and SLCO1B3 (OR, 9.44) was observed.ConclusionOur data suggest that ABCB1 (2677G/T) and SLCO1B3 (rs11055585) might be major genetic predictors of docetaxel-related toxicities in patients receiving docetaxel chemotherapy.

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

“…fever, pleural effusions and febrile neutropenia) [120]. An increased risk of docetaxel-induced haematological toxicities was also observed among Korean cancer patients with the 3435TT and 2677G/T genotypes [121].…”

Efflux Transporter Variants as Predictors of Drug Toxicity in Lung Cancer Patients: Systematic Review and Meta-Analysis

“…Significantly improved tumor response to docetaxel, as determined by complete response, partial response, stable disease and progressive disease markers, was noted in lung cancer patients expressing ABCB1 2677G>T/A [41]. A separate study further showed an future science group Efflux transporter variants as predictors of drug toxicity in lung cancer patients Systematic Review ?…”

“…Patient sample size varied widely, ranging between 14 and 731 (total 3578; median 90), with the majority of patient ethnicity being derived from east Asia (Table 1). Many studies focused on patients with advanced stages of NSCLC (stage III and IV), however, cancer type and stages were not given for eight studies (Table 1) [26,27,31,38,39,[41][42][43]. Of the studies described here only five documented the smoking status for their patient cohort [21,34,[44][45][46][47][48].…”

“…A total of 16 publications were identified for ABCB1, including one retrospective case-control [25], two Phase II RCT [26,29] and 13 observation studies [19][20][21][22]27,28,41,48,[51][52][53]55,56]. Publication quality, as determined by the Cochrane Collaboration Risk of Bias Tool, is summarized in Figure 2.…”

Cytochrome P-450 Polymorphisms and Clinical Outcome in Patients with Non-Small Cell Lung Cancer

“…Choi et al 26 investigated the influences of CYP3A4 polymorphisms on response to chemotherapy in patients who had various type of cancer, including lung cancer ( Table 4). The authors genotyped CYP3A4 polymorphisms, namely CYP3A4*1B, CYP3A4*3, and CYP3A4*18, but could find no association between these polymorphisms and response to chemotherapy in patients with lung cancer treated with docetaxel concomitantly with cisplatin, doxorubicin, capecitabine, cisplatin-cetuximab, and ifosfamide.…”