Meta-Analysis of ABCG2 and ABCB1 Polymorphisms With Sunitinib-Induced Toxicity and Efficacy in Renal Cell Carcinoma

Abstract

Background: ABCG2 and ABCB1 are genes related to the pharmacokinetics of sunitinib and have been associated with its toxicity and efficacy. However, the results have been controversial. This study aimed to evaluate the associations of ABCG2 and ABCB1 polymorphisms with sunitinib-induced toxicity and efficacy in renal cell carcinoma (RCC) by meta-analysis. Methods: PubMed, EMBASE, Cochrane Library, and Web of Science were systematically searched for studies investigating the associations of the ABCG2 rs2231142 polymorphism with sunitinib-induced toxicity and the associations of the ABCB1 rs1128503 and ABCB1 rs2032582 polymorphisms with sunitinib-induced toxicity and clinical outcomes. The associations were evaluated by effect size (ES) with 95% confidence intervals (CIs). Results: Eight and five studies were included in the toxicity and efficacy analysis, respectively, including a total of 1081 RCC patients. The ABCG2 rs2231142 A allele was associated with an increased risk of sunitinib-induced thrombocytopenia and hand-foot syndrome (HFS) in Asians (ES = 1.65, 95% CI = 1.15-2.36, p = 0.006; ES = 1.52, 95% CI = 1.02-2.27, p = 0.041). However, the ABCG2 rs2231142 polymorphism was not associated with sunitinib-induced hypertension or neutropenia (ES = 1.09, 95% CI = 0.69-1.73, p = 0.701; ES = 0.87, 95% CI = 0.57-1.31, p = 0.501). Compared with the C allele, the ABCB1 rs1128503 T allele was associated with a decreased risk of sunitinib-induced hypertension but worse progression-free survival (PFS) (ES = 0.44, 95% CI = 0.26-0.77, p = 0.004; ES = 1.36, 95% CI = 1.07-1.73, p = 0.011). There was no significant association between the T allele or C allele of ABCB1 rs1128503 and overall survival (OS) (ES = 0.82, 95% CI = 0.61-1.10, p = 0.184). The ABCB1 rs2032582 T allele was associated with worse PFS than the other alleles (ES = 1.46, 95% CI = 1.14-1.87, p = 0.003), while there was no significant association between the T allele or other alleles and sunitinib-induced hypertension, HFS, or OS (ES = 0.77, 95% CI = 0.46-1.29, p = 0.326; ES = 1.02, 95% CI = 0.65-1.62, p = 0.919; ES = 1.32, 95% CI = 0.85-2.05, p = 0.215). Conclusion: The results indicate that the ABCG2 rs2231142 polymorphism may serve as a predictor of sunitinib-induced thrombocytopenia and HFS in Asians, while the ABCB1 rs1128503 polymorphism may serve as a predictor of sunitinib-induced hypertension, and both the ABCB1 rs1128503 and rs2032582 polymorphisms may serve as predictors of PFS in RCC. These results suggest a possible application of individualized use of sunitinib according to the genetic background of patients.

Keywords: ABCB1; ABCG2; meta-analysis; polymorphism; renal cell carcinoma; sunitinib.

FIGURE 1

Flow diagram of the study selection process.

FIGURE 2

Forest plots estimating the associations of ABCG2 rs2231142 polymorphism with sunitinib-induced toxicity and the corresponding sensitivity analysis (A allele vs. C allele). The ABCG2 rs2231142 A allele was significantly associated with an increased risk of thrombocytopenia in Asians compared with the C allele, while there were no significant associations between the A allele and C allele in hypertension, HFS, or neutropenia. The sensitivity analysis showed that no single study qualitatively altered the pooled ES of thrombocytopenia and neutropenia; however, the study by Diekstra et al. altered the hypertension results, and the study by Garcia-Donas et al. altered the HFS results.

FIGURE 3

Forest plots estimating the associations of the ABCG2 rs2231142 polymorphism with sunitinib-induced toxicities in Asians and the corresponding sensitivity analysis (A allele vs. C allele). Compared with the C allele, the ABCG2 rs2231142 A allele was significantly associated with an increased risk of HFS in Asians. There were no significant associations between the A allele and C allele in hypertension in this population. The sensitivity analysis showed that no single study qualitatively altered the pooled ES.

FIGURE 4

Forest plots estimating the associations of the ABCB1 rs1128503 polymorphism with sunitinib-induced hypertension, progression-free survival (PFS), and overall survival (OS), and the corresponding sensitivity analysis (T allele vs. C allele). Compared with the C allele, the ABCB1 rs1128503 T allele was significantly associated with a decreased risk of hypertension and worse PFS. There was no significant association between the T allele and C allele in OS. The sensitivity analysis showed that no single study qualitatively altered the pooled ES of hypertension; however, the study by Beuselinck et al. altered the PFS results, and the study by Diekstra et al. altered the OS results.

FIGURE 5

Forest plots estimating the associations of the ABCB1 rs2032582 polymorphism with sunitinib-induced hypertension, hand-foot syndrome (HFS), progression-free survival (PFS), and overall survival (OS), and the corresponding sensitivity analysis (T allele vs. other alleles). Compared with the other alleles, the ABCB1 rs2032582 T allele was significantly associated with worse PFS. In contrast, there was no significant association between the T allele and other alleles in sunitinib-induced hypertension, HFS, or OS. The sensitivity analysis showed that no single study qualitatively altered the pooled ES.

FIGURE 6

Forest plots estimating the associations of ABCB1 rs1128503 polymorphism with sunitinib-induced progression-free survival (PFS) and overall survival (OS) when we omitted the article that altered the pooled ES (T allele vs. C allele). The ABCB1 rs1128503 polymorphism was associated with PFS but not OS, and no single study qualitatively altered the pooled ES in both analysis.