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. 2024 Apr 30;15(2):577-584.
doi: 10.21037/jgo-24-188. Epub 2024 Apr 28.

Contribution of genetic polymorphism in ABCB1 to individual variations of imatinib plasma levels in patients with gastrointestinal stromal tumor

Yinggang Ge  1 , Huili Bai  2 , Alessandro Mazzocca  3 , Jun Zhang  1 , Ziwei Wang #  1 , Xingye Wu #  1
Affiliations

Contribution of genetic polymorphism in ABCB1 to individual variations of imatinib plasma levels in patients with gastrointestinal stromal tumor

Yinggang Ge et al. J Gastrointest Oncol. .

Abstract

Background: Imatinib mesylate (IM) is a first-line treatment option for the majority of patients diagnosed with gastrointestinal stromal tumors (GISTs). Although the clinical benefit is high, interindividual response is variable. This study thus aimed to assess how genetic polymorphisms can affect the blood levels of IM and treatment outcomes in patients with GIST.

Methods: A total of 31 single-nucleotide polymorphisms (SNPs) in selected cytochrome P450 (P450), ATP-binding cassette transporter (ABC), solute carrier family (SLC), interleukin-4 receptor (IL4R), and vascular endothelial growth factor (VEGF) genes were genotyped using an SNP mass array platform. A total of 192 consecutive patients with GIST who received 400 mg of IM daily were enrolled into the study, with 1,485 blood samples being analyzed. According to genotypes, IM trough concentrations were tested and compared. Progression-free survival (PFS) and overall survival (OS) were also assessed.

Results: With a mean follow-up of 75.99 months, trough concentrations of imatinib were examined at average time points of 7.73 for each patient. Polymorphism in ABCB1 rs1045642 was found to be associated with steady-state IM trough plasma levels (P=0.008). Patients with the C genotype (CT + CC) of rs1045642 exhibited higher IM trough concentrations (1,271.09±306.69 ng/mL) compared to those with the TT genotype (1,106.60±206.05 ng/mL). No statistically significant differences in IM plasma concentration were observed for the other SNPs tested. None of the tested SNPs displayed a significant association with patients' survival in this study.

Conclusions: This is the largest cohort study evaluating the associations of SNP and imatinib blood trough levels. The ABCB1 rs1045642 genetic polymorphism may exert an effect on the pharmacokinetics of imatinib. The presence of the C allele in ABCB1 rs1045642 is predictive of a higher plasma concentration of IM.

Keywords: ABCB1; Imatinib; gastrointestinal stromal tumor (GIST); single-nucleotide polymorphism (SNP).

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-188/coif). The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Comparison of imatinib trough plasma concentrations among the ABCB1 rs1045642 genotypes (A, TT vs. CT + CC; B, CC vs. CT + TT) in 192 Chinese patients with gastrointestinal stromal tumor. **, P<0.01. IM, imatinib mesylate.
Figure 2
Figure 2
The Kaplan-Meier survival related to the ABCB1 rs1045642 genotypes (TT vs. CT + CC) in 192 Chinese patients with GIST. (A,B) Progression-free survival and overall survival in all the patients receiving IM. (C,D) Progression-free survival and overall survival in 145 patients receiving IM as adjuvant treatment after surgery. (E,F) Progression-free survival and overall survival in 47 patients (24.48%) receiving IM as palliative therapy for locally advanced and metastatic GIST. IM, imatinib mesylate; GIST, gastrointestinal stromal tumor.
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