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

Yinggang Ge; Huili Bai; Alessandro Mazzocca; Jun Zhang; Ziwei Wang; Xingye Wu

doi:10.21037/jgo-24-188

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

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

Authors

Yinggang Ge¹, Huili Bai², Alessandro Mazzocca³, Jun Zhang¹, Ziwei Wang^#¹, Xingye Wu^#¹

Affiliations

¹ Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
² The Center for Clinical Molecular Medical Detection, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
³ Department of Medical Oncology, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, Roma, Italy.

^# Contributed equally.

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).