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Efflux pump ABCB1 single nucleotide polymorphisms and dose reductions in patients with metastatic renal cell

Benoit Beuselinck1, Diether Lambrechts, Thomas Van Brussel

  • 1Department of General Medical Oncology and Laboratory for Experimental Oncology, University Hospitals Leuven, Leuven Cancer Institute , KU Leuven, Leuven , Belgium.

Acta Oncologica (Stockholm, Sweden)
|May 31, 2014
PubMed
Abstract

Insights

Genetic variations in the ABCB1 gene, specifically rs1125803 and rs2032582, are linked to fewer sunitinib dose reductions in metastatic renal cell carcinoma (mRCC) patients. These findings suggest a role for pharmacogenetics in optimizing sunitinib treatment.

Area of Science:

  • Pharmacogenomics
  • Oncology

Background:

  • Sunitinib plasma levels influence treatment outcomes in metastatic renal cell carcinoma (mRCC).
  • Single nucleotide polymorphisms (SNPs) in pharmacokinetic and pharmacodynamic genes may affect sunitinib dosing.

Purpose of the Study:

  • To investigate the impact of specific SNPs in pharmacokinetic (ABCB1, NR1/2, NR1/3, CYP3A5) and pharmacodynamic (VEGFR1, VEGFR3) genes on sunitinib dose reductions in mRCC patients.
  • To explore the association between germline DNA variations and time-to-dose-reduction (TTDR).

Main Methods:

  • Retrospective analysis of germline DNA from 96 mRCC patients treated with first-line sunitinib.
  • Genotyping of 11 key SNPs in genes including ABCB1, NR1/2, NR1/3, CYP3A5, VEGFR1, and VEGFR3.
  • Cox regression analysis to assess the association between SNPs and TTDR.

Main Results:

  • Patients with the TT-genotype in ABCB1 rs1125803 showed increased TTDR (19 vs. 7 cycles, p=0.012 multivariate).
  • Patients with the TT/TA-variant in ABCB1 rs2032582 also exhibited increased TTDR (19 vs. 7 cycles, p=0.024 multivariate).
  • These ABCB1 variants, encoding an efflux pump, correlated with fewer dose reductions due to adverse events.

Conclusions:

  • Specific variants in the ABCB1 gene (rs1125803 TT and rs2032582 TT/TA) are associated with a reduced need for sunitinib dose reductions in mRCC patients.
  • These findings highlight the potential of pharmacogenetic profiling to personalize sunitinib therapy and manage adverse events.
  • The ABCB1 efflux pump appears to play a significant role in sunitinib disposition and its impact on dose adjustments.

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