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Pharmacogenetics of ABCG2 and adverse reactions to gefitinib

George Cusatis1, Vanesa Gregorc, Jing Li

  • 1The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.

Journal of the National Cancer Institute
|December 7, 2006
PubMed

Insights

A common genetic variant in the ABCG2 gene increases the risk of diarrhea in patients treated with gefitinib, an EGFR inhibitor. This finding may help optimize cancer treatment by identifying patients prone to this side effect.

Area of Science:

  • Pharmacogenomics
  • Oncology
  • Molecular Biology

Background:

  • Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor used for non-small-cell lung cancer.
  • Diarrhea and skin toxicity are common adverse events limiting gefitinib treatment.
  • Gefitinib is a substrate of the ABCG2 efflux transporter, highly expressed in the intestines.

Purpose of the Study:

  • To investigate the association between genetic variants in EGFR, ABCG2, and ABCB1 and gefitinib-induced diarrhea and skin toxicity.
  • To determine if ABCG2 allelic variants influence the risk of adverse events in patients receiving gefitinib.

Main Methods:

  • Genotyping of EGFR, ABCG2, and ABCB1 single-nucleotide polymorphisms (SNPs) in 124 gefitinib-treated patients.
  • Statistical analysis to correlate specific genetic variants with the incidence of diarrhea and skin toxicity.

Main Results:

  • A common functional SNP in the ABCG2 gene (421C>A, Q141K) was significantly associated with an increased risk of diarrhea.
  • Patients heterozygous for ABCG2 421C>A had a 44% incidence of diarrhea, compared to 12% for wild-type homozygotes (P = .0046).
  • This ABCG2 variant was not associated with skin toxicity (P = .99).

Conclusions:

  • Reduced ABCG2 transporter activity due to common genetic variants increases the risk of gefitinib-induced diarrhea.
  • Pharmacogenetic profiling of ABCG2 may help predict and manage gefitinib-related diarrhea.
  • These findings have implications for optimizing cancer therapy by personalizing treatment based on genetic predispositions.

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