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Irinotecan pharmacogenetics: influence of pharmacodynamic genes

Janelle M Hoskins1, Eugenio Marcuello, Albert Altes

  • 1Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|March 19, 2008
PubMed
Abstract

Insights

Genetic variations in pharmacodynamic genes, including TOP1, TDP1, and XRCC1, may impact irinotecan efficacy in advanced colorectal cancer patients. This study explored these genetic associations with treatment outcomes.

Area of Science:

  • Pharmacogenomics
  • Oncology
  • Molecular Biology

Background:

  • Irinotecan is a key chemotherapy for solid tumors.
  • Pharmacokinetic gene variants affect irinotecan toxicity, but pharmacodynamic gene roles are unexplored.
  • Candidate genes (CDC45L, NFKB1, PARP1, TDP1, XRCC1) and the drug target (TOP1) are implicated in camptothecin cytotoxicity.

Purpose of the Study:

  • To investigate the association between pharmacodynamic gene polymorphisms and irinotecan treatment outcomes.
  • To explore the influence of genetic variants in TOP1, TDP1, and XRCC1 on neutropenia and treatment response.
  • To assess the impact of XRCC1 haplotypes on objective response rates in colorectal cancer patients.

Main Methods:

  • Retrospective candidate gene haplotype association study.
  • Haplotype construction for six genes in European, East Asian, and West African populations.
  • Genotyping of European colorectal cancer patients for single nucleotide polymorphisms (SNPs) and assessment of associations with toxicity and efficacy.

Main Results:

  • TOP1 and TDP1 single nucleotide polymorphisms (SNPs) correlated with grade 3/4 neutropenia and objective response, respectively (P=0.04).
  • A specific XRCC1 haplotype (GGCC-G) was significantly associated with higher objective response rates (83% vs. 30%, P=0.02).
  • Multivariate analysis confirmed the association of the XRCC1 haplotype with improved response (OR, 11.9; P=0.04). No variants linked to diarrhea.

Conclusions:

  • This is the first comprehensive pharmacogenetic study of irinotecan pharmacodynamic factors.
  • Genetic variations in pharmacodynamic genes, particularly TOP1, TDP1, and XRCC1, may influence irinotecan efficacy.
  • Findings suggest potential for genetic markers to guide irinotecan therapy in advanced colorectal cancer.

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