Impact of single nucleotide polymorphisms on severe hepatotoxicity induced by EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring EGFR mutations

Lung Cancer : Journal of the International Association for the Study of Lung Cancer
Eri SugiyamaKoichi Goto

Abstract

Many patients are forced to discontinue treatment with EGFR tyrosine kinase inhibitors (TKIs), particularly gefitinib, due to severe hepatotoxicity. Here, we investigated the association between the rate of severe hepatotoxicity and single nucleotide polymorphisms (SNPs) in metabolic enzymes. Multi-SNP analyses were performed in 60 patients with EGFR-mutated non-small cell lung cancer using blood samples obtained prior to starting treatment with gefitinib. The poor metabolizer (PM) phenotype was defined as homozygosity or double heterozygosity for variant alleles that confer reduced enzyme activities. Associated enzymes were screened using univariate logistic regression analyses adjusted for multiplicity and were further evaluated using multivariate logistic regression analyses to determine the influence of these enzymes on severe hepatotoxicity. Severe hepatotoxicity was detected in 19 (32%) of the 60 patients. Patient phenotypes consisted of CYP3A5, PM/non-PM (31/29) and CYP2D6, PM/non-PM (5/55). In multivariate logistic regression analyses, the rate of severe hepatotoxicity was significantly higher among patients with PM phenotypes than those without (CYP3A5 PM vs. non-PM: 48.4% vs. 13.8%, P=0.0069; CYP2D6 PM vs. non-PM: 80....Continue Reading

References

Mar 25, 2005·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·D McKillopM Hutchison
Sep 24, 2005·Clinical Pharmacokinetics·Helen C SwaislandMartin J Wild
Oct 20, 2005·Clinical Pharmacokinetics·Helen C SwaislandThierry Duvauchelle
Feb 17, 2006·The New England Journal of Medicine·Victor J Navarro, John R Senior
Mar 16, 2007·Analytical Biochemistry·Nao NishidaKatsushi Tokunaga
Jun 19, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jing LiSharyn D Baker
Dec 7, 2007·Chemical Research in Toxicology·F Peter Guengerich
May 5, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Kostandinos SiderasMatthew P Goetz
Jun 25, 2010·The New England Journal of Medicine·Makoto MaemondoUNKNOWN North-East Japan Study Group
Sep 8, 2010·Lung Cancer : Journal of the International Association for the Study of Lung Cancer·Geoffrey Y KuGilberto de Lima Lopes
Jan 31, 2012·The Lancet Oncology·Rafael RosellUNKNOWN Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia T
Feb 1, 2012·Expert Opinion on Drug Metabolism & Toxicology·Joseph McGraw, Donald Waller
Mar 30, 2012·Japanese Journal of Clinical Oncology·Masayuki TakedaKazuhiko Nakagawa
May 15, 2013·Clinical Lung Cancer·Takayuki TakimotoAtsushi Kumanogoh
Jul 3, 2013·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Lecia V SequistMartin Schuler
Feb 24, 2015·Lung Cancer : Journal of the International Association for the Study of Lung Cancer·Masayuki TakedaKazuhiko Nakagawa
Apr 30, 2015·The New England Journal of Medicine·Pasi A JänneMalcolm Ranson

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Citations

May 18, 2016·Expert Opinion on Drug Metabolism & Toxicology·Kirsty Wai-Chung Lee, Stephen Lam Chan
May 24, 2016·Expert Opinion on Drug Safety·Emily Han-Chung HsiueJames Chih-Hsin Yang
Feb 14, 2020·Expert Opinion on Drug Metabolism & Toxicology·Qiang ShiWilliam B Mattes
Aug 15, 2018·International Journal of Molecular Sciences·Klarissa D JacksonMatthew J Vergne
Oct 12, 2020·The Journal of Allergy and Clinical Immunology. in Practice·Ana Dioun BroylesMariana Castells

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