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Identification of polymorphic variants associated with erlotinib-related skin toxicity in advanced non-small cell

Mariamena Arbitrio1, Maria Teresa Di Martino2, Vito Barbieri3

  • 1ISN-CNR, Roccelletta di Borgia, Catanzaro, Italy.

Cancer Chemotherapy and Pharmacology
|November 27, 2015
PubMed
Abstract

Insights

Genetic variations in the CYP27B1 gene, specifically rs8176345, are linked to erlotinib-induced skin rash in advanced non-small cell lung cancer patients. This finding may help predict and manage treatment toxicity.

Area of Science:

  • Pharmacogenomics
  • Oncology
  • Dermatology

Background:

  • Erlotinib is a targeted therapy for advanced non-small cell lung cancer (aNSCLC).
  • Drug-induced skin rash (SR) is a common toxicity of erlotinib, impacting patient quality of life and treatment adherence.
  • Interindividual variability in drug response is influenced by genetic polymorphisms in drug-metabolizing enzymes and transporters.

Purpose of the Study:

  • To identify genetic determinants in adsorption, distribution, metabolism, and excretion (ADME) genes associated with erlotinib-induced skin rash (SR) in aNSCLC patients.
  • Utilize the Affymetrix drug-metabolizing enzyme and transporter (DMET) microarray platform for comprehensive genetic profiling.

Main Methods:

  • Retrospective study of 34 erlotinib-treated aNSCLC patients (23 with SR, 11 without).
  • Genotyping performed using the DMET Plus chip on peripheral blood DNA.
  • Association analysis using Fisher's exact test and Ingenuity Pathway Analysis (IPA) for toxicity-related gene sets.

Main Results:

  • Seven single nucleotide polymorphisms (SNPs) in six genes (CYP27B1, MAT1A1, CHST1, CYP4B1, ADH6, SLC22A1) showed association with SR.
  • The SNP rs8176345 in the CYP27B1 gene was significantly correlated with SR (p = 0.0003, OR 55.55).
  • IPA revealed involvement of vitamin D3 biosynthesis and S-adenosyl-L-methionine pathways in SR development.

Conclusions:

  • The rs8176345 polymorphism in CYP27B1 is a significant correlate of erlotinib-induced SR in aNSCLC.
  • Vitamin D3 metabolism and inflammation at the skin level are potential mechanisms underlying this association.
  • These findings may contribute to personalized medicine approaches for erlotinib therapy.
Keywords:
DMETErlotinibNon-small cell lung cancerSingle nucleotide polymorphismsSkin rash

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