AGXT and ERCC2 polymorphisms are associated with clinical outcome in metastatic colorectal cancer patients treated with 5-FU/oxaliplatin

Pharmacogenomics J. 2016 Jun;16(3):272-9. doi: 10.1038/tpj.2015.54. Epub 2015 Aug 11.

Abstract

The objective of the study was to investigate whether specific single nucleotide polymorphisms (SNPs) with influence on drug transport, biotransformation and repair mechanisms are associated with treatment outcome and toxicity in metastatic colorectal cancer (mCRC). We genotyped blood samples from 519 mCRC patients treated with first-line 5-fluorouracil and oxaliplatin +/- cetuximab for 17 SNPs in 10 genes involved in membrane transport (ABCC1 and ABCC2), drug biotransformation (GSTP1 and AGXT) and DNA repair (ERCC1, ERCC2, XRCC1, XRCC3, XPG and MSH6). The AGXT-rs34116584 and the ERCC2-rs238406 polymorphisms were significantly associated with progression-free survival (P=0.002 and P=0.001, respectively). Associations between 18 toxicity variables and SNPs were identified, although none were significant after Bonferroni correction for multiple comparisons. The study identified SNPs of potential use as markers of clinical outcome in oxaliplatin-treated mCRC patients. If validated in other studies, they could improve the selection of therapy in mCRC.

Trial registration: ClinicalTrials.gov NCT00145314.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / genetics*
  • Clinical Trials, Phase III as Topic
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology
  • Disease-Free Survival
  • Female
  • Fluorouracil / adverse effects
  • Fluorouracil / therapeutic use*
  • Genetic Association Studies
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Organoplatinum Compounds / adverse effects
  • Organoplatinum Compounds / therapeutic use*
  • Oxaliplatin
  • Pharmacogenomic Variants / genetics*
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Randomized Controlled Trials as Topic
  • Retrospective Studies
  • Risk Factors
  • Scandinavian and Nordic Countries
  • Time Factors
  • Transaminases / genetics*
  • Treatment Outcome
  • Xeroderma Pigmentosum Group D Protein / genetics*
  • Young Adult

Substances

  • Biomarkers, Tumor
  • Organoplatinum Compounds
  • Oxaliplatin
  • Transaminases
  • Alanine-glyoxylate transaminase
  • Xeroderma Pigmentosum Group D Protein
  • ERCC2 protein, human
  • Fluorouracil

Associated data

  • ClinicalTrials.gov/NCT00145314