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Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228)
BACKGROUND: The hepatic artery infusion (HAI) of irinotecan, oxaliplatin and 5-fluorouracil with intravenous cetuximab achieved outstanding efficacy in previously treated patients with initially unresectable liver metastases from colorectal cancer. This planned study aimed at the identification of p...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625679/ https://www.ncbi.nlm.nih.gov/pubmed/28817838 http://dx.doi.org/10.1038/bjc.2017.278 |
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author | Lévi, Francis Karaboué, Abdoulaye Saffroy, Raphaël Desterke, Christophe Boige, Valerie Smith, Denis Hebbar, Mohamed Innominato, Pasquale Taieb, Julien Carvalho, Carlos Guimbaud, Rosine Focan, Christian Bouchahda, Mohamed Adam, René Ducreux, Michel Milano, Gérard Lemoine, Antoinette |
author_facet | Lévi, Francis Karaboué, Abdoulaye Saffroy, Raphaël Desterke, Christophe Boige, Valerie Smith, Denis Hebbar, Mohamed Innominato, Pasquale Taieb, Julien Carvalho, Carlos Guimbaud, Rosine Focan, Christian Bouchahda, Mohamed Adam, René Ducreux, Michel Milano, Gérard Lemoine, Antoinette |
author_sort | Lévi, Francis |
collection | PubMed |
description | BACKGROUND: The hepatic artery infusion (HAI) of irinotecan, oxaliplatin and 5-fluorouracil with intravenous cetuximab achieved outstanding efficacy in previously treated patients with initially unresectable liver metastases from colorectal cancer. This planned study aimed at the identification of pharmacogenetic predictors of outcomes. METHODS: Circulating mononuclear cells were analysed for 207 single-nucleotide polymorphisms (SNPs) from 34 pharmacology genes. Single-nucleotide polymorphisms passing stringent Hardy–Weinberg equilibrium test were tested for their association with outcomes in 52 patients (male/female, 36/16; WHO PS, 0–1). RESULTS: VKORC1 SNPs (rs9923231 and rs9934438) were associated with early and objective responses, and survival. For rs9923231, T/T achieved more early responses than C/T (50% vs 5%, P=0.029) and greatest 4-year survival (46% vs 0%, P=0.006). N-acetyltransferase-2 (rs1041983 and rs1801280) were associated with up to seven-fold more macroscopically complete hepatectomies. Progression-free survival was largest in ABCB1 rs1045642 T/T (P=0.026) and rs2032582 T/T (P=0.035). Associations were found between toxicities and gene variants (P<0.05), including neutropenia with ABCB1 (rs1045642) and SLC0B3 (rs4149117 and rs7311358); and diarrhoea with CYP2C9 (rs1057910), CYP2C19 (rs3758581), UGT1A6 (rs4124874) and SLC22A1 (rs72552763). CONCLUSION: VKORC1, NAT2 and ABCB1 variants predicted for HAI efficacy. Pharmacogenetics could guide the personalisation of liver-targeted medico-surgical therapies. |
format | Online Article Text |
id | pubmed-5625679 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-56256792018-09-26 Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228) Lévi, Francis Karaboué, Abdoulaye Saffroy, Raphaël Desterke, Christophe Boige, Valerie Smith, Denis Hebbar, Mohamed Innominato, Pasquale Taieb, Julien Carvalho, Carlos Guimbaud, Rosine Focan, Christian Bouchahda, Mohamed Adam, René Ducreux, Michel Milano, Gérard Lemoine, Antoinette Br J Cancer Translational Therapeutics BACKGROUND: The hepatic artery infusion (HAI) of irinotecan, oxaliplatin and 5-fluorouracil with intravenous cetuximab achieved outstanding efficacy in previously treated patients with initially unresectable liver metastases from colorectal cancer. This planned study aimed at the identification of pharmacogenetic predictors of outcomes. METHODS: Circulating mononuclear cells were analysed for 207 single-nucleotide polymorphisms (SNPs) from 34 pharmacology genes. Single-nucleotide polymorphisms passing stringent Hardy–Weinberg equilibrium test were tested for their association with outcomes in 52 patients (male/female, 36/16; WHO PS, 0–1). RESULTS: VKORC1 SNPs (rs9923231 and rs9934438) were associated with early and objective responses, and survival. For rs9923231, T/T achieved more early responses than C/T (50% vs 5%, P=0.029) and greatest 4-year survival (46% vs 0%, P=0.006). N-acetyltransferase-2 (rs1041983 and rs1801280) were associated with up to seven-fold more macroscopically complete hepatectomies. Progression-free survival was largest in ABCB1 rs1045642 T/T (P=0.026) and rs2032582 T/T (P=0.035). Associations were found between toxicities and gene variants (P<0.05), including neutropenia with ABCB1 (rs1045642) and SLC0B3 (rs4149117 and rs7311358); and diarrhoea with CYP2C9 (rs1057910), CYP2C19 (rs3758581), UGT1A6 (rs4124874) and SLC22A1 (rs72552763). CONCLUSION: VKORC1, NAT2 and ABCB1 variants predicted for HAI efficacy. Pharmacogenetics could guide the personalisation of liver-targeted medico-surgical therapies. Nature Publishing Group 2017-09-26 2017-08-17 /pmc/articles/PMC5625679/ /pubmed/28817838 http://dx.doi.org/10.1038/bjc.2017.278 Text en Copyright © 2017 Cancer Research UK http://creativecommons.org/licenses/by-nc-sa/4.0/ From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/ |
spellingShingle | Translational Therapeutics Lévi, Francis Karaboué, Abdoulaye Saffroy, Raphaël Desterke, Christophe Boige, Valerie Smith, Denis Hebbar, Mohamed Innominato, Pasquale Taieb, Julien Carvalho, Carlos Guimbaud, Rosine Focan, Christian Bouchahda, Mohamed Adam, René Ducreux, Michel Milano, Gérard Lemoine, Antoinette Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228) |
title | Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228) |
title_full | Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228) |
title_fullStr | Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228) |
title_full_unstemmed | Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228) |
title_short | Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228) |
title_sort | pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (european trial optiliv, nct00852228) |
topic | Translational Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625679/ https://www.ncbi.nlm.nih.gov/pubmed/28817838 http://dx.doi.org/10.1038/bjc.2017.278 |
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