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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)

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Lévi, Francis A., 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 and Lemoine, Antoinette (2017) Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228). British Journal of Cancer, 117 (7). pp. 965-973. doi:10.1038/bjc.2017.278

Research output not available from this repository, contact author.
Official URL: http://dx.doi.org/10.1038/bjc.2017.278

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Abstract

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.

Item Type: Journal Article
Divisions: Faculty of Medicine > Warwick Medical School > Biomedical Sciences
Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine
Faculty of Medicine > Warwick Medical School
Journal or Publication Title: British Journal of Cancer
Publisher: Nature Publishing Group
ISSN: 0007-0920
Official Date: 26 September 2017
Dates:
DateEvent
26 September 2017Published
24 July 2017Accepted
Volume: 117
Number: 7
Page Range: pp. 965-973
DOI: 10.1038/bjc.2017.278
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access

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