Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228).

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.

• Authors: Francis Lévi, Abdoulaye Karaboué, Raphaël Saffroy, Christophe Desterke, Valerie Boige, Denis Smith, Mohamed Hebbar, Pasquale Innominato, Julien Taieb, Carlos Carvalho, Rosine Guimbaud, Christian Focan, Mohamed Bouchahda, René Adam, Michel Ducreux, Gérard Milano, Antoinette Lemoine
• Journal: British journal of cancer (Br J Cancer) Vol. 117 Issue 7 Pg. 965-973 (Sep 26 2017) ISSN: 1532-1827 [Electronic] England
• PMID: 28817838 (Publication Type: Clinical Trial, Phase II, Journal Article)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• Catecholamine Plasma Membrane Transport Proteins
• Organoplatinum Compounds
• Slc22a1 protein, mouse
• Oxaliplatin
• Irinotecan
• CYP2C9 protein, human
• Cytochrome P-450 CYP2C9
• Cytochrome P-450 CYP2C19
• VKORC1 protein, human
• Vitamin K Epoxide Reductases
• Arylamine N-Acetyltransferase
• NAT2 protein, human
• UDP-glucuronosyltransferase, UGT1A6
• Glucuronosyltransferase
• Cetuximab
• Fluorouracil
• Camptothecin

Topics

• ATP Binding Cassette Transporter, Subfamily B (genetics)
• Administration, Intravenous
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Arylamine N-Acetyltransferase (genetics)
• Camptothecin (administration & dosage, analogs & derivatives)
• Catecholamine Plasma Membrane Transport Proteins (genetics)
• Cetuximab (administration & dosage)
• Colorectal Neoplasms (genetics, pathology)
• Cytochrome P-450 CYP2C19 (genetics)
• Cytochrome P-450 CYP2C9 (genetics)
• Diarrhea (chemically induced, genetics)
• Disease-Free Survival
• Female
• Fluorouracil (administration & dosage)
• Glucuronosyltransferase (genetics)
• Hepatectomy
• Hepatic Artery
• Humans
• Infusions, Intra-Arterial
• Irinotecan
• Liver Neoplasms (drug therapy, genetics, secondary, surgery)
• Male
• Middle Aged
• Neutropenia (chemically induced, genetics)
• Organoplatinum Compounds (administration & dosage)
• Oxaliplatin
• Pharmacogenetics
• Polymorphism, Single Nucleotide
• Survival Rate
• Treatment Outcome
• Vitamin K Epoxide Reductases (genetics)