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.

Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics

“…Carriers of another ABCB1 SNP (rs1045642) had an increased risk for early toxicity and lower treatment response [ 268 ]. In patients with liver metastases treated with hepatic artery infusion of irinotecan, oxaliplatin and 5-fluorouracil and intravenous cetuximab, this SNP was also associated with toxicity (grade 3–4 neutropenia), increased systemic concentrations of oxaliplatin and cetuximab, and prolonged PFS [ 269 ]. Furthermore, carriers of the ABCB1 haplotype (including rs1045642, rs1128503, rs2032582) responded less frequently and had shorter survival [ 268 ].…”

An Optimal Time for Treatment—Predicting Circadian Time by Machine Learning and Mathematical Modelling

“…The concept of chronotherapy and its interplay with circadian time assessment including its different methods [ 94 ] is visualized in Figure 1 . The raising potential of chronotherapy has motivated an increasing collection of clinical studies that have been conducted to examine the effect of time-of-day adjusted treatment [ 6 , 75 , 95 , 96 , 97 , 98 ]. Hence, the usage of time-of-day adapted therapies personalized with the internal clock of the patient might be superior to standard treatment, however the results are sometimes varying in terms of the desired effect of chronotherapy in comparison to standard treatment in particular concerning gender-related efficacy of chronotherapy [ 99 , 100 ].…”

Immune-Modulating Effects of Conventional Therapies in Colorectal Cancer

“…A number of early-phase trials have investigated the concept, using oxaliplatin as the HAI compound for unresectable CLM with treatment toxicity and response as endpoints, but only one study has been carried on with the aim of transforming to resectable disease by using oxaliplatin, irinotecan, and fluorouracil [ 111 ]. The investigators have also examined systemic exposure of the HAI chemotherapeutics in terms of pharmacokinetics analyses [ 112 ] and pharmacogenetics determinants of outcome [ 113 ].…”