Meeting
2017 ASCO Annual Meeting
Vitamin K epoxide reductase complex subunit 1 (VKORC1): A pharmacogenomic predictor of response and survival in patients (pts) on triplet hepatic artery infusion (HAI) and intravenous cetuximab (IV-Cet) for initially unresectable liver metastases from colorectal cancer (uLM-CRC) (EU trial OPTILIV).
Authors
Francis Levi
Cancer Chronotherapy Unit, Warwick Medical School, Coventry, United Kingdom
Francis Levi , Raphael Saffroy , Abdoulaye Karaboue , Christophe Desterke , Valerie Boige , Mohamed Hebbar , Denis Michel Smith , Mohamed Bouchahda , Pasquale Innominato , Julien Taieb , Carlos Carvalho , Rosine Guimbaud , C. N. J. Focan , Michel Ducreux , Rene Adam , Antoinette Lemoine
Organizations
Cancer Chronotherapy Unit, Warwick Medical School, Coventry, United Kingdom, Hopital Paul Brousse Biochemistry Department, University Paris-Sud, Villejuif, France, AK-SCIENCE, Vitry Sur Seine, France, Universite Paris Sud 11 UMS33 INSERM Unit, Villejuif, France, Service d'Oncologie Digestive, Gustave Roussy, Villejuif, France, University Hospital, Marcq En Baroeul, France, Medical Oncology, Bordeaux University Hospital, Bordeaux, France, Paul Brousse Hospital, Oncology Department, Villejuif, French Southern Territories, University of Warwick, Medical School, Coventry, United Kingdom, Georges Pompidou European Hospital, Paris, France, Champalimaud Clinical Centre, Lisbon, Portugal, University Hospital of Rangueil, Toulouse, France, Department of Oncology, Centre Hospitalier Chrétien, Clinique Saint-Joseph, Liege, Belgium, Institut Gustave Roussy, Service d'Oncologie Digestive, Villejuif, France, Centre Hépato-Biliaire, AP-HP, Hôpital Paul Brousse, Villejuif, France, Paul Brousse Hospital, Villejuif, France
Research Funding
Other
Background: The HAI of Irinotecan-Oxaliplatin-5-Fluorouracil (IFO) with IV-Cet achieved 29.7% complete uLM-CRC resections (R0+R1) and an overall median survival (OS) of 25.7 months in previously treated pts (Lévi, Ann Oncol 2016). Methods: To identify pharmacogenomic predictors of outcomes, 207 single nucleotide polymorphisms (SNPs) from 34 pharmacology genes were analysed in blood mononuclear cells (ADME PGx, MassArray platform, Sequenom, USA). Relations between SNPs and tumor response, R0+R1, survival, and toxicities were tested using adjusted Mann Whitney, Fisher Exact, Log Rank tests and Hardy-Weinberg Equilibrium. Results: Pts (16F;36M; 33-76 yo; WHO performance status 0-1) received protocol treatment as 2nd (21 pts) or 3-4thline (31 pts). VKORC1 SNPs in promoter (rs9923231) and intron (rs9934438) were consistently associated with early and objective responses, and overall survival. For rs9923231, T/T (N = 8) as compared to C/T (N = 21) had greatest chance of achieving early response (50% vs 5%, p = 0.029) or 4-y survival (46% vs 0%, p = 0.006). VKORC1 SNPs also related to HA thrombosis (rs992331, T/T, 77% vs C/C, 30%, p = 0.04). In contrast, NAT2 SNPs (rs1041983 and rs1801280) were associated with up to 5-fold differences in R0-R1 resection rate. Statistically significant associations (p < 0.05) of SNPs with clinical outcomes were found for oxydo-reduction (CYP2E1 and HA thrombosis; CYP2C9 and diarrhea; CYP2C19 and diarrhea, fatigue, and early response), conjugation (UGT1A1 and diarrhea; NAT2 and fatigue); and transport (ABCB1 or SLC0B3 and neutropenia; SLC22A1 and diarrhea; SLC 15A2 and early response). Conclusions: VKORC1 was highlighted for the first time, as a pharmacogenomic predictor of HAI efficacy for LM-CRC. Conversion-to-resection was associated with NAT2 polymorphism. VKORC1 γ-carboxylates vitamin K-dependent proteins. Its polymorphism guides personalized warfarin dosing. VKORC1 SNPs determination could help identify the uLM-CRC pts who best benefit from intensive HAI therapy. Clinical trial information: NCT00852228
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Abstract Details
Session Type
Poster Session
Session Title
Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics
Track
Developmental Therapeutics and Translational Research
Sub Track
Pharmacology
Clinical Trial Registration Number
NCT00852228
Citation
J Clin Oncol 35, 2017 (suppl; abstr 2569)
DOI
10.1200/JCO.2017.35.15_suppl.2569
Abstract #
2569
Poster Bd #
61
Abstract Disclosures
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