三联肝动脉灌注及静脉注射西妥昔单抗治疗结直肠癌肝转移疗效的药物遗传学决定因素（欧洲试验OPTIMILIV，NCT00852228）

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

作者信息

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

机构信息

INSERM, UMRS 935 Team 'Cancer Chronotherapy and Postoperative Liver Function', Campus CNRS, 7 rue Guy Môquet, and UMRS 1193 'Physiopathology and treatment of Liver diseases', Paul Brousse Hospital, 14 avenue Paul-Vaillant-Couturier, 94800 Villejuif, France.

Université Paris Sud, UFR médecine, Institut André Lwoff, Paul Brousse Hospital, 14 avenue Paul-Vaillant-Couturier, 94800 Villejuif, France.

出版信息

Br J Cancer. 2017 Sep 26;117(7):965-973. doi: 10.1038/bjc.2017.278. Epub 2017 Aug 17.

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.

背景

伊立替康、奥沙利铂和5-氟尿嘧啶经肝动脉灌注（HAI）联合静脉注射西妥昔单抗，在先前接受过治疗的、最初不可切除的结直肠癌肝转移患者中取得了显著疗效。这项计划开展的研究旨在确定疗效的药物遗传学预测指标。

方法

对来自34个药理学基因的207个单核苷酸多态性（SNP）进行循环单核细胞分析。对通过严格哈迪-温伯格平衡检验的单核苷酸多态性，检测其与52例患者（男/女，36/16；世界卫生组织体力状况评分，0 - 1）预后的相关性。

结果

维生素K环氧化物还原酶复合体亚单位1（VKORC1）单核苷酸多态性（rs9923231和rs9934438）与早期和客观缓解以及生存相关。对于rs9923231，T/T基因型比C/T基因型有更多的早期缓解（50%对5%，P = 0.029），且4年生存率最高（46%对0%，P = 0.006）。N - 乙酰转移酶2（rs1041983和rs1801280）与宏观上完全肝切除的发生率高出多达7倍相关。无进展生存期在ABCB1 rs1045642 T/T（P = 0.026）和rs2032582 T/T（P = 0.035）时最长。毒性与基因变异之间存在相关性（P < 0.05），包括ABCB1（rs1045642）和溶质载体有机阴离子转运体家族成员3（SLC0B3，rs4149117和rs7311358）与中性粒细胞减少；以及细胞色素P450 2C9（CYP2C9，rs1057910）、细胞色素P450 2C19（CYP2C19，rs375858 – 1）、尿苷二磷酸葡萄糖醛酸基转移酶1家族多肽A6（UGT1A6，rs4124874）和溶质载体有机阳离子转运体家族成员1（SLC2A1，rs72552763）与腹泻。