Multifactorial pharmacogenetic analysis in colorectal cancer patients receiving 5-fluorouracil-based therapy together with cetuximab-irinotecan

被引：35

作者：

Etienne-Grimaldi, Marie-Christine

Bennouna, Jaafar ^{[2
]}

Formento, Jean-Louis

Douillard, Jean-Yves ^{[2
]}

Francoual, Mireille

Hennebelle, Isabelle ^{[3
]}

Chatelut, Etienne ^{[3
]}

Francois, Eric

Faroux, Roger ^{[4
]}

El Hannani, Chaza ^{[5
]}

Jacob, Jacques-Henri ^{[6
]}

Milano, Gerard ^{[1
]}

机构：

[1] Ctr Antoine Lacassagne, Oncopharmacol Unit, EA3836, F-06189 Nice 2, France

[2] Inst Cancerol Ouest, F-44805 St Herblain, France

[3] Ctr Claudius Regaud, F-31052 Toulouse, France

[4] CHD Les Oudairies, F-85925 La Roche Sur Yon 9, France

[5] Polyclin Parc, F-49300 Cholet, France

[6] Ctr Francois Baclesse, F-14076 Caen 05, France

来源：

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY | 2012年 / 73卷 / 05期

关键词：

antibody-dependent cell cytotoxicity; cetuximab; epidermal growth factor receptor; pharmacogenetics; tegafur-uracil; TYMS; GROWTH-FACTOR-RECEPTOR; FC-GAMMA-RIIIA; THYMIDYLATE-SYNTHASE GENE; SQUAMOUS-CELL CARCINOMA; TEGAFUR PLUS LEUCOVORIN; SINGLE-AGENT CETUXIMAB; METHYLENETETRAHYDROFOLATE REDUCTASE; 1ST-LINE TREATMENT; KRAS MUTATIONS; BREAST-CANCER;

D O I：

10.1111/j.1365-2125.2011.04141.x

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

METHODS Fifty-two patients with advanced colorectal cancer were enrolled in an ancillary pharmacogenetic study of the phase II CETUFTIRI trial. Treatment consisted of 21 day cycles of cetuximab (day 1day 8day 15, 250 mg m-2 week-1 following a 400 mg m-2 initial dose) together with irinotecan (day 1, 250 mg m-2) and UFTfolinic acid (days 114, 250 mg m-2 day-1 UFT, 90 mg day-1 folinic acid). Analysed gene polymorphisms (blood DNA) were as follows: EGFR (CA repeats in intron 1, -216G>T, -191C>A), EGF (61A>G), FCGR2A (131Arg>His), FCGR3A (158Phe>Val), UDP-glycosyltransferase1-polypeptide A1 (TA repeats), TYMS (28 bp repeats, including the G>C mutation on the 3R allele, 6 bp deletion in 3' UTR) and MTHFR (677C>T, 1298A>C). METHODS Fifty-two patients with advanced colorectal cancer were enrolled in an ancillary pharmacogenetic study of the phase II CETUFTIRI trial. Treatment consisted of 21 day cycles of cetuximab (day 1-day 8-day 15, 250 mgm-2 week-1 following a 400 mgm-2 initial dose) together with irinotecan (day 1, 250 mgm-2) and UFT-folinic acid (days 1-14, 250 mgm-2 day-1 UFT, 90mg day-1 folinic acid). Analysed gene polymorphisms (blood DNA) were as follows: EGFR (CA repeats in intron 1, -216G> T, -191C> A), EGF (61A> G), FCGR2A (131Arg> His), FCGR3A (158Phe> Val), UDP-glycosyltransferase1polypeptide A1 (TA repeats), TYMS (28 bp repeats, including the G> C mutation on the 3R allele, 6 bp deletion in 3' UTR) and MTHFR (677C> T, 1298A> C). RESULTS Maximum toxicity grade was linked to EGFR -191C> A polymorphism, with 71.1% grade 3-4 toxicity in CC patients vs. 28.6% in other patients (P = 0.010). A tendency to a better response was observed in patients bearing the TYMS 3RG allele (P = 0.029) and those bearing the FCGR3A 158Val genotype (P = 0.020). The greater the score of favourable TYMS and FCGR3A genotypes, the better the response rate (P = 0.009) and the longer the overall survival (P = 0.007). In multivariate analysis, the score of favourable genotypes was a stronger survival predictor than the performance status. CONCLUSIONS Present data suggest the importance

引用

页码：776 / 785

页数：10

共 57 条

[1] Combinations of Polymorphisms in Genes Involved in the 5-Fluorouracil Metabolism Pathway Are Associated with Gastrointestinal Toxicity in Chemotherapy-Treated Colorectal Cancer Patients [J].