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题目:: Pharmacogenetic (PGx) analysis of toxicity after oxaliplatin (Ox), capecitabine (Cap), bevacizumab (Bev) and cetuximab (Cet) therapy for advanced colorectal cancer (ACC): First results from the Dutch Colorectal Cancer Group (DCCG)-CAIRO2 trial.
作者:: Pander(J),Tol(J),Gelderblom(H),Antonini(N F),van der Straaten(R J),Punt(C J),Guchelaar(H)
状态:: 发布时间2016-12-12 , 更新时间 2016-12-12
期刊:: J Clin Oncol
摘要:: 2574 Background: In the CAIRO2 study the addition of Cet to the combination Cap, Ox and Bev for patients with untreated ACC is investigated. The aim of this side study is to evaluate predictive PGx factors for toxicity for Cet and Cap in the EGFR/FCGR pathway and thymidylate synthase (TYMS) gene, respectively.,Treatment was administered q3wk until progression: Ox 130 mg/m iv cycle 1-6, Cap 1,000 mg/m orally bid on day 1-14 (1,250 mg/m after 6 cycles) and Bev 7.5 mg/kg iv on day 1 (arm A) with the addition of Cet 400 mg/m2 iv on day 1 of cycle 1, thereafter weekly 250 mg/m2 (arm B). Toxicity (NCI-CTC v3) was evaluated in the first 400 patients. Cet and Cap related toxicities were evaluated and DNA was isolated from peripheral blood after informed consent. Genotype of FCGR2A His131Arg (n=259), FCGR3A Phe158Val (n=253), EGF 61A>G (n=217) and CCND1 870G>A (n=273) were analyzed with Taqman, EGFR CA-repeat (n=221; both alleles <20 vs. any allele >/=20 repeats) was analyzed with fragment analysis and TYMS 2/3C/3G (n=255) was analyzed with direct sequencing. Multivariate logistic regression was performed with gender, age, performance status, treatment arm and number of affected organs as confounders.,Germline DNA from 299 (arm A: 153; arm B: 146) eligible patients was available. The FCGR2A polymorphism was associated with grade 3-4 acneiform skin reaction and/or nail changes (ASR/NC) (P=0.037). Carriage of the FCGR2A-His allele (n=199/259) was associated with an increased risk of grade 3-4 ASR/NC (OR=3.85; 95%CI=1.02-14.29). The FCGR3A, EGF, CCND1 and EGFR polymorphisms were not associated with grade 3-4 ASR/NC. Non-carriage of the TYMS-3G allele (n=156/255) was associated with an increased risk of grade 2-4 hand-foot syndrome (HFS) (OR=1.82; 95%CI=1.03-3.23) but not with the risk of grade 3-4 diarrhea.,These results indicate that the FCGR2A His131Arg and TYMS-3G polymorphisms may be useful markers for predicting ASR/NC after Cet treatment and HFS after Cap treatment, respectively. No significant financial relationships to disclose.
语言:: eng
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