A prospective validation pharmacogenomic study in the adjuvant setting of colorectal cancer patients treated with the 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) regimen

被引：66
作者：
Cecchin, E. [1 ]
D'Andrea, M. [2 ]
Lonardi, S. [3 ]
Zanusso, C. [1 ]
Pella, N. [4 ]
Errante, D. [5 ]
De Mattia, E. [1 ]
Polesel, J. [6 ]
Innocenti, F. [7 ]
Toffoli, G. [1 ]
机构：
[1] Natl Canc Inst, Ctr Riferimento Oncol, Expt & Clin Pharmacol Unit, I-33081 Aviano, Italy
[2] San Filippo Neri Hosp, Med Oncol Unit, Rome, Italy
[3] IRCCS, Ist Oncol Veneto, Med Oncol Unit 1, Padua, Italy
[4] Univ Hosp, Med Oncol Unit, Udine, Italy
[5] Osped Civile Vittorio Veneto, Med Oncol Unit, Treviso, Italy
[6] Natl Canc Inst, Ctr Riferimento Oncol, Epidemiol & Biostat Unit, I-33081 Aviano, Italy
[7] Univ N Carolina, Lineberger Comprehens Canc Ctr, Inst Pharmacogen & Individualized Therapy, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA
来源：
PHARMACOGENOMICS JOURNAL | 2013年 / 13卷 / 05期
关键词：
pharmacogenomics; FOLFOX4; colorectal cancer; neurotoxicity; INDUCED PERIPHERAL NEUROPATHY; HAPLOTYPE RECONSTRUCTION; 1ST-LINE CHEMOTHERAPY; CUMULATIVE NEUROPATHY; MOLECULAR-MECHANISMS; GENE POLYMORPHISMS; COLON-CANCER; DNA-REPAIR; OXALIPLATIN; NEUROTOXICITY;
D O I：
10.1038/tpj.2012.31
中图分类号：
Q3 [遗传学];
学科分类号：
071007 ; 090102 ;
摘要：
The discovery of pharmacogenomic markers in colorectal cancer (CRC) could be setting-specific. FOLFOX4 is employed in the adjuvant and metastatic setting in CRC. This prospective study is aimed to validate in the adjuvant setting the pharmacogenomic markers of toxicity reported in the metastatic setting (that is, GSTP1-rs947894, and -rs1138272; GSTM1-null genotype; AGXT-rs4426527, -rs34116584 and del-74 bp), and to discover additional markers. CRC patients (n=144) treated with adjuvant FOLFOX4 were genotyped for 57 polymorphisms in 29 genes. Grade >= 2 neurotoxicity was associated (false discovery rate-adjusted q-value < 0.1) with single-nucleotide polymorphisms in ABCC1 (rs2074087: odds ratio=0.43(0.22-0.86)), and ABCC2 (rs3740066: 2.99(1.16-7.70); rs1885301: 3.06(1.35-6.92); rs4148396: 4.69(1.60-13.74); rs717620: 14.39(1.63-127.02)). hMSH6-rs3136228 was associated with grade 3-4 neutropenia (3.23(1.38-7.57), q-value 0.0937). XRCC3-rs1799794 was associated with grade 3-4 non-hematological toxicity (8.90(2.48-31.97), q-value = 0.0150). The markers previously identified in metastatic CRC were not validated. We have identified new markers of toxicity in genes of transport and DNA repair. If validated in other studies, they could help to identify patients at risk of toxicity.
引用
收藏
页码：403 / 409
页数：7
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