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Multiple genetic polymorphisms in the prediction of clinical outcome of metastatic colorectal cancer patients treated with first-line FOLFOX-4 chemotherapy

Huang, Ming-Yiia,f,g; Huang, Meng-Linm; Chen, Ming-Jennn; Lu, Chien-Yub,d,h; Chen, Chin-Fani; Tsai, Pei-Chienk; Chuang, Shih-Change,j; Hou, Ming-Fengc,f,j; Lin, Shiu-Ruo,p; Wang, Jaw-Yuanc,f,j,k,l

Pharmacogenetics and Genomics: January 2011 - Volume 21 - Issue 1 - p 18–25
doi: 10.1097/FPC.0b013e3283415124
ORIGINAL ARTICLES
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Objectives The objective of the study is to investigate whether multiple chemotherapeutic agent-related genetic polymorphisms are associated with the clinical outcomes of Taiwanese metastatic colorectal cancers (mCRC) patients treated with the first-line FOLFOX-4 chemotherapy.

Methods Consecutive mCRC patients were prospectively enrolled into this study. Peripheral blood samples were used for genotyping of polymorphisms in MTHFR, DPD, GSTP1, MDR1, TYMS, ERCC1, XRCC1, and ERCC2 genes by polymerase chain reaction–restriction fragment length polymorphism technique and DNA sequencing. The primary end point of the study was to investigate the association of each genetic polymorphism with progression-free survival and overall survival (OS).

Results Favorable genotypes from polymorphisms in ERCC1 codon 118C/C [hazard ratio (HR)=0.061, 95% confidence interval (CI): 0.014–0.274, P<0.001] and XRCC1 codon 399G/G (HR=0.306, 95% CI: 0.103–0.905, P=0.032) that are associated with progression-free survival were identified. Furthermore, ERCC1 codon 118C/C (HR=0.065, 95% CI: 0.011–0.377, P=0.002) and XRCC1 codon 399G/G (HR=0.152, 95% CI: 0.041–0.568, P=0.005) were significantly associated with favorable OS. Combining ERCC1 and XRCC1 genetic polymorphisms, patients with both favorable genotypes of ERCC1 codon 118C/C and XRCC1 codon 399G/G were associated with the better OS than those with one or without any favorable genotypes (P<0.001).

Conclusion The genetic polymorphisms of ERCC1 and XRCC1 may be useful in predicting clinical outcome in Taiwanese mCRC patients treated with FOLFOX-4. However, further prospective studies will be needed for the potential clinical implication.

Departments of aRadiation Oncology

bInternal Medicine

cDivision of Gastrointestinal and General Surgery, Department of Surgery

dDivision of Gastroenterology, Department of Internal Medicine

eDivision of Hepatobiliary Surgery, Department of Surgery

fCancer Center, Kaohsiung Medical University Hospital

Departments of gRadiation Oncology

hInternal Medicine, Faculty of Medicine

iEmergency Medicine

jSurgery, Faculty of Medicine

kMedical Genetics

lGraduate Institute of Medicine, College of Medicine, Kaohsiung Medical University

mDivision of Proctology, Department of Surgery, ZuoYing Armed Forces General Hospital, Kaohsiung

nDepartment of Surgery, Chi-Mei Medical Center, Tainan

oSchool of Medical and Health Sciences, Fooyin University

pDepartment of Medical Research, Fooyin University Hospital, Pingtung, Taiwan

Correspondence to Jaw-Yuan Wang, MD, PhD, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan Tel: +886 7 3122805; fax: +886 7 3114679; e-mail: cy614112@ms14.hinet.net

Received June 10, 2010

Accepted October 6, 2010

© 2011 Lippincott Williams & Wilkins, Inc.