Original Article
The Pharmacogenomics Journal (2008) 8, 278–288; doi:10.1038/sj.tpj.6500463; published online 5 June 2007
Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy
A Ruzzo1,11, F Graziano2,11, F Loupakis3, D Santini4, V Catalano5, R Bisonni6, R Ficarelli7, A Fontana3, F Andreoni1, A Falcone8, E Canestrari1, G Tonini4, D Mari9, P Lippe10, F Pizzagalli1, G Schiavon4, P Alessandroni5, L Giustini7, P Maltese1, E Testa2, E T Menichetti6 and M Magnani1
- 1Institute of Biochemistry 'G Fornaini', University of Urbino, Urbino, Italy
- 2Medical Oncology, Hospital of Urbino, Urbino, Italy
- 3Medical Oncology, Hospital of Livorno, Livorno, Italy
- 4Medical Oncology, University Campus Biomedico, Rome, Italy
- 5Medical Oncology, Hospital of Pesaro, Pesaro, Italy
- 6Medical Oncology, Hospital of Fermo, Fermo, Italy
- 7Medical Oncology, Hospital of Senigallia, Senigallia, Italy
- 8Medical Oncology, Hospital of Livorno and University of Pisa, Livorno, Italy
- 9Medical Oncology, Hospital of Fabriano, Fabriano, Italy
- 10Medical Oncology, Hospital of Fano, Fano, Italy
Correspondence: Dr F Graziano, Medical Oncology Unit, Hospital of Urbino, via Bonconte da Montefeltro 61029, Urbino, Italy. E-mail: frada@tin.it
11These authors contributed equally to the study.
Received 19 January 2007; Revised 8 April 2007; Accepted 18 April 2007; Published online 5 June 2007.
Abstract
The primary end point of the study was the analysis of associations between polymorphisms with putative influence on 5-fluorouracil/irinotecan activity and progression-free survival (PFS) of patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Peripheral blood samples from 146 prospectively enrolled patients were used for genotyping polymorphisms in thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), excision repair cross-complementation group-1 (ERCC 1) xeroderma pigmentosum group-D (XPD), X-ray cross-complementing-1 (XRCC 1), X-ray cross-complementing-3 (XRCC 3) and uridine diphosphate-glucuronosyltransferases-A1 (UGT1 A1). TS 3'-UTR 6+/6+ and XRCC3-241 C/C genotypes were associated with adverse PFS. Hazard ratio for PFS achieved 2.89 (95% confidence interval=1.56–5.80; P=0.002) in 30 patients (20%) with both risk genotypes. Risk for Grade III–IV neutropenia was significantly associated with UGT1A1*28 7/7 genotype. These promising findings deserve further investigations and their validation in independent prospective studies.
Keywords:
colorectal cancer, polymorphism, prognosis, chemotherapy, pharmacogenetics
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