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Pharmacogenetic Profiling in Patients With Advanced Colorectal Cancer Treated With First-Line FOLFOX-4 Chemotherapy

Annamaria Ruzzo, Francesco Graziano, Fotios Loupakis, Eliana Rulli, Emanuele Canestrari, Daniele Santini, Vincenzo Catalano, Rita Ficarelli, Paolo Maltese, Renato Bisonni, Gianluca Masi, Gaia Schiavon, Paolo Giordani, Lucio Giustini, Alfredo Falcone, Giuseppe Tonini, Rosarita Silva, Rodolfo Mattioli, Irene Floriani, Mauro Magnani

From the Institute of Biochemistry G Fornaini, University of Urbino; Medical Oncology, Hospital of Urbino, Urbino; Medical Oncology, Hospital of Livorno, Livorno; Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri, Milan; Medical Oncology, University Campus Biomedico, Rome; Medical Oncology, Hospital of Pesaro, Pesaro; Medical Oncology, Hospital of Senigallia, Senigallia; Medical Oncology, Hospital of Fermo, Fermo; Medical Oncology, University of Pisa, Pisa; Medical Oncology, Hospital of Fabriano, Fabriano; and Medical Oncology, Hospital of Fano, Fano, Italy

Address reprint requests to Francesco Graziano, MD, Medical Oncology Unit, Hospital of Urbino, via Bonconte da Montefeltro, 61029, Urbino, Italy; e-mail: frada{at}tin.it

Purpose The objective is to investigate whether polymorphisms with putative influence on fluorouracil/oxaliplatin activity are associated with clinical outcomes of patients with advanced colorectal cancer treated with first-line oxaliplatin, folinic acid, and fluorouracil palliative chemotherapy.

Materials and Methods Consecutive patients were prospectively enrolled onto medical oncology units in Central Italy. Patients were required to have cytologically/histologically confirmed metastatic disease with at least one measurable lesion. Peripheral blood samples were used for genotyping 12 polymorphisms in thymidylate synthase, methylenetetrahydrofolate reductase, xeroderma pigmentosum group D (XPD), excision repair cross complementing group 1 (ERCC1), x-ray cross complementing group 1, x-ray cross complementing protein 3, glutathione S-transferases (GSTs) genes. The primary end point of the study was to investigate the association between genotypes and progression-free survival (PFS).

Results In 166 patients, ERCC1-118 T/T, XPD-751 A/C, and XPD-751 C/C genotypes were independently associated with adverse PFS. The presence of two risk genotypes (ERCC1-118 T/T combined with either XPD-751 A/C or XPD-751 C/C) occurred in 50 patients (31%). This profiling showed an independent role for unfavorable PFS with a hazard ratio of 2.84% and 95% CI of 1.47 to 5.45 (P = .002). Neurotoxicity was significantly associated with GSTP1-105 A/G. Carriers of the GSTP1-105 G/G genotype were more prone to suffer from grade 3 neurotoxicity than carriers of GSTP1-105 A/G and GSTP1-105 A/A genotypes.

Conclusion A pharmacogenetic approach may be an innovative strategy for optimizing palliative chemotherapy in patients with advanced colorectal cancer. These findings deserve confirmation in additional prospective studies.

Supported by Consorzio Interuniversitario per le Biotecnologie and Fanoateneo.

A.R. and F.G. contributed equally to the study.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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