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Pharmacogenetic Profiling and Clinical Outcome of Patients With Advanced Gastric Cancer Treated With Palliative Chemotherapy

Annamaria Ruzzo, Francesco Graziano, Kazuyuki Kawakami, Go Watanabe, Daniele Santini, Vincenzo Catalano, Renato Bisonni, Emanuele Canestrari, Rita Ficarelli, Ettore Tito Menichetti, Davide Mari, Enrica Testa, Rosarita Silva, Bruno Vincenzi, Paolo Giordani, Stefano Cascinu, Lucio Giustini, Giuseppe Tonini, Mauro Magnani

From the Medical Oncology Unit, Hospital of Urbino; Institute of Biochemistry "G Fornaini," University of Urbino, Urbino; Medical Oncology Unit, University Campus Biomedico, Rome; Medical Oncology Unit, Hospital of Pesaro, Pesaro; Medical Oncology Unit, Hospital of Fermo, Fermo; Medical Oncology Unit, Hospital of Senigallia, Senigallia; Medical Oncology Unit, Hospital of Fabriano, Fabriano; Medical Oncology Unit, University of Ancona, Ancona, Italy; Department of Surgery, Kanazawa University School of Medicine, Kanazawa, Japan

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: To investigate whether polymorphisms with putative influence on fluorouracil/cisplatin activity are associated with clinical outcomes of patients with advanced gastric cancer (AGC).

PATIENTS AND METHODS: Peripheral blood samples from 175 prospectively enrolled AGC patients treated with fluorouracil/cisplatin palliative chemotherapy were used for genotyping 13 polymorphisms in nine genes (TS, MTHFR, XPD, ERCC1, XRCC1, XRCC3, GSTPI, GSTTI, GSTMI). Genotypes were correlated to response and survival.

RESULTS: The overall response rate was 41%, the median progression-free survival (PFS) was 24 weeks (range, 4 to 50 weeks), and the median overall survival (OS) was 39 weeks (range, 8 to 72+ weeks). Chemoresistance and poor survival were significantly associated with TS 5'-UTR 3G-genotype (2R/3G, 3C/3G, 3G/3G) and GSTP1 105 A/A homozygous genotype. Sixty-one patients (35%) did not show any of these risk genotypes (group 0), 57 patients (32.5%) showed one of the two risk genotypes (group 1), and 57 patients (32.5%) showed both risk genotypes (group 2). Median PFS and OS in group 0 patients were 32 weeks (range, 8 to 50 weeks) and 49 weeks (range, 18 to 72+ weeks), respectively. Group 1 and group 2 patients showed significantly worse PFS (median, 26 weeks [range, 6 to 44 weeks] and 14 weeks [range, 4 to 38 weeks], respectively) and worse OS (median, 39 weeks [range, 10 to 58 weeks] and 28 weeks [range, 8 to 56 weeks]), respectively, than group 0 patients. This adverse effect was retained in multivariate analysis.

CONCLUSION: Specific polymorphisms may influence clinical outcomes of AGC patients. Selecting palliative chemotherapy on the basis of pretreatment genotyping may represent an innovative strategy that warrants prospective studies.

Supported by Consorzio Interuniversitario per le Biotecnologie (CIB) and Fanoateneo.

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

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

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