Originally published as JCO Early Release 10.1200/JCO.2008.19.1718 on March 30 2009

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Pharmacogenetic Analyses of a Phase III Trial in Metastatic Gastroesophageal Adenocarcinoma With Fluorouracil and Leucovorin Plus Either Oxaliplatin or Cisplatin: A Study of the Arbeitsgemeinschaft Internistische Onkologie

Department of Internal Medicine I, University Hospital Carl Gustav Carus, University of Dresden, Dresden; Klinik für Onkologie und Hämatologie, Krankenhaus Nordwest, Frankfurt; Department of Medical Oncology, Hematology, Immunology, Rheumatology, Pneumology, Eberhard-Karls-University, Tübingen; and the Department of Oncology, Hematology, Bone Marrow Transplantation With Section Pneumology, University Hospital Hamburg Eppendorf, University of Hamburg, Germany.

Corresponding author: Jan Stoehlmacher, MD, University Hospital Carl Gustav Carus, Department of Internal Medicine I, Fetscherstr. 74, 01307 Dresden, Germany; e-mail: jan.stoehlmacher{at}uniklinikum-dresden.de.

Purpose To evaluate the association of germ-line polymorphisms of genes that may impact treatment outcome of platinum and fluorouracil combination chemotherapy in advanced gastric cancer (AGC).

Patients and Methods Blood samples of 156 patients enrolled onto a phase III study comparing fluorouracil, leucovorin, and oxaliplatin with fluorouracil, leucovorin, and cisplatin were collected. Polymorphisms within genes of TS, MTHFR, MTR, OPRT, XPD, ERCC1, XRCC1, XPA, GSTP1, GSTT1, and GSTM1 were genotyped using polymerase chain reaction–based techniques.

Results Median overall survival (OS) was 11.8 months (95% CI, 9.75 to 13.79 months) and median progression-free survival (PFS) was 5.8 months (95% CI, 4.99 to 6.61 months). The TS-3R/+6 haplotype (P = .004), the GSTT1 deletion polymorphism (P = .015), and genotypes of OPRT-Gly213Ala (P = .003) and XRCC1-Arg399Gln (P = .023) could be identified as independent predictors of OS. For PFS analyses, the TS-3R/+6 haplotye (P = .003) and MTR-A2756G (P = .01) were identified as independent positive predictors. The association between the GSTT1 deletion polymorphism and PFS showed only borderline significance (P = .053). Treatment related hematotoxicity in terms of grade 3/4 leukopenia was lowest among TS-3R/+6 haplotype carriers (P = .037). Grade 3/4 neutropenia was directly associated with the MTR-2756G/G genotype (P = .011), GSTP1-105Ile/Ile genotype (P = .02), and with the ERCC1-118T/8092C-haplotype (P = .042). In addition, significant associations between GSTP1-105Ile/Ile genotype and neurotoxicity and between the XPD-Asn312/751Gln haplotype and nephrotoxicity could be identified (P = .028 and P = .005, respectively).

Conclusion These findings underline the hypothesis that germ-line polymorphisms may play an important role in individualizing chemotherapy in AGC and deserve further prospective evaluation in AGC patients.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-16, 2005; and the Annual Meeting of the European Society for Medical Oncology, Istanbul, Turkey, 2006.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

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

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