Originally published as JCO Early Release 10.1200/JCO.2005.04.8587 on July 5 2006

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FGFR4 Arg388 Allele Is Associated With Resistance to Adjuvant Therapy in Primary Breast Cancer

Christoph Thussbas, Jorg Nahrig, Sylvia Streit, Johannes Bange, Monika Kriner, Ronald Kates, Kurt Ulm, Marion Kiechle, Heinz Hoefler, Axel Ullrich, Nadia Harbeck

From the Department of Obstetrics and Gynecology, Institute of Pathology, and Institute for Medical Statistics and Epidemiology, Technical University of Munich, Munich; and the Department of Molecular Biology, Max-Planck-Institute of Biochemistry and U3 Pharma AG, Martinsried, Germany

Address reprint requests to Nadia Harbeck, MD, Department of Obstetrics and Gynecology, Technical University of Munich, Ismaninger Strasse 22, D-81675 Munich, Germany; e-mail: nadia.harbeck{at}lrz.tum.de

Purpose: A recent study presented first evidence that a single nucleotide polymorphism (SNP) at codon 388 of fibroblast growth factor receptor 4 (FGFR4) gene, causing a transmembrane domain missense mutation (Gly388Arg), is associated with disease outcome in node-positive breast cancer. This article addresses the clinical relevance of this SNP, FGFR4 genotype, phenotype, and HER2 regarding patient outcome and influence of adjuvant systemic therapy in a substantial primary breast cancer collective (n = 372; median follow-up, 94.5 months).

Methods: Polymerase chain reaction restriction fragment length polymorphism analysis of germ-line polymorphism was performed in uninvolved lymph nodes; FGFR4 and HER2 expression were assessed immunohistochemically in tissue microarrays.

Results: In 51% of patients, homo- or heterozygous Arg388 allele was present. No correlation existed between FGFR4 genotype and expression or HER2 status. In node-negative patients, FGFR4 genotype was not correlated with disease outcome. In node-positive patients, however, FGFR4 Arg388 was significantly associated with poor disease-free survival (DFS; P = .02) and overall survival (OS; P = .04). Notably, this association seems to be attributable to relatively poor therapy response in Arg388 carriers, reflected in their significantly shorter DFS (P = .02) and OS (P = .045) among patients receiving adjuvant systemic therapy. It is also seen as a significant interaction term in a multivariate proportional hazards model with Arg388 carriers having only about half as much benefit from adjuvant systemic therapy as wild-type carriers.

Conclusion: According to this study, FGFR4 Arg388 genotype is a marker for breast cancer progression in patients with adjuvant systemic therapy, particularly chemotherapy, and thus may indicate therapy resistance.

published online ahead of print at www.jco.org on July 5, 2006.

Supported by grants from Universal Mobile Telecommunications System (# 01GS0105, part 11) to H.H. and A.U., as well as the State of Bavaria (KKF Project # 8756159) and the Wilhelm Sander Foundation (2000.017.2) to N.H.

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

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

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