FGFR4 Arg388 allele is associated with resistance to adjuvant therapy in primary breast cancer.

Abstract

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.

• Authors: Christoph Thussbas, Jorg Nahrig, Sylvia Streit, Johannes Bange, Monika Kriner, Ronald Kates, Kurt Ulm, Marion Kiechle, Heinz Hoefler, Axel Ullrich, Nadia Harbeck
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 24 Issue 23 Pg. 3747-55 (Aug 10 2006) ISSN: 1527-7755 [Electronic] United States
• PMID: 16822847 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Genetic Markers
• Arginine
• Receptor, Fibroblast Growth Factor, Type 4
• Glycine

Topics

• Adult
• Aged
• Alleles
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Arginine
• Biomarkers, Tumor (metabolism)
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Chemotherapy, Adjuvant
• Disease Progression
• Drug Resistance, Neoplasm
• Female
• Genetic Markers
• Genotype
• Glycine
• Humans
• Immunohistochemistry
• Middle Aged
• Multivariate Analysis
• Mutation, Missense
• Phenotype
• Polymorphism, Single Nucleotide
• Predictive Value of Tests
• Prognosis
• Proportional Hazards Models
• Receptor, Fibroblast Growth Factor, Type 4 (genetics, metabolism)