title: FGFR4 Arg388 allele is associated with resistance to adjuvant therapy in primary breast cancer.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Obstetrics and Gynecology, Institute of Pathology, and Institute for Medical Statistics and Epidemiology, Technical University of Munich, Munich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Thussbas
authors.forename: Jorg
authors.initials: J
authors.lastname: Nahrig
authors.forename: Sylvia
authors.initials: S
authors.lastname: Streit
authors.forename: Johannes
authors.initials: J
authors.lastname: Bange
authors.forename: Monika
authors.initials: M
authors.lastname: Kriner
authors.forename: Ronald
authors.initials: R
authors.lastname: Kates
authors.forename: Kurt
authors.initials: K
authors.lastname: Ulm
authors.forename: Marion
authors.initials: M
authors.lastname: Kiechle
authors.forename: Heinz
authors.initials: H
authors.lastname: Hoefler
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001120:Arginine; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D005998:Glycine; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D015999:Multivariate Analysis; D020125:Mutation, Missense; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D005819:Genetic Markers; D001120:Arginine; D051499:Receptor, Fibroblast Growth Factor, Type 4; D005998:Glycine