title: Fibroblast Growth Factor Receptor Family Members as Prognostic Biomarkers in Head and Neck Squamous Cell Carcinoma: A Systematic Review.
abstract: BACKGROUND
  Since head and neck cancer is characterized by poor survival rates, there is a demand for novel therapeutic targets and prognostic biomarkers. An upcoming therapeutic target is the fibroblast growth factor receptor (FGFR) family. However, their prognostic role in head and neck cancer remains unclear.
  
  
  OBJECTIVE
  To systematically review current evidence on the prognostic value of FGFR family members in head and neck squamous cell carcinoma (HNSCC).
  
  
  METHODS
  A systematic search of PubMed, Embase, and the Cochrane Library was performed for publications up to 14 May 2014. Two reviewers screened all articles and included prognostic studies on the molecular biomarkers FGFR1-5 in any type of HNSCC. Relevant studies were assessed on risk of bias using the Quality in Prognostic Studies (QUIPS) tool. Data on FGFR aberrations and survival outcome were extracted from relevant studies. The prognostic value of FGFR aberrations was compared among studies.
  
  
  RESULTS
  The initial search yielded 1568 publications of which 12 fulfilled the inclusion criteria. Four studies reported FGFR1 gene amplification (9.3-17.4 %) and FGFR1 protein overexpression (11.8 %) in HNSCC. FGFR1 protein expression by cancer-associated fibroblasts correlated with poor survival outcome in one study (p < 0.01). Eight studies reported high rates of FGFR4 Gly388Arg polymorphisms (32.5-54.2 %) and FGFR4 protein overexpression (16-35 %), with varying correlations with survival. So far, no studies assessed the prognostic role of FGFR2, FGFR3, or FGFR5 in HNSCC.
  
  
  CONCLUSIONS
  Significant risk of bias has been identified among included studies. Therefore, cautious interpretation of the results is recommended.
  
  
  CONCLUSIONS
  In conclusion, evidence was found for prognostic value of FGFR1 expression in cancer-associated fibroblasts in HNSCC. Prognostic evidence on the other FGFR family members in HNSCC is limited and conflicting. This emphasizes the need for future well-conducted prognostic studies.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, PO box 885500, 3508 GA, Utrecht, The Netherlands. norbertipenburg@gmail.com.
authors.forename: Norbertus A
authors.initials: NA
authors.lastname: Ipenburg
authors.affiliation: Department of Pathology, University Medical Center Utrecht, PO box 885500, 3508 GA, Utrecht, The Netherlands. K.Koole-2@umcutrecht.nl.
authors.forename: Koos
authors.initials: K
authors.lastname: Koole
authors.affiliation: Department of Pathology, University Medical Center Utrecht, PO box 885500, 3508 GA, Utrecht, The Netherlands. sengliem@gmail.com.
authors.forename: K Seng
authors.initials: KS
authors.lastname: Liem
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, University Medical Center Utrecht, PO box 885500, 3508 GA, Utrecht, The Netherlands. P.M.W.vanKempen-2@umcutrecht.nl.
authors.forename: Pauline M W
authors.initials: PM
authors.lastname: van Kempen
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Medical Center Utrecht, PO box 885500, 3508 GA, Utrecht, The Netherlands. R.Koole@umcutrecht.nl.
authors.forename: Ron
authors.initials: R
authors.lastname: Koole
authors.affiliation: Department of Pathology, University Medical Center Utrecht, PO box 885500, 3508 GA, Utrecht, The Netherlands. P.J.vanDiest@umcutrecht.nl.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Medical Center Utrecht, PO box 885500, 3508 GA, Utrecht, The Netherlands. R.J.J.vanes@umcutrecht.nl.
authors.forename: Robert J J
authors.initials: RJ
authors.lastname: van Es
authors.affiliation: Department of Pathology, University Medical Center Utrecht, PO box 885500, 3508 GA, Utrecht, The Netherlands. S.M.Willems-4@umcutrecht.nl.|Department of Molecular Carcinogenesis, Netherlands Cancer Institute, PO box 90203, 1006 BE, Amsterdam, The Netherlands. S.M.Willems-4@umcutrecht.nl.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Willems
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis* / Q000378:metabolism / Q000628:therapy; D006258:Head and Neck Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000628:therapy; D006801:Humans; D011379:Prognosis; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D017468:Receptors, Fibroblast Growth Factor