title: Serum heparan sulfate concentration is correlated with the failure of epidermal growth factor receptor tyrosine kinase inhibitor treatment in patients with lung adenocarcinoma.
abstract: BACKGROUND
  The epidermal growth factor receptor (EGFR) mutation status is a validated biomarker for the stratification of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) treatment in patients with non-small cell lung cancer (NSCLC); however, its use is limited in patients with wild-type EGFR, and new biomarkers are needed. We hypothesized that the serum concentration of heparan sulfate (HS), which activates oncogenic growth factor receptor signaling through EGFR and non-EGFR signaling pathways, may be a novel glycobiological biomarker for EGFR-TKIs treatment in NSCLC.
  
  
  METHODS
  The pretreatment serum HS concentrations were determined using enzyme-linked immunosorbent assay in 83 patients with stage IV non-small cell lung adenocarcinoma who received EGFR-TKIs treatment. The relationship between the serum HS concentrations and patient characteristics, tumor response, progression-free survival (PFS), and overall survival (OS) were analyzed.
  
  
  RESULTS
  Patient sex, performance status, smoking history, and EGFR mutation status were associated with tumor response. The serum HS concentrations were significantly higher among patients with progressive disease than among those without progressive disease (p = 0.003). Furthermore, the serum HS concentrations were strongly associated with a poor PFS and OS in a univariate Cox analysis (p = 0.0022 and p = 0.0003, respectively). A stratified multivariate Cox model according to the EGFR mutation status showed that higher HS concentrations were significantly associated with a shorter PFS and OS (p = 0.0012 and p = 0.0003).
  
  
  CONCLUSIONS
  We concluded that a high-serum HS concentration was strongly related to a poor treatment outcome of EGFR-TKIs and may be a promising noninvasive and repeatable glycobiological biomarker in cancer treatment.
authors.affiliation: Thoracic Oncology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nishio
authors.forename: Takeharu
authors.initials: T
authors.lastname: Yamanaka
authors.forename: Kazuko
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Hideharu
authors.initials: H
authors.lastname: Kimura
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sakai
authors.forename: Asao
authors.initials: A
authors.lastname: Sakai
authors.forename: Takashi
authors.initials: T
authors.lastname: Sone
authors.forename: Atsushi
authors.initials: A
authors.lastname: Horiike
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Koizumi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kasahara
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Ohira
authors.forename: Norihiko
authors.initials: N
authors.lastname: Ikeda
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.forename: Tokuzo
authors.initials: T
authors.lastname: Arao
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
mesh_terms: D000230:Adenocarcinoma / Q000097:blood* / Q000188:drug therapy / Q000473:pathology; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood* / Q000188:drug therapy / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D006497:Heparan Sulfate / Q000097:blood*; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage; D012189:Retrospective Studies; D017211:Treatment Failure
chemical_list: D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006497:Heparan Sulfate; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C512478:EGFR protein, human