title: Circulating cytokines and monocyte subpopulations as biomarkers of outcome and biological activity in sunitinib-treated patients with advanced neuroendocrine tumours.
abstract: BACKGROUND
  Sunitinib is approved worldwide for treatment of advanced pancreatic neuroendocrine tumours (pNET), but no validated markers exist to predict response. This analysis explored biomarkers associated with sunitinib activity and clinical benefit in patients with pNET and carcinoid tumours in a phase II study.
  
  
  METHODS
  Plasma was assessed for vascular endothelial growth factor (VEGF)-A, soluble VEGF receptor (sVEGFR)-2, sVEGFR-3, interleukin (IL)-8 (n=105), and stromal cell-derived factor (SDF)-1α (n=28). Pre-treatment levels were compared between tumour types and correlated with response, progression-free (PFS), and overall survival (OS). Changes in circulating myelomonocytic and endothelial cells were also analysed.
  
  
  RESULTS
  Stromal cell-derived factor-1α and sVEGFR-2 levels were higher in pNET than in carcinoid (P=0.003 and 0.041, respectively). High (above-median) baseline SDF-1α was associated with worse PFS, OS, and response in pNET, and high sVEGFR-2 with longer OS (P⩽0.05). For carcinoid, high IL-8, sVEGFR-3, and SDF-1α were associated with shorter PFS and OS, and high IL-8 and SDF-1α with worse response (P⩽0.05). Among circulating cell types, monocytes showed the largest on-treatment decrease, particularly CD14+ monocytes co-expressing VEGFR-1 or CXCR4.
  
  
  CONCLUSIONS
  Interleukin-8, sVEGFR-3, and SDF-1α were identified as predictors of sunitinib clinical outcome. Putative pro-tumorigenic CXCR4+ and VEGFR-1+ monocytes represent novel candidate markers and biologically relevant targets explaining the activity of sunitinib.
authors.affiliation: University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1374 Houston, TX, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Zurita
authors.affiliation: University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1374 Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Khajavi
authors.affiliation: University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1374 Houston, TX, USA.
authors.forename: H-K
authors.initials: HK
authors.lastname: Wu
authors.affiliation: Pfizer Inc., La Jolla, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Tye
authors.affiliation: Pfizer Inc., La Jolla, CA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Kulke
authors.affiliation: USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Lenz
authors.affiliation: University Hospitals Case Medical Center Seidman Cancer Center, Case Comprehensive Cancer Center and Case Western Reserve University, Cleveland, OH, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Meropol
authors.affiliation: Pfizer Inc., La Jolla, CA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Carley
authors.affiliation: Pfizer Inc., La Jolla, CA, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: DePrimo
authors.affiliation: University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1374 Houston, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Lin
authors.affiliation: University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1374 Houston, TX, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Pfizer Inc., La Jolla, CA, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Harmon
authors.affiliation: University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1374 Houston, TX, USA.
authors.forename: J V
authors.initials: JV
authors.lastname: Heymach
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood* / Q000276:immunology; D002276:Carcinoid Tumor / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D016207:Cytokines / Q000097:blood* / Q000276:immunology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D007958:Leukocyte Count; D009000:Monocytes / Q000276:immunology / Q000473:pathology*; D018358:Neuroendocrine Tumors / Q000097:blood* / Q000188:drug therapy* / Q000276:immunology; D011758:Pyrroles / Q000627:therapeutic use*; D000077210:Sunitinib; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D016207:Cytokines; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib