TY - JOUR
T1 - Circulating cytokines and monocyte subpopulations as biomarkers of outcome and biological activity in sunitinib-treated patients with advanced neuroendocrine tumours
AU - Zurita, A. J.
AU - Khajavi, M.
AU - Wu, H. K.
AU - Tye, L.
AU - Huang, X.
AU - Kulke, M. H.
AU - Lenz, H. J.
AU - Meropol, N. J.
AU - Carley, W.
AU - DePrimo, S. E.
AU - Lin, E.
AU - Wang, X.
AU - Harmon, C. S.
AU - Heymach, J. V.
N1 - Funding Information:
We thank Dr James C Yao for valuable insights. This study was sponsored by Pfizer Inc. Editorial assistance was provided by Susanne Gilbert and Emily Seidman at ACUMED (New York, NY, USA) and was funded by Pfizer Inc.
Publisher Copyright:
© 2015 Cancer Research UK. All rights reserved.
PY - 2015/3/31
Y1 - 2015/3/31
N2 - 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-1a 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 protumorigenic CXCR4+ and VEGFR-1+ monocytes represent novel candidate markers and biologically relevant targets explaining the activity of sunitinib.
AB - 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-1a 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 protumorigenic CXCR4+ and VEGFR-1+ monocytes represent novel candidate markers and biologically relevant targets explaining the activity of sunitinib.
KW - Carcinoid
KW - Cellular responses to anticancer drugs
KW - Circulating biomarkers
KW - Pancreatic neuroendocrine tumours
KW - Pro-tumorigenic myeloid cells
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U2 - 10.1038/bjc.2015.73
DO - 10.1038/bjc.2015.73
M3 - Article
C2 - 25756398
AN - SCOPUS:84938548522
SN - 0007-0920
VL - 112
SP - 1199
EP - 1205
JO - British journal of cancer
JF - British journal of cancer
IS - 7
ER -