Circulating cytokines and monocyte subpopulations as biomarkers of outcome and biological activity in sunitinib-treated patients with advanced neuroendocrine tumours

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)-1 alpha (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-1 alpha and sVEGFR-2 levels were higher in pNET than in carcinoid (P 0.003 and 0.041, respectively). High (above-median) baseline SDF-1 alpha 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-1 alpha were associated with shorter PFS and OS, and high IL-8 and SDF-1 alpha 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-1 alpha 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.