Molecular Diagnosis & Therapy

, Volume 16, Issue 3, pp 151–161 | Cite as

Circulating Biomarkers of Response to Sunitinib in Gastroenteropancreatic Neuroendocrine Tumors

Current Data and Clinical Outlook
  • Joaquin Mateo
  • John V. Heymach
  • Amado J. Zurita
Review Article


After years of limited progress in the treatment of patients with advanced-stage gastroenteropancreatic neuroendocrine tumors (GEP-NETs), strategies using targeted agents have been developed on the basis of increased knowledge of the biology of these tumors. Some of these agents, targeting vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway, have shown efficacy in randomized clinical trials. The tyrosine kinase inhibitor sunitinib and the mTOR inhibitor everolimus have received international approval for the treatment of advanced well differentiated pancreatic NETs after showing survival benefit in randomized phase III trials. There is now an imperative need to identify biomarkers of the biologic activity of such targeted therapies in specific disease contexts, as well as new markers of response and prognosis. This approach may allow rational development of drugs and early identification of patients who may obtain benefit from treatments. In this article, we review recent developments in circulating biomarkers of the clinical benefit of targeted therapies for GEP-NET, including soluble proteins and circulating cells, with an emphasis on sunitinib. No validated molecular biomarkers are yet integrated into clinical practice for sunitinib in NET, although some markers have shown correlation with clinical outcomes and may be implicated in resistance. The VEGF-pathway proteins and interleukin-8 (IL-8) are possibly prognostic in GEP-NET; other possible soluble markers of the activity of sunitinib and everolimus include stromal cell-derived factor 1α, chromogranin A, and neuron-specific enolase. We additionally discuss treatment-induced modulation of circulating endothelial cells and progenitors and subpopulations of cells of the myeloid lineage. These candidate markers should be considered in the development of future combination or sequential therapies.


Vascular Endothelial Growth Factor Sunitinib Everolimus Carcinoid Tumor Vascular Endothelial Growth Factor Concentration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This research was supported in part by the National Institutes of Health through MD Anderson Cancer Center Support Grant Number CA016672. John Heymach has received a research grant from the LUNGevity Foundation and research funding and advisory board honoraria from Pfizer, AstraZeneca, and GlaxoSmithKline. Amado Zurita has received a research grant from the MD Anderson–AstraZeneca alliance.

Joaquin Mateo now works in the Drug Development Unit at the Royal Marsden Hospital – Institute of Cancer Research, Sutton, Surrey, UK.

The authors would like to thank Karen F. Phillips for editorial assistance.


  1. 1.
    Bosman FT, Carneiro F, Hruban RH, et al., editors. WHO classification of tumours of the digestive system. 4th ed. Lyon: International Agency for Research on Cancer, 2010.Google Scholar
  2. 2.
    Reubi JC, Kvols LK, Waser B, et al. Detection of somatostatin receptors in surgical and percutaneous needle biopsy samples of carcinoids and islet cell carcinomas. Cancer Res 1990 Sep 15; 50 (18): 5969–77.PubMedGoogle Scholar
  3. 3.
    Woltering EA, Barrie R, O’Dorisio TM, et al. Somatostatin analogues inhibit angiogenesis in the chick chorioallantoic membrane. J Surg Res 1991 Mar; 50 (3): 245–51.PubMedCrossRefGoogle Scholar
  4. 4.
    Gorden P, Comi RJ, Maton PN, et al. NIH conference: somatostatin and somatostatin analogue (SMS 201–995) in treatment of hormone-secreting tumors of the pituitary and gastrointestinal tract and non-neoplastic diseases of the gut. Ann Intern Med 1989 Jan 1; 110 (1): 35–50.PubMedCrossRefGoogle Scholar
  5. 5.
    Susini C, Buscail L. Rationale for the use of somatostatin analogs as antitumor agents. Ann Oncol 2006 Dec; 17 (12): 1733–42.PubMedCrossRefGoogle Scholar
  6. 6.
    Koizumi M, Onda M, Tanaka N, et al. Antiangiogenic effect of octreotide inhibits the growth of human rectal neuroendocrine carcinoma. Digestion 2002; 65 (4): 200–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Rinke A, Müller H-H, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009 Oct 1; 27 (28): 4656–63.PubMedCrossRefGoogle Scholar
  8. 8.
    Moertel CG, Lefkopoulo M, Lipsitz S, et al. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 1992 Feb 20; 326 (8): 519–23.PubMedCrossRefGoogle Scholar
  9. 9.
    Cassier PA, Walter T, Eymard B, et al. Gemcitabine and oxaliplatin combination chemotherapy for metastatic well-differentiated neuroendocrine carcinomas: a single-center experience. Cancer 2009 Aug 1; 115 (15): 3392–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Bajetta E, Catena L, Procopio G, et al. Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low-grade and high-grade neuroendocrine tumours? Cancer Chemother Pharmacol 2007 Apr; 59 (5): 637–42.Google Scholar
  11. 11.
    Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer 2011 Jan 15; 117 (2): 268–75.PubMedCrossRefGoogle Scholar
  12. 12.
    Raymond E, Dahan L, Raoul J-L, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011 Feb 10; 364 (6): 501–13.PubMedCrossRefGoogle Scholar
  13. 13.
    Valle J, Niccoli P, Raoul JL, et al. Updated overall survival data from a phase 3 study of sunitinib vs. placebo in patients with advanced, unresectable pancreatic neuroendocrine tumor (NET) [abstract no. 6569]. European Society for Medical Oncology, European Multidisciplinary Cancer Congress; 2011 Sep 23–27; Stockholm.Google Scholar
  14. 14.
    Yao JC, Shah MH, Ito T, et al., for the RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011 Feb 10; 364 (6): 514–23.PubMedCrossRefGoogle Scholar
  15. 15.
    Kulke MH, Lenz H-J, Meropol NJ, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 2008 Jul 10; 26 (20): 3403–10.PubMedCrossRefGoogle Scholar
  16. 16.
    Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007 Jan 11; 356 (2): 115–24.PubMedCrossRefGoogle Scholar
  17. 17.
    Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006 Oct 14; 368 (9544): 1329–38.PubMedCrossRefGoogle Scholar
  18. 18.
    Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU 11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003 Jan; 9 (1): 327–37.PubMedGoogle Scholar
  19. 19.
    Faivre S, Delbaldo C, Vera K, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006 Jan 1; 24 (1): 25–35.PubMedCrossRefGoogle Scholar
  20. 20.
    Yao JC, Phan AT, Chang DZ, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol 2008 Sep 10; 26 (26): 4311–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Rini BI, Cohen DP, Lu DR, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2011 May 4; 103 (9): 763–73.PubMedCrossRefGoogle Scholar
  22. 22.
    Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev 1997 Feb; 18 (1): 4–25.PubMedCrossRefGoogle Scholar
  23. 23.
    Ferrara N. Vascular endothelial growth factor and the regulation of angiogenesis. Recent Prog Horm Res 2000; 55: 15–36.PubMedGoogle Scholar
  24. 24.
    Li X, Eriksson U. Novel VEGF family members: VEGF-B, VEGF-C and VEGF-D. Int J Biochem Cell Biol 2001 Apr; 33 (4): 421–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Karkkainen MJ, Petrova TV. Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene 2000 Nov 20; 19 (49): 5598–605.PubMedCrossRefGoogle Scholar
  26. 26.
    DePrimo SE, Bello CL, Smeraglia J, et al. Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J Transl Med 2007 Jul 2; 5: 32.PubMedCrossRefGoogle Scholar
  27. 27.
    Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006 Jan 1; 24 (1): 16–24.PubMedCrossRefGoogle Scholar
  28. 28.
    Rini BI, Michaelson MD, Rosenberg JE, et al. Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol 2008 Aug 1; 26 (22): 3743–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Burstein HJ, Elias AD, Rugo HS, et al. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2008 Apr 10; 26 (11): 1810–6.PubMedCrossRefGoogle Scholar
  30. 30.
    DePrimo SE, Huang X, Blackstein ME, et al. Circulating levels of soluble KIT serve as a biomarker for clinical outcome in gastrointestinal stromal tumor patients receiving sunitinib following imatinib failure. Clin Cancer Res 2009 Sep 15; 15 (18): 5869–77.CrossRefGoogle Scholar
  31. 31.
    Bellmunt J, González-Larriba JL, Prior C, et al. Phase II study of sunitinib as first-line treatment of urothelial cancer patients ineligible to receive cisplatin-based chemotherapy: baseline interleukin-8 and tumor contrast enhancement as potential predictive factors of activity. Ann Oncol 2011 Dec; 22 (12): 2646–53.PubMedCrossRefGoogle Scholar
  32. 32.
    Zhu AX, Sahani DV, Duda DG, et al. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol 2009 Jun 20; 27 (18): 3027–35.PubMedCrossRefGoogle Scholar
  33. 33.
    Bello CL, Deprimo SE, Friece C, et al. Analysis of circulating biomarkers of sunitinib malate in patients with unresectable neuroendocrine tumors (NET): VEGF, IL-8, and soluble VEGF receptors 2 and 3 [abstract no. 4045]. J Clin Oncol 2006 Jun 20; 24 (18 Suppl.): abstract 4045.Google Scholar
  34. 34.
    Zurita AJ, Heymach JV, Khajavi M, et al. Circulating protein and cellular biomarkers of sunitinib in patients with advanced neuroendocrine tumors [abstract no. 4079]. J Clin Oncol 2011 May 20; 29 (15 Suppl.): abstract 4079.Google Scholar
  35. 35.
    Zhang J, Jia Z, Li Q, et al. Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumors. Cancer 2007 Apr 15; 109 (8): 1478–86.PubMedCrossRefGoogle Scholar
  36. 36.
    Pavel ME, Hassler G, Baum U, et al. Circulating levels of angiogenic cytokines can predict tumour progression and prognosis in neuroendocrine carcinomas. Clin Endocrinol (Oxf) 2005 Apr; 62 (4): 434–43.CrossRefGoogle Scholar
  37. 37.
    Yao JC, Pavel M, Phan AT, et al. Chromogranin A and neuron-specific enolase as prognostic markers in patients with advanced pNET treated with everolimus. J Clin Endocrinol Metab 2011 Dec; 96 (12): 3741–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Baudin E, Wolin EM, Castellano D, et al. Correlation of PFS with early response of chromogranin A and 5-hydroxyindoleacetic acid levels in patients with advanced neuroendocrine tumors: phase III RADIANT-2 study results [abstract no. 6564]. European Society for Medical Oncology, European Multidisciplinary Cancer Congress; 2011 Sep 23–27; Stockholm.Google Scholar
  39. 39.
    Terris B, Scoazec JY, Rubbia L, et al. Expression of vascular endothelial growth factor in digestive neuroendocrine tumours. Histopathology 1998 Feb; 32 (2): 133–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Xie K. Interleukin-8 and human cancer biology. Cytokine Growth Factor Rev 2001 Dec; 12 (4): 375–91.PubMedCrossRefGoogle Scholar
  41. 41.
    Kunz M, Hartmann A, Flory E, et al. Anoxia-induced up-regulation of interleukin-8 in human malignant melanoma: a potential mechanism for high tumor aggressiveness. Am J Pathol 1999 Sep; 155 (3): 753–63.PubMedCrossRefGoogle Scholar
  42. 42.
    Inoue K, Slaton JW, Eve BY, et al. Interleukin 8 expression regulates tumorigenicity and metastases in androgen-independent prostate cancer. Clin Cancer Res 2000 May; 6 (5): 2104–19.PubMedGoogle Scholar
  43. 43.
    Hussain F, Wang J, Ahmed R, et al. The expression of IL-8 and IL-8 receptors in pancreatic adenocarcinomas and pancreatic neuroendocrine tumours. Cytokine 2010 Feb; 49 (2): 134–40.PubMedCrossRefGoogle Scholar
  44. 44.
    Tecimer T, Dlott J, Chuntharapai A, et al. Expression of the chemokine receptor CXCR2 in normal and neoplastic neuroendocrine cells. Arch Pathol Lab Med 2000 Apr; 124 (4): 520–5.PubMedGoogle Scholar
  45. 45.
    Li A, Dubey S, Varney ML, et al. IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol 2003 Mar 15; 170 (6): 3369–76.PubMedGoogle Scholar
  46. 46.
    Huang S, Mills L, Mian B, et al. Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am J Pathol 2002 Jul; 161 (1): 125–34.PubMedCrossRefGoogle Scholar
  47. 47.
    Huang D, Ding Y, Zhou M, et al. Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res 2010 Feb 1; 70 (3): 1063–71.PubMedCrossRefGoogle Scholar
  48. 48.
    Zheng H, Fu G, Dai T, et al. Migration of endothelial progenitor cells mediated by stromal cell-derived factor-1α/CXCR4 via PI3K/Akt/eNOS signal transduction pathway. J Cardiovasc Pharmacol 2007 Sep; 50 (3): 274–80.PubMedCrossRefGoogle Scholar
  49. 49.
    Kryczek I, Wei S, Keller E, et al. Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis. Am J Physiol Cell Physiol 2007 Mar; 292 (3): C987–95.PubMedCrossRefGoogle Scholar
  50. 50.
    Ebos JML, Lee CR, Christensen JG, et al. Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci U S A 2007 Oct 23; 104 (43): 17069–74.PubMedCrossRefGoogle Scholar
  51. 51.
    Duda DG, Kozin SV, Kirkpatrick ND, et al. CXCL12 (SDF1α)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies? Clin Cancer Res 2011 Apr 15; 17 (8): 2074–80.PubMedCrossRefGoogle Scholar
  52. 52.
    Guleng B, Tateishi K, Ohta M, et al. Blockade of the stromal cell-derived factor-1/CXCR4 axis attenuates in vivo tumor growth by inhibiting angiogenesis in a vascular endothelial growth factor-independent manner. Cancer Res 2005 Jul 1; 65 (13): 5864–71.PubMedCrossRefGoogle Scholar
  53. 53.
    Arvidsson Y, Bergström A, Arvidsson L, et al. Hypoxia stimulates CXCR4 signalling in ileal carcinoids. Endocr Relat Cancer 2010 Jun 1; 17 (2): 303–16.PubMedCrossRefGoogle Scholar
  54. 54.
    Beerepoot LV, Mehra N, Vermaat JSP, et al. Increased levels of viable circulating endothelial cells are an indicator of progressive disease in cancer patients. Ann Oncol 2004 Jan; 15 (1): 139–45.PubMedCrossRefGoogle Scholar
  55. 55.
    Mancuso P, Burlini A, Pruneri G, et al. Resting and activated endothelial cells are increased in the peripheral blood of cancer patients. Blood 2001 Jun 1; 97 (11): 3658–61.PubMedCrossRefGoogle Scholar
  56. 56.
    Nolan DJ, Ciarrocchi A, Mellick AS, et al. Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization. Genes Dev 2007 Jun 15; 21 (12): 1546–58.PubMedCrossRefGoogle Scholar
  57. 57.
    Gao D, Nolan DJ, Mellick AS, et al. Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 2008 Jan 11; 319 (5860): 195–8.PubMedCrossRefGoogle Scholar
  58. 58.
    Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997 Feb 14; 275 (5302): 964–7.PubMedCrossRefGoogle Scholar
  59. 59.
    Beaudry P, Force J, Naumov GN, et al. Differential effects of vascular endothelial growth factor receptor-2 inhibitor ZD6474 on circulating endothelial progenitors and mature circulating endothelial cells: implications for use as a surrogate marker of antiangiogenic activity. Clin Cancer Res 2005 May 1; 11 (9): 3514–22.PubMedCrossRefGoogle Scholar
  60. 60.
    Mancuso P, Calleri A, Cassi C, et al. Circulating endothelial cells as a novel marker of angiogenesis. Adv Exp Med Biol 2003; 522: 83–97.PubMedCrossRefGoogle Scholar
  61. 61.
    Khan SS, Solomon MA, McCoy Jr JP. Detection of circulating endothelial cells and endothelial progenitor cells by flow cytometry. Cytometry B Clin Cytom 2005 Mar; 64 (1): 1–8.PubMedGoogle Scholar
  62. 62.
    Kalka C, Masuda H, Takahashi T, et al. Vascular endothelial growth factor165 gene transfer augments circulating endothelial progenitor cells in human subjects. Circ Res 2000 Jun 23; 86 (12): 1198–202.PubMedCrossRefGoogle Scholar
  63. 63.
    Vroling L, van der Veldt AAM, de Haas RR, et al. Increased numbers of small circulating endothelial cells in renal cell cancer patients treated with sunitinib. Angiogenesis 2009; 12 (1): 69–79.PubMedCrossRefGoogle Scholar
  64. 64.
    Norden-Zfoni A, Desai J, Manola J, et al. Blood-based biomarkers of SU 11248 activity and clinical outcome in patients with metastatic imatinib-resistant gastrointestinal stromal tumor. Clin Cancer Res 2007 May 1; 13 (9): 2643–50.PubMedCrossRefGoogle Scholar
  65. 65.
    Fernandez Pujol B, Lucibello FC, Gehling UM, et al. Endothelial-like cells derived from human CD14 positive monocytes. Differentiation 2000 May; 65 (5): 287–300.PubMedCrossRefGoogle Scholar
  66. 66.
    Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 2006 Jan 27; 124 (2): 263–6.PubMedCrossRefGoogle Scholar
  67. 67.
    Sawano A, Iwai S, Sakurai Y, et al. Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood 2001 Feb 1; 97 (3): 785–91.PubMedCrossRefGoogle Scholar
  68. 68.
    Finke J, Ko J, Rini B, et al. MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy. Int Immunopharmacol 2011 Jul; 11 (7): 856–61.PubMedCrossRefGoogle Scholar
  69. 69.
    Yao JC, Panneerselvam A, Bugarini R, et al. Effect of everolimus treatment on markers of angiogenesis in patients with advanced pancreatic neuroendocrine tumors: results from the phase III RADIANT-3 study [abstract no. 6573]. European Society for Medical Oncology, European Multidisciplinary Cancer Congress; 2011 Sep 23–27; Stockholm.Google Scholar
  70. 70.
    Modlin IM, Gustafsson BI, Moss SF, et al. Chromogranin A — biological function and clinical utility in neuro endocrine tumor disease. Ann Surg Oncol 2010 Sep; 17 (9): 2427–43.PubMedCrossRefGoogle Scholar
  71. 71.
    Lawrence B, Gustafsson BI, Kidd M, et al. The clinical relevance of chromogranin A as a biomarker for gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am 2011 Mar; 40 (1): 111–34.PubMedCrossRefGoogle Scholar
  72. 72.
    Bajetta E, Ferrari L, Martinetti A, et al. Chromogranin A, neuron specific enolase, carcinoembryonic antigen, and hydroxyindole acetic acid evaluation in patients with neuroendocrine tumors. Cancer 1999 Sep 1; 86 (5): 858–65.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2012

Authors and Affiliations

  • Joaquin Mateo
    • 1
  • John V. Heymach
    • 2
  • Amado J. Zurita
    • 1
  1. 1.Department of Genitourinary Medical Oncology, Unit 1374University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Thoracic Head and Neck Medical OncologyUniversity of Texas MD Anderson Cancer CenterHoustonUSA

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