Circulating Biomarkers of Response to Sunitinib in Gastroenteropancreatic Neuroendocrine Tumors
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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.
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.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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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.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
- 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
- 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
- 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