Research Papers:

Biomarkers and polymorphisms in pancreatic neuroendocrine tumors treated with sunitinib

Paula Jiménez-Fonseca _, Miguel Navarro Martín, Alberto Carmona-Bayonas, Alfonso Calvo, Javier Fernández-Mateos, Miriam Redrado, Jaume Capdevila, Nieves Martínez Lago, Adelaida Lacasta, Javier Muñarriz, Ángel Segura, Josep Fuster, Francisco Barón, Marta Llanos, Raquel Serrano, Alfredo Castillo, Juan Jesús Cruz Hernández and Enrique Grande

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Oncotarget. 2018; 9:36894-36905. https://doi.org/10.18632/oncotarget.26380

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Paula Jiménez-Fonseca1, Miguel Navarro Martín2, Alberto Carmona-Bayonas3, Alfonso Calvo4, Javier Fernández-Mateos5, Miriam Redrado6, Jaume Capdevila7, Nieves Martínez Lago8, Adelaida Lacasta9, Javier Muñarriz10, Ángel Segura11, Josep Fuster12, Francisco Barón13, Marta Llanos14, Raquel Serrano15, Alfredo Castillo1, Juan Jesús Cruz Hernández2 and Enrique Grande16

1Medical Oncology Department, Hospital Universitario Central de Asturias, Oviedo, Spain

2Medical Oncology Department, Hospital Universitario de Salamanca, IBSAL, Salamanca, Spain

3Hematology and Medical Oncology Department, Hospital Universitario Morales Meseguer, UMU, IMIB, Murcia, Spain

4IDISNA and Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), Department of Histology and Pathology, University of Navarra, CIBERONC, ISC-II, Pamplona, Spain

5Molecular Medicine Unit, IBSAL, Department of Medicine, University of Salamanca, Salamanca, Spain

6IDISNA and Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), Department of Histology and Pathology, University of Navarra, Pamplona, Navarra, Spain

7Medical Oncology Department, Hospital Universitario Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain

8Medical Oncology Department, Hospital Universitario de A Coruña, La Coruña, Spain

9Medical Oncology Department, Hospital Universitario Donostia, Guipúzcoa, Spain

10Medical Oncology Department, Hospital General Universitario de Castellón, Castellón, Spain

11Medical Oncology Department, Hospital Universitario La Fe, Valencia, Spain

12Medical Oncology Department, Hospital Universitario Son Espases, Palma de Mallorca, Spain

13Medical Oncology Department, Hospital Universitario de Santiago de Compostela, Santiago de Compostela, Spain

14Medical Oncology Department, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain

15Medical Oncology Department, Hospital Universitario Reina Sofia, Cordoba, Spain

16Medical Oncology Department, MD Anderson Cancer Center, Madrid, Spain

Correspondence to:

Paula Jiménez-Fonseca, email: [email protected]

Keywords: sunitinib; osteopontin; IL-6; VEGFR-3; pancreatic neuroendocrine tumors

Received: September 13, 2018    Accepted: October 31, 2018    Published: December 11, 2018


Several circulating biomarkers and single nucleotide polymorphisms (SNPs) have been correlated with efficacy and tolerability to antiangiogenic agents. These associations remain unexplored in well-differentiated, metastatic pancreatic neuroendocrine tumors treated with the multitargeted tyrosine kinase inhibitor sunitinib. We have assessed the effect on tumor response at 6 months, overall survival, progression-free survival and safety of 14 SNPs, and 6 soluble proteins. Forty-three patients were recruited. Two SNPs in the vascular endothelial growth factor receptor 3 (VEGFR-3) gene predicted lower overall survival: rs307826 with hazard ratio (HR) 3.67 (confidence interval [CI] 95%, 1.35-10.00) and rs307821 with HR 3.84 (CI 95%, 1.47-10.0). Interleukin-6 was associated with increased mortality: HR 1.06 (CI 95%, 1.01-1.12), and osteopontin was associated with shorter PFS: HR 1.087 (1.01-1.16), independently of Ki-67. Furthermore, levels of osteopontin remained higher at the end of the study in patients considered non-responders: 38.5 ng/mL vs. responders: 18.7 ng/mL, p-value=0.039. Dynamic upward variations were also observed with respect to IL-8 levels in sunitinib-refractory individuals: 28.5 pg/mL at baseline vs. 38.3 pg/mL at 3 months, p-value=0.024. In conclusion, two VEGFR-3 SNPs as well as various serum biomarkers were associated with diverse clinical outcomes in patients with well-differentiated pancreatic neuroendocrine tumors treated with sunitinib.

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