Biomarkers and polymorphisms in pancreatic neuroendocrine tumors treated with sunitinib

// Paula Jimenez-Fonseca 1 , Miguel Navarro Martin 2 , Alberto Carmona-Bayonas 3 , Alfonso Calvo 4 , Javier Fernandez-Mateos 5 , Miriam Redrado 6 , Jaume Capdevila 7 , Nieves Martinez Lago 8 , Adelaida Lacasta 9 , Javier Munarriz 10 , Angel Segura 11 , Josep Fuster 12 , Francisco Baron 13 , Marta Llanos 14 , Raquel Serrano 15 , Alfredo Castillo 1 , Juan Jesus Cruz Hernandez 2 and Enrique Grande 16 1 Medical Oncology Department, Hospital Universitario Central de Asturias, Oviedo, Spain 2 Medical Oncology Department, Hospital Universitario de Salamanca, IBSAL, Salamanca, Spain 3 Hematology and Medical Oncology Department, Hospital Universitario Morales Meseguer, UMU, IMIB, Murcia, Spain 4 IDISNA 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 5 Molecular Medicine Unit, IBSAL, Department of Medicine, University of Salamanca, Salamanca, Spain 6 IDISNA and Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), Department of Histology and Pathology, University of Navarra, Pamplona, Navarra, Spain 7 Medical Oncology Department, Hospital Universitario Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain 8 Medical Oncology Department, Hospital Universitario de A Coruna, La Coruna, Spain 9 Medical Oncology Department, Hospital Universitario Donostia, Guipuzcoa, Spain 10 Medical Oncology Department, Hospital General Universitario de Castellon, Castellon, Spain 11 Medical Oncology Department, Hospital Universitario La Fe, Valencia, Spain 12 Medical Oncology Department, Hospital Universitario Son Espases, Palma de Mallorca, Spain 13 Medical Oncology Department, Hospital Universitario de Santiago de Compostela, Santiago de Compostela, Spain 14 Medical Oncology Department, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain 15 Medical Oncology Department, Hospital Universitario Reina Sofia, Cordoba, Spain 16 Medical Oncology Department, MD Anderson Cancer Center, Madrid, Spain Correspondence to: Paula Jimenez-Fonseca, email: palucaji@hotmail.com Keywords: sunitinib; osteopontin; IL-6; VEGFR-3; pancreatic neuroendocrine tumors Received: September 13, 2018     Accepted: October 31, 2018     Published: December 11, 2018 ABSTRACT 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.