Biomarkers and polymorphisms in pancreatic neuroendocrine tumors treated with sunitinib

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.

Pharmacogenomic Analyses of Sunitinib In Patients With Pancreatic Neuroendocrine Tumors

“…Due to the rare nature of panNETs, it is challenging to recruit large numbers of patients for clinical trials and subsequent analyses. The genotyped population (n = 56) of our study was of a comparable size with other SNP studies in patients with panNETs, including studies by Jiménez-Fonseca et al (n = 43) [34], Karakaxas et al (n = 51) [36] and Cigrovski Berković et al (n = 60) [19]. Consequently, our analyses, like many SNP panNET studies, are also limited by the small sample sizes in some of the subgroups, as well as the exploratory nature of the study.…”

“…Our analyses did not investigate VEGFR3 SNPs, reported by others to be correlated with a decreased tumor response to pazopanib [31], divergent tumor responses to sunitinib [18,20,25,[32][33][34] and poor prognosis in patients with gastroenteropancreatic neuroendocrine neoplasms [35]. A recent Spanish multicenter SNP analysis in patients with well-differentiated panNETs reported that VEGFR3 rs307826 and rs307821 predicted lower OS, but not PFS [34]; however, following correction for multiple testing, no correlations remained significant. Consistent with our study, no statistically significant correlation was observed between PFS or OS and the SNPs VEGFA rs2010963, ABCB1 rs1128503 or ABCB1 rs2032582 [34].…”

“…A recent Spanish multicenter SNP analysis in patients with well-differentiated panNETs reported that VEGFR3 rs307826 and rs307821 predicted lower OS, but not PFS [34]; however, following correction for multiple testing, no correlations remained significant. Consistent with our study, no statistically significant correlation was observed between PFS or OS and the SNPs VEGFA rs2010963, ABCB1 rs1128503 or ABCB1 rs2032582 [34].…”

Validation of the Correlation Between Single Nucleotide Polymorphism rs307826 in VEGFR3 and Outcome in Metastatic Clear-Cell Renal Cell Carcinoma Patients Treated with Sunitinib

“…In 43 patients treated with sunitinib, Jimenez-Fonseca has shown a better OS (p = 0.01) for AA-carriers compared to AG/GG-carriers. No significant impact on RR or PFS was observed, although the HR was in favor of the AA-carriers (0.70 for RR and 0.76 for PFS, respectively) [23]. In 44 patients with NETs from pancreatic origin, treated with pazopanib, Grande et al have shown a trend to better PFS (HR 0.14; p = 0.055) for AA-carriers compared to AG-carriers (12 versus 2 months, respectively).…”

Evaluating radiological response in pancreatic neuroendocrine tumours treated with sunitinib: comparison of Choi versus RECIST criteria (CRIPNET_ GETNE1504 study)

“…This structure is sustained by a host of proangiogenic molecules, such as vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptor (PDGFR) and others. 2,3 As a result, PanNETs appear as hypervascular masses on computed tomographies (CT), with avid contrast enhancement in the arterial phase. 4 The intensity of radiological enhancement correlates with the microvascular density.…”