Prognostic relevance of circulating PIGF levels in patients with neuroendocrine tumors.

Abstract

4128 Background: Placental growth factor (PlGF), a VEGF homolog implicated in tumor angiogenesis and adaptation to antiangiogenic therapy, is emerging as candidate target in malignancies. As antiangiogenic treatments are introduced in the management of neuroendocrine tumors (NETs), we addressed the expression and function of PlGF in NETs. Methods: Serum levels of PlGF were determined in two independent cohorts of NET patients collected retrospectively and prospectively (n=87 and n=84) using Roche Elecsys and correlated with clinical data. Expression of PlGF in tumors was evaluated by immunohistochemistry. PlGF effects on proliferation and migration were examined in vitro using NET cell lines. Results: Circulating and tumoral PlGF were found elevated in NET patients as compared to control sera and pancreatic tissues in a retrospective analysis restricted to patients with pancreatic NETs (pNETs). De novo expression of PlGF occurred primarily in the tumor stroma, suggesting paracrine stimulatory circuits. Indeed, PlGF enhanced proliferation and migration of NET cells, and elevated circulating PlGF levels correlated with advanced tumor grading, suggesting that PlGF supported a more aggressive phenotype. In line with this notion, circulating PlGF levels above median predicted reduced tumor related survival in pNET patients (p=0.012). Furthermore, pathologic PlGF levels were associated with poor prognosis within the subgroup of grade 2 tumors. Subsequent prospective PlGF determinations confirmed and extended our observation of elevated PlGF levels for both, pNETs (n=32, p<0.001) and midgut NETs (n=58, p<0.001). Since median follow up was too short to determine survival, time to progression (TTP) was analyzed instead. Most pNETs were progressive at the time of sample collection, precluding an informative evaluation of TTP in this subgroup. However, PlGF levels above median were correlated with shorter TTP in midgut NETs (p=0.0091; TTP 27 months versus undefined, HR 3.802). Conclusions: These data assign to PlGF a novel function in the pathobiology of NETs and propose PlGF as a prognostic parameter in patients with NETs.