Somatostatin Analogues in the Treatment of Neuroendocrine Tumors: Past, Present and Future.

In recent decades, the incidence of neuroendocrine tumors (NETs) has steadily increased. Due to the slow-growing nature of these tumors and the lack of early symptoms, most cases are diagnosed at advanced stages, when curative treatment options are no longer available. Prognosis and survival of patients with NETs are determined by the location of the primary lesion, biochemical functional status, differentiation, initial staging, and response to treatment. Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning neuroendocrine tumors, which cause various clinical symptoms depending on hormonal hypersecretion. Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumor growth via the somatostatin receptor 2 (SSTR2). Both the PROMID (placebo-controlled, prospective, randomized study in patients with metastatic neuroendocrine midgut tumors) and the CLARINET (controlled study of lanreotide antiproliferative response in neuroendocrine tumors) trial showed a statistically significant prolongation of time to progression/progression-free survival (TTP/PFS) upon SSA treatment, compared to placebo. Moreover, the combination of SSA with peptide receptor radionuclide therapy (PRRT) in small intestinal NETs has proven efficacy in the phase 3 neuroendocrine tumours therapy (NETTER 1) trial. PRRT is currently being tested for enteropancreatic NETs versus everolimus in the COMPETE trial, and the potential of SSTR-antagonists in PRRT is now being evaluated in early phase I/II clinical trials. This review provides a synopsis on the pharmacological development of SSAs and their use as antisecretory drugs. Moreover, this review highlights the clinical evidence of SSAs in monotherapy, and in combination with other treatment modalities, as applied to the antiproliferative management of neuroendocrine tumors with special attention to recent high-quality phase III trials.

Soluble Urokinase Plasminogen Activator Receptor (suPAR) Concentrations are Elevated in Patients with Neuroendocrine Malignancies.

Neuroendocrine neoplasia (NEN) comprises heterogeneous tumors that are challenging to diagnose and, especially in cases of poorly differentiated (G3) NEN, are associated with very limited survival. Novel biomarkers allowing an early diagnosis as well as an optimal selection of suitable treatment options are urgently needed to improve the outcome of these patients. Recently, alterations of soluble urokinase-type plasminogen activator receptor (suPAR) serum levels were described in various types of cancers. However, the role of circulating suPAR as a biomarker in patients with NEN is unknown. In this study, we measured suPAR serum levels in a large and well-characterized cohort of 187 patients with NEN (neuroendocrine carcinomas (NEC) n = 30; neuroendocrine tumors (NET), n = 157) as well as 44 healthy controls. suPAR concentrations were significantly elevated in patients compared to controls. However, suPAR concentrations were independent of tumor-related factors such as the proliferation activity according to Ki-67, tumor grading, TNM (TNM classification of malignant tumors) stage, somatostatin receptor expression or clinical features such as functional or nonfunctional disease and the presence of tumor relapse. Interestingly, suPAR concentrations in NET patients were similar when compared to those measured in NEC patients. In contrast to previous results from other malignancies, in our analysis suPAR levels were not a significant predictor of overall survival. In conclusion, our data suggests that suPAR serum concentrations are elevated in NEN patients but do not allow prediction of outcome.

Analysis of miR-29 Serum Levels in Patients with Neuroendocrine Tumors-Results from an Exploratory Study.

BACKGROUND AND AIMS: Due to its involvement in tumor biology as well as tumor-associated stroma cell responses, recent data suggested a potential role of miR-29 as a biomarker for different malignancies. However, its role in neuroendocrine tumors (NETs) is only poorly understood. METHODS: We measured circulating levels of miR-29b in 45 patients with NET and compared them to 19 healthy controls. Results were correlated with clinical records. RESULTS: In our cohort of NET patients treated between 2010 and 2019 at our department, miR-29b serum levels were significantly downregulated when compared to healthy control samples. Further, a significant correlation between chromogranin A (CgA) and relative miR-29b levels was noted. However, serum levels of miR-29b were independent of tumor-related factors such as proliferation activity according to Ki-67 index, tumor grading, the TMN stage of malignant tumors, somatostatin receptor expression or clinical features such as functional or non-functional disease and presence of tumor relapse. Finally, in contrast to previous results from other malignancies, miR-29b serum levels were not a significant predictor of overall survival in NET patients. CONCLUSION: Our data suggest a role for miR-29b serum levels as a previously unrecognized biomarker for diagnosis of NET. However, miR-29 does not allow for predicting tumor stage or patients' outcome.