Addressing the Role of Angiogenesis in Patients with Advanced Pancreatic Neuroendocrine Tumors Treated with Everolimus: A Biological Prospective Analysis of Soluble Biomarkers and Clinical Outcomes
by
, , , , , , ,
Chiara Alessandra Cella
1,*, 
Francesca Spada
1,*,
Alfredo Berruti
2
,
Francesco Bertolini
3,4
,
Patrizia Mancuso
3,4,
Massimo Barberis
5
,
Eleonora Pisa
5,
Manila Rubino
1,
Lorenzo Gervaso
1,6,
Alice Laffi
7,
Stefania Pellicori
8,
Davide Radice
9,
Laura Zorzino
10,
Angelica Calleri
11,
Luigi Funicelli
12,13,
Giuseppe Petralia
14,15 and
Nicola Fazio
1 1
Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, 20141 Milan, Italy
2
Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia at the Azienda Socio Sanitaria Territoriale (ASST)-Spedali Civili, 25121 Brescia, Italy
3
Laboratory of Hematology-Oncology, European Institute of Oncology, IRCCS, 20141 Milan, Italy
4
Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, 20019 Milan, Italy
5
Division of Pathology and Laboratory Medicine, European Institute of Oncology, IRCCS, 20141 Milan, Italy
6
Molecular Medicine Department, University of Pavia, 27100 Pavia, Italy
7
Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy
8
Oncology Department, Azienda Ospedaliera di Lodi, 26900 Lodi, Italy
9
Division of Epidemiology and Biostatistics European Institute of Oncology, IRCCS, 20141 Milan, Italy
10
Division of Laboratory Medicine, European Institute of Oncology, IRCCS, 20141 Milan, Italy
11
Division of Diagnostic Haematopathology, European Institute of Oncology, IRCCS, 20141 Milan, Italy
12
Division of Medical Imaging and Radiation Sciences, European Institute of Oncology, IRCCS, 20141 Milan, Italy
13
SIRM, Italian College of Computed Tomography, Italian Society of Medical and Interventional Radiology, 20122 Milan, Italy
14
Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
15
Precision Imaging and Research Unit, Department of Medical Imaging and Radiation Sciences, European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, Italy
*
Authors to whom correspondence should be addressed.
Cancers 2022, 14(18), 4471; https://doi.org/10.3390/cancers14184471
Submission received: 28 July 2022
/
Revised: 30 August 2022
/
Accepted: 5 September 2022
/
Published: 15 September 2022
(This article belongs to the Special Issue Endocrine and Neuroendocrine Cancers)
Simple Summary
Despite the approval of new targeted therapies for pancreatic neuroendocrine tumors (PanNETs) over the past decades, the early identification of resistant tumors remains the major challenge, mainly because clear signs of tumor shrinkage are rarely achieved by imaging assessment. Starting from the hypothesis that angiogenesis can be implicated in the resistance to mTOR inhibitors, we evaluated a specific angiogenesis panel (through the measurement of soluble biomarkers for angiogenesis turnover, circulating endothelial cells, and circulating progenitors) as possible predictors of resistance to everolimus or everolimus efficacy in PanNETs. Our study showed that none of the investigated categories of biomarkers had a predictive value for everolimus resistance or efficacy. However, we suggest that circulating endothelial progenitors might be surrogate biomarkers for angiogenesis activity in PanNETs during everolimus treatment, and their baseline levels might correlate with survival outcomes. These data have never been reported before for NETs.
Abstract
Background: The success of targeted therapies in the treatment of pancreatic neuroendocrine tumors has emphasized the strategy of targeting angiogenesis and the PI3K/AKT/mTOR pathway. However, the major challenge in the targeted era remains the early identification of resistant tumors especially when the efficacy is rarely associated to a clear tumor shrinkage at by imaging assessment. Methods: In this prospective study (NCT02305810) we investigated the predictive and prognostic role of soluble biomarkers of angiogenesis turnover (VEGF, bFGF, VEGFR2, TSP-1) circulating endothelial cells and progenitors, in 43 patients with metastatic panNET receiving everolimus. Results: Among all tested biomarkers, we found a specific subpopulation of circulating cells, CD31+CD140b-, with a significantly increased tumor progression hazard for values less or equal to the first quartile. Conclusion: Our study suggested the evidence that circulating cells might be surrogate biomarkers of angiogenesis activity in patients treated with everolimus and their baseline levels can be correlated with survival. However, further studies are now needed to validate the role of these cells as surrogate markers for the selection of patients to be candidates for antiangiogenic treatments.
