1121P Prognostic value of soluble transforming growth factor-β and soluble programmed death-ligand 1 in patients with non-functioning neuroendocrine tumors or pheochromocytomas/paragangliomas

4094 Background: We previously reported that soluble programmed death-Ligand 1 (sPD-L1) at pre-chemotherapy indicated the prognostic value for overall survival (OS) and the dynamics of sPD-L1 during palliative chemotherapy correlated with disease burden in biliary tract cancer (BTC). Transforming growth factor (TGF) -β attenuates tumor response to PD1/PD-L1 inhibitors. Strategy of dual targeting of PD1/PD-L1 and TGF-β is now under investigation. This study aimed to evaluate the association between soluble TGF-β (sTGF-β) and sPD-L1, dynamics during chemotherapy and its prognostic role in BTC. Methods: Study population consisted of 90 BTC patients treated with first line chemotherapy. Blood samples at pre-and post-chemotherapy and at disease progression (PD) were prospectively collected. Plasma sTGF-β and sPD-L1 levels were measured by using an enzyme-linked immunosorbent assay. Results: The median progression free survival (PFS) and OS of all patients was 6.9 months (m) (95% CI, 5.2-8.6) and 11.5 m (95% CI, 9.4-13.6). The best response was CR in 7 (7.8%), PR in 20 (22.2%), SD in 52 (57.8%), and PD in 11 patients (12.2%). The mean baseline sTGF-β and sPD-L1 were 16.4 ng/ml and 1.3 ng/ml. There was a positive association between sTGF-β and sPD-L1 in terms of baseline levels and changes after chemotherapy (at pre-chemo, Pearson correlation = 0.578, p < 0.001; change after chemotherapy, Pearson correlation = 0.542, p < 0.001). Patients with higher pre-chemotherapy sPD-L1 ( > 1.3 ng/ml) showed worse OS (9.2 vs 16.2 m, p < 0.001). Both sPD-L1 (1.8 vs 1.0 ng/ml, p < 0.001) and sTGF-β (20.5 vs 11.6 ng/ml, p < 0.001) were increased significantly at the time of PD compared with pre-chemotherapy. Regarding changes after chemotherapy, increased sTGF-β after chemotherapy (Δ > 3.2 ng/ml) had worse prognosis (PFS: 5.1 vs 7.3 m, p = 0.024; OS: 9.2 vs 12.3 m, p = 0.028). This prognostic value of change of sTGF-β after chemotherapy was also significant in multivariable analysis with other clinical factors (PFS: HR = 1.78, p = 0.022; OS: HR = 1.86, p = 0.018). Conclusions: In BTC, there is a positive association between sTGF-β and sPD-L1 value in terms of baseline levels and changes after chemotherapy. sTGF-β could be associated with the survival, particularly, increased value after chemotherapy indicates worse prognosis.

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The prognostic role of soluble transforming growth factor-β (sTGFb) and soluble programmed death-ligand 1 (sPDL1) in biliary tract cancer patients treated with binimetinib and capecitabine.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.257 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 257-257

Author(s):

Jin Won Kim ◽

Kyung-Hun Lee ◽

Ji-Won Kim ◽

Koung Jin Suh ◽

Ah-Rong Nam ◽

...

Keyword(s):

Growth Factor ◽

Biliary Tract ◽

Biliary Tract Cancer ◽

Transforming Growth Factor ◽

Enzyme Linked Immunosorbent Assay ◽

Prognostic Role ◽

Programmed Death Ligand 1 ◽

Positive Correlation ◽

Tract Cancer ◽

Programmed Death

257 Background: Transforming growth factor (TGF) -β signaling is important for tumor growth and metastasis in biliary tract cancer (BTC). TGF-β attenuates tumor response to programmed death-ligand 1 (PD-L1) blockade. This study aimed to evaluate a correlation between soluble TGF-β (s TGF-β) and soluble PD-L1 (sPD-L1) and its prognostic role in BTC. Methods: Study population consisted of 34 patients enrolled in phase Ib clinical trial of binimetinib (MEK inhibitor) with capecitabine in gemcitabine-pretreated BTC (ClinicalTrials.gov: NCT02773459). Blood samples at screening, after first cycle, after second cycle, and at disease progression were prospectively collected. Plasma sTGF-β and sPD-L1 values were measured by using an enzyme-linked immunosorbent assay. Results: In total 34 patients, 25 (73.5%) and 9 patients (26.5%) were second-line and third-line setting, respectively. Median progression-free survival (PFS) and overall survival (OS) were 4.1 and 7.8 months. The mean baseline sTGF-β and sPD-L1 were 18.7 ng/ml and 3.1 ng/ml. There was a positive correlation between sTGF-β and sPD-L1 value (pearson correlation = 0.596, p < 0.001). Mean baseline value was likely to be higher in best response of progressive disease, followed by stable disease and partial response. Similarly, higher baseline sTGF-β showed significantly shorter PFS (3.4 vs 5.1 months (m), p = 0.047) and OS (5.4 vs 9.7 m, p = 0.042). Higher baseline sPD-L1 also had a trend for poor PFS and OS (PFS: 3.0 vs 4.3 m, p = 0.220; OS: 6.4 vs 9.7 m, p = 0.140). Regarding changes from baseline to after first cycle, sTGF-β change of > 3.6 ng/ml demonstrated significantly shorter OS (5.9 vs 10.8 m, p = 0.020), although PFS did not differ according to sTGF-β change (p = 0.210). In contrast, OS did not differ according to sPD-L1 change (p = 0.190). sPD-L1 change > -1.7 ng/ml even had longer PFS (5.1 vs 2.2 m, p = 0.005). Conclusions: In BTC patients with binimetinib and capecitabine, there is a positive correlation between sTGF-β and sPD-L1 value and higher baseline sTGF-β and sPD-L1 indicate a worse prognosis. The early change of sTGF-β and sPD-L1 during treatment could predict the survival.

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The Tumor Microenvironment in Neuroendocrine Tumors: Biology and Therapeutic Implications

Neuroendocrinology ◽

10.1159/000497355 ◽

2019 ◽

Vol 109 (2) ◽

pp. 83-99 ◽

Cited By ~ 15

Author(s):

Mauro Cives ◽

Eleonora Pelle’ ◽

Davide Quaresmini ◽

Francesca Maria Rizzo ◽

Marco Tucci ◽

...

Keyword(s):

Growth Factor ◽

Neuroendocrine Tumors ◽

Transforming Growth Factor ◽

Current Knowledge ◽

Tumor Infiltrating Lymphocytes ◽

Transforming Growth Factor Β ◽

Tissue Growth ◽

The Other ◽

Matrix Remodeling ◽

Therapeutic Implications

Neuroendocrine tumors (NETs) include a heterogeneous group of malignancies arising in the diffuse neuroendocrine system and characterized by indolent growth. Complex interactions take place among the cellular components of the microenvironment of these tumors, and the recognition of the molecular mediators of their interplay and cross talk is crucial to discover novel therapeutic targets. NET cells overexpress a plethora of proangiogenic molecules including vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, semaphorins, and angiopoietins that promote both recruitment and proliferation of endothelial cell precursors, thus resulting among the most vascularized cancers with a microvessel density 10-fold higher than epithelial tumors. Also, NETs operate multifaceted interactions with stromal cells, both at local and distant sites, and whether their paracrine secretion of serotonin, connective tissue growth factor, and transforming growth factor β primarily drives the fibroblast activation to enhance the tumor proliferation, on the other side NET-derived profibrotic factors accelerate the extracellular matrix remodeling and contribute to heart valves and/or mesenteric fibrosis development, namely, major complications of functioning NETs. However, at present, little is known on the immune landscape of NETs, but accumulating evidence shows that tumor-infiltrating neutrophils, mast cells, and/or macrophages concur to promote the neoangiogenic switch of these tumors by either direct or indirect mechanisms. On the other hand, immune checkpoint molecules are heterogeneously expressed in NETs’ surrounding cells, and it is unclear whether or not tumor-infiltrating lymphocytes are antitumor armed within the microenvironment, given their low mutational load. Here, we review the current knowledge on both gastroenteropancreatic and pulmonary NETs’ microenvironment as well as both established and innovative treatments aimed at targeting the tumor-host interplay.

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