Intravenous versus oral etoposide: efficacy and correlation to clinical outcome in patients with high-grade metastatic gastroenteropancreatic neuroendocrine neoplasms (WHO G3)

High-grade Gastroenteropancreatic Neuroendocrine neoplasms (H-NENs) comprehend well-differentiated tumors (NET G3) and poorly differentiated carcinomas (NEC) with proliferative activity indexes as mitotic count (MC) >20 mitoses/10 HPF and Ki-67 >20%. At present, no specific therapy for H-NENs exists and the several evidences of microenvironment involvement in their pathogenesis pave the way for tailored therapies. Forty-five consecutive cases, with available information about T-cell, immune, and non-immune markers, from surgical pathology and clinical databases of 2 Italian institutions were immunostained for Arginase, CD33, CD163 and CD66 myeloid markers. The association between features was assessed by Spearman’s correlation coefficient. A unsupervised K-means algorithm was used to identify clusters of patients according to inputs of microenvironment features and the relationship between clusters and clinicopathological features, including cancer-specific survival (CSS), was analyzed. The H-NEN population was composed of 6 (13.3%) NET G3 and 39 (86.7%) NEC. Overall, significant positive associations were found between myeloid (CD33, CD163 and Arginase) and T/immune markers (CD3, CD4, CD8, PD-1 and HLA-I). Myeloid and T-cell markers CD3 and CD8 identified two clusters of patients from unsupervised K-means analysis. Cases grouped in cluster 1 with more myeloid infiltrates, T cell, HLA and expression of inhibitory receptors and ligands in the stroma (PD-1, PD-L1) had significantly better CSS than patients in cluster 2. Multivariable analysis showed that Ki-67 (>55 vs. <55, HR 8.60, CI 95% 2.61–28.33, p < 0.0001) and cluster (1 vs. 2, HR 0.43, CI 95% 0.20–0.93, p = 0.03) were significantly associated with survival. High grade gastroenteropancreatic neuroendocrine neoplasms can be further classified into two prognostic sub-populations of tumors driven by different tumor microenvironments and immune features able to generate the framework for evaluating new therapeutic strategies.

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Elevated Flt3L Predicts Long-Term Survival in Patients with High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms

Cancers ◽

10.3390/cancers13174463 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4463

Author(s):

Katharina M. Detjen ◽

Raik Otto ◽

Yvonne Giesecke ◽

Lukas Geisler ◽

Pamela Riemer ◽

...

Keyword(s):

Gene Expression ◽

Mrna Expression ◽

Tumor Tissue ◽

Treatment Decisions ◽

Neuroendocrine Neoplasms ◽

High Grade ◽

Patient Stratification ◽

Term Survival ◽

Gastroenteropancreatic Neuroendocrine Neoplasms ◽

Related Survival

Background: The clinical management of high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is challenging due to disease heterogeneity, illustrating the need for reliable biomarkers facilitating patient stratification and guiding treatment decisions. FMS-like tyrosine kinase 3 ligand (Flt3L) is emerging as a prognostic or predictive surrogate marker of host tumoral immune response and might enable the stratification of patients with otherwise comparable tumor features. Methods: We evaluated Flt3L gene expression in tumor tissue as well as circulating Flt3L levels as potential biomarkers in a cohort of 54 patients with GEP-NEN. Results: We detected a prominent induction of Flt3L gene expression in individual G2 and G3 NEN, but not in G1 neuroendocrine tumors (NET). Flt3L mRNA expression levels in tumor tissue predicted the disease-related survival of patients with highly proliferative G2 and G3 NEN more accurately than the conventional criteria of grading or NEC/NET differentiation. High level Flt3L mRNA expression was associated with the increased expression of genes related to immunogenic cell death, lymphocyte effector function and dendritic cell maturation, suggesting a less tolerogenic (more proinflammatory) phenotype of tumors with Flt3L induction. Importantly, circulating levels of Flt3L were also elevated in high grade NEN and correlated with patients’ progression-free and disease-related survival, thereby reflecting the results observed in tumor tissue. Conclusions: We propose Flt3L as a prognostic biomarker for high grade GEP-NEN, harnessing its potential as a marker of an inflammatory tumor microenvironment. Flt3L measurements in serum, which can be easily be incorporated into clinical routine, should be further evaluated to guide patient stratification and treatment decisions.

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29 Elevated Flt3L predicts long-term survival in patients with high-grade gastroenteropancreatic neuroendocrine neoplasms

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.029 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A34-A34

Author(s):

Katharina Detjen ◽

Raik Otto ◽

Yvonne Giesecke ◽

Lukas Geisler ◽

Pamela Riemer ◽

...

Keyword(s):

Gene Expression ◽

Tumor Tissue ◽

Surrogate Marker ◽

Ethics Committee ◽

Neuroendocrine Neoplasms ◽

High Grade ◽

Patient Stratification ◽

Gastroenteropancreatic Neuroendocrine Neoplasms ◽

Ethical Approval ◽

Related Survival

BackgroundGastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) are a rare and heterogeneous family of tumors arising from the disseminated neuroendocrine system of the gastrointestinal tract and pancreas. Clinical management of high-grade GEP-NEN is challenging due to disease heterogeneity, illustrating the need for reliable biomarkers facilitating patient stratification and guiding treatment decisions. FMS-like tyrosine kinase 3 ligand (Flt3L) is emerging as a prognostic or predictive surrogate marker of host tumoral immune response and might enable stratification of patients with otherwise comparable tumor features.MethodsWe used RNAseq data from human foregut-derived pancreatic and gastric GEP-NEN to evaluate Flt3L gene expression in tumor tissue. The data set (n=54) represented the full range of NEN grades and differentiation, and expression levels were compared to healthy control tissue as well. We also analyzed circulating Flt3L levels in serum samples of a separate cohort of G2/G3 GEP-NEN (n=59) an healthy controls (n=4). The study was approved by the local ethics committee at Charité Universitätsmedizin Berlin, Germany (ethical approval number EA1/229/17) and patient informed consent was obtained.ResultsWe detected a prominent induction of Flt3L gene expression in individual G2 and G3 NEN, but not in G1 neuroendocrine tumors (NET). Flt3L mRNA expression levels in tumor tissue predicted disease related survival of patients with highly proliferative G2 and G3 NEN more accurately than the conventional criteria of grading or NEC/NET differentiation. High level Flt3L mRNA expression was associated with increased expression of genes related to immunogenic cell death, lymphocyte effector function and dendritic cell maturation, suggesting a less tolerogenic (more proinflammatory) phenotype of tumors with Flt3L induction. Importantly, circulating levels of Flt3L were also elevated in high grade NEN and correlated with patients´ progression-free and disease-related survival, thereby reflecting the results observed in tumor tissue.ConclusionsOur results suggest Flt3L as a surrogate marker of an inflammatory tumor microenvironment. Therefore, we propose Flt3L as a prognostic biomarker for high grade GEP-NEN. Flt3L measurements in serum, which can be easily be incorporated into clinical routine, may hold the promise to guide patient stratification and tailor treatment decisions and should be further evaluated, especially in the context of immunotherapies.Ethics ApprovalThe study was approved by the local ethics committee at Charité Universitätsmedizin Berlin, Germany (ethical approval number EA1/229/17) and patient informed consent was obtained.

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The Problem of High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms

Endocrinology and Metabolism Clinics of North America ◽

10.1016/j.ecl.2018.05.001 ◽

2018 ◽

Vol 47 (3) ◽

pp. 683-698 ◽

Cited By ~ 20

Author(s):

Halfdan Sorbye ◽

Eric Baudin ◽

Aurel Perren

Keyword(s):

Neuroendocrine Neoplasms ◽

High Grade ◽

Gastroenteropancreatic Neuroendocrine Neoplasms

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1100MO Molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms

Annals of Oncology ◽

10.1016/j.annonc.2021.08.182 ◽

2021 ◽

Vol 32 ◽

pp. S910-S911

Author(s):

H. Sorbye ◽

A. Venizelos ◽

H. Elvebakken ◽

A. Perren ◽

I.M.B. Lothe ◽

...

Keyword(s):

Molecular Characteristics ◽

Neuroendocrine Neoplasms ◽

High Grade ◽

Gastroenteropancreatic Neuroendocrine Neoplasms

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PRRT in high-grade gastroenteropancreatic neuroendocrine neoplasms (WHO G3)

Endocrine Related Cancer ◽

10.1530/erc-19-0400 ◽

2020 ◽

Vol 27 (3) ◽

pp. R67-R77 ◽

Cited By ~ 7

Author(s):

Halfdan Sorbye ◽

Grace Kong ◽

Simona Grozinsky-Glasberg

Keyword(s):

Residual Disease ◽

Somatostatin Receptor ◽

Progression Free Survival ◽

Neuroendocrine Neoplasms ◽

Receptor Imaging ◽

High Grade ◽

Ki 67 ◽

Free Survival ◽

Gastroenteropancreatic Neuroendocrine Neoplasms ◽

Net G3

Peptide receptor radionuclide therapy (PRRT) is an established treatment for grade 1 and 2 gastroenteropancreatic neuroendocrine tumors with an increased uptake on somatostatin receptor imaging (SRI). Patients with metastatic high-grade (WHO G3) gastroenteropancreatic neuroendocrine neoplasms (NET G3 and NEC) represent a heterogeneous subgroup with poor prognosis and standard platinum-etoposide chemotherapy have limited therapeutic benefit. However, there is promising emerging evidence supporting the effectiveness of PRRT in SRI-positive G3 disease. A review search for studies reporting on PRRT in gastroenteropancreatic neuroendocrine neoplasms G3 was performed: four studies with more than ten cases were found. PRRT was mainly given as second- or third-line treatment in patients with progressive disease. Most patients had a pancreatic primary, 50% had well-differentiated tumors, and most had a Ki-67 <55%. Three studies showed similar results with promising response rates (31–41%) and disease control rates (69–78%). Progression-free survival (11–16 months) and survival (22–46 months) were best concerning patients with a Ki-67 <55%. Progression-free survival was 19 months in NET G3, 11 months for lowNEC (Ki-67 ≤55%) and 4 months for highNEC (Ki-67 >55%). PRRT should be considered for patients with increased uptake on SRI, both in gastroenteropancreatic NET G3 cases and as well as in NEC cases with a Ki-67 21–55%. PRRT for NEC with a Ki-67 >55% is less defined, but could be considered in highly selected cases after response to initial chemotherapy where all residual disease have high uptake on SRI. Dual tracer using 18F-FDG PET/CT and SRI provides important information for patient selection for PRRT in this heterogeneous complex high-grade disease.

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