Gastroenteropancreatic Neuroendocrine Tumors Patients Research Articles

Bcl-2 and Noxa are potential prognostic indicators for patients with gastroenteropancreatic neuroendocrine neoplasms.

Bcl-2 family proteins are of great significance in the pathogenesis and development of tumors. In this study, the correlations between the expression of Bcl-2 family proteins and clinicopathological features and prognosis of neuroendocrine neoplasms (NENs) were further investigated. 105 Patients diagnosed with gastroenteropancreatic NENs (GEP-NENs) with the paraffin specimen of the tumor available were retrospectively included. Immunohistochemistry (IHC) was performed to detect the expression of Bcl-2 family proteins in paraffin-embedded samples. Student's t-test and Chi-square test were applied to compare the difference of quantitative and categorical variables, respectively. Survival analysis was conducted according to Kaplan-Meier method. Univariate and multivariate cox regression analysis were used to identify the independent prognostic factors. The IHC score of Bcl-2 was significantly higher in neuroendocrine carcinoma (NEC) patients (65.6%), while a higher IHC score of Noxa was more common in neuroendocrine tumor (NET) patients (49.3%). Survival analysis indicated that patients with higher Bcl-2 expression and lower Noxa expression had worse 5-year survival (39.3% vs. 75.6%, p < 0.001; 40.6% vs. 84.9%, p < 0.001). Multivariate cox analysis indicated that high Bcl-2 expression was an independent factor associated with inferior DFS (hazard ratio [HR]: 2.092; 95% confidence interval [CI]: 1.106-3.955; p = 0.023) and OS (HR: 2.784; 95% CI: 1.326-5.846; p = 0.007), while higher Noxa expression was associated with superior DFS (HR:0.398; 95% CI: 0.175-0.907; p = 0.028) and OS (HR: 0.274; 95% CI: 0.110-0.686; p = 0.006). Higher expression of Bcl-2 and lower expression of Noxa were associated with unfavorable prognosis of GEP-NENs patients.

Survival Outcomes in Metastatic Gastroenteropancreatic Neuroendocrine Tumor Patients receiving Concomitant 225Ac-DOTATATE Targeted Alpha Therapy and Capecitabine: A Real-world Scenario Management Based Long-term Outcome Study.

Rationale: Although the short-term results of targeted alpha therapy (TAT) with 225Ac-DOTATATE in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have proven effective, none have assessed the long-term outcome results. In this study, we aimed to evaluate the long-term outcome of 225Ac-DOTATATE targeted alpha therapy (TAT) in patients with somatostatin receptor (SSTR)-expressing advanced-stage metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Methods: Patients with 68Ga-DOTANOC PET/CT scans showing moderate-to-high SSTR expression were recruited. Systemic TAT was performed in 91 adults with GEP-NET [54 males, and 37 females] mean age 54 years (y) (range: 25-75y)] using 225Ac-DOTATATE (100-120 kBq/kg body weight). All patients were given capecitabine therapy as a radiosensitizer (dose 2 g/day) from day 0 to 14 of every 225Ac-DOTATATE treatment cycle. Patients were categorized into three groups based on the status of prior 177Lu-PRRT: prior 177Lu-PRRT-refractory-group; prior 177Lu-PRRT-disease-control group; and 177Lu-PRRT naïve group. Primary endpoints were overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective tumour response, clinical response, and the assessment of treatment-related toxicities. Results: Among the 91 patients, 57 underwent prior 177Lu-DOTATATE therapy [24 disease controlled (PR/SD), 33 progressive diseases (PD)]. A total of 453 225Ac-DOTATATE TAT cycles were administered [median four cycles per patient; range 1-10] in a median follow-up duration of 24 months (range 5-41mo). Median OS was not attained with a 24-month overall survival probability of 70.8%. In multivariate analysis, prognostic factors associated with a poor OS included, the presence bone metastases [HR: 2.501; 95% CI: 1.826 - 5.791; P<0.032], and 225Ac-DOTATATE therapy refractory disease [HR: 8.781; 95% CI: 3.843 - 20.062; P<0.0001]. Median PFS was also not reached with a 24-month progression-free survival probability of 67.5%. The multivariate analysis revealed only 177Lu-PRRT refractory disease significantly associated with a reduced PFS. [HR: 14.338; 95% CI: 1.853 - 97.698; P = 0.011]. Two of 79 patients (2.5%) with assessable disease experienced complete response; 38 (48%) had a partial response, 23 (29%) had SD, and 16 (20.2%) had PD. PD was observed in more patients from the prior 177Lu-PRRT-refractory group (11/33; 34%) as compared to 177Lu-PRRT-naïve patients (4/24; 11%), P-0.056. Patients from the prior 177Lu-PRRT-refractory group had the highest risk of poor PFS [HR:13.91; 95% CI: 4.45 - 42.271; P = 0.0009]. A significant clinical benefit was achieved post 225Ac-DOTATATE therapy with minimal treatment-related toxicities. Conclusion: The long-term results reveal 225Ac-DOTATATE TAT has shown promising results and improves overall survival, even in patients refractory to prior 177Lu-DOTATATE treatment, with transient and acceptable adverse effects.

Volumetric parameters from [18 F]FDG PET/CT predicts survival in patients with high-grade gastroenteropancreatic neuroendocrine neoplasms.

A positive fluorine‐18 labelled 2‐deoxy‐2‐fluoroglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) has been associated with more aggressive disease and less differentiated neuroendocrine neoplasms (NEN). Although a high maximum standardized uptake value (SUVmax) predicts poor outcome in NEN, volumetric parameters from [18F]FDG PET have not been evaluated for prognostication in a pure high‐grade gastroenteropancreatic (GEP) NEN cohort. In this retrospective observational study, we evaluated the volumetric PET parameters total metabolic tumour volume (tMTV) and total total lesion glycolysis (tTLG) for independent prognostication of overall survival (OS). High‐grade GEP NEN patients with [18F]FDG PET/CT examination and biopsy within 90 days were included. Total MTV and tTLG were calculated using an adaptive thresholding software. Patients were dichotomised into low and high metabolic groups based on median tMTV and tTLG. OS was compared using Kaplan–Meier estimator and log‐rank test. Uni and multivariable Cox regression was used to estimate effect sizes and adjust for tumour differentiation and SUVmax. Sixty‐six patients (median age 64 years) were included with 14 NET G3 and 52 NEC cases after histological re‐evaluation. Median tMTV was 208 cm3 and median tTLG 1899 g. Median OS in the low versus high tMTV‐group was 21.2 versus 5.7 months (HR 2.53, p = 0.0007) and 22.8 versus 5.7 months (HR 2.42, p = 0.0012) in the tTLG‐group. Adjusted for tumour differentiation and SUVmax, tMTV and tTLG still predicted for poor OS, and both tMTV and tTLG were stronger prognostic parameters than SUVmax. Both regression models showed a strong association between volumetric parameters and OS for both neuroendocrine tumours (NET) G3 and neuroendocrine carcinomas (NEC). OS for the tTLG low metabolic NEC was much higher than for the tTLG high metabolic NET G3 (18.3 vs. 5.7 months). High‐grade GEP NEN patients with high tMTV or tTLG had a worse OS regardless of tumour differentiation (NET G3 or NEC). Volumetric PET parameters were stronger prognostic parameters than SUVmax.

HRAS expression predicts Lenvatinib responsiveness in human primary gastroenteropancreatic neuroendocrine tumor cells.

e16211 Background: Neuroendocrine neoplasms (NENs) are a rare group of heterogeneous tumors, with clinical presentation ranging from indolent and small lesions to very aggressive, metastatic and therapy refractory forms. Despite a high number of trials, few drugs have been introduced in the clinical practice and therapeutic options for systemic intervention are limited. The recent TALENT trial demonstrated the efficacy of Lenvatinib, a multi-tyrosine kinase inhibitor (MKI), in the treatment of patients with advanced well differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing from targeted therapies or somatostatin analogues with no other treatment indication. Lenvatinib might represent a novel therapeutic opportunity for these rare tumor patients. However, the treatment approach with MKI lacks clinically validated tissue or blood biomarkers to guide patient selection and improve efficacy. Methods: Here we established 11 human primary cultures from patients with GEP-NEN of different grades and sites of origin and assessed the antitumor activity of Lenvatinib compared with standard treatment agents. All primary cultures were molecularly characterized to identify possible predictors of response. Results: Lenvatinib exerted a significant inhibition of cell growth in primary GEP-NET cells, with median survival inhibitions similar or higher than those of standard treatments. Of the 11 primary cultures analyzed in our case series, 6 were classified as responder with survival inhibition higher than 15%, and 5 as non-responder with survival inhibition lower than 15%. A high expression of HRAS in the tumor tissues compared to the matched healthy tissues significantly correlated with responsiveness of primary cells to Lenvatinib. All 5 non-responder patients showed low expression of HRAS, while of the 6 responder patients, 5 showed a high HRAS expression and only 1 low. None of the other evaluated clinical variables (grade, Ki67, site of origin and syndromic disease) correlated with response. Conclusions: In conclusion, we believe that the evaluation of HRAS expression and mutation might be of great interest in GEP-NET patients receiving Lenvatinib to improve patient selection.

Recent advances in diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a rare group of tumors originating from neuroendocrine cells of the digestive system. Their incidence has increased over the last decades. The specific pathogenetic mechanisms underlying GEP-NEN development have not been completely revealed. Unfunctional GEP-NENs are usually asymptomatic; some grow slowly and thus impede early diagnosis, which ultimately results in a high rate of misdiagnosis. Therefore, many GEP-NEN patients present with later staged tumors. Motivated hereby, research attention for diagnosis and treatment for GEP-NENs increased in recent years. The result of which is great progress in clinical diagnosis and treatment. According to the most recent clinical guidelines, improved grading standards can accurately define poorly differentiated grade 3 neuroendocrine tumors and neuroendocrine carcinomas (NECs), which are subclassified into large and small cell NECs. Combining different functional imaging methods facilitates precise diagnosis. The expression of somatostatin receptors helps to predict prognosis. Genetic analyses of mutations affecting death domain associated protein (DAXX), multiple endocrine neoplasia type 1 (MEN 1), alpha thalassemia/intellectual disability syndrome X-linked (ATRX), retinoblastoma transcriptional corepressor 1 (RB 1), and mothers against decapentaplegic homolog 4 (SMAD 4) help distinguishing grade 3 NENs from poorly differentiated NECs. The aim of this review is to summarize the latest research progress on diagnosis and treatment of GEP-NENs.

Real-world comparison of healthcare resource utilization and costs of [177Lu]Lu-DOTA-TATE in patients with progressive neuroendocrine tumors in England: a matched cohort analysis using data from the hospital episode statistics dataset

Objective To explore the healthcare resource utilization (HCRU) and costs for patients with progressive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with [177Lu]Lu-DOTA-TATE and matched patients treated with somatostatin analogs (SSAs), chemotherapy, or targeted therapies. Methods Hospital Episode Statistics (HES) dataset 2016–2018 was used to compare HCRU and costs between the two cohorts. The [177Lu]Lu-DOTA-TATE cohort included patients assigned with a diagnosis code relevant to GEP-NET, a procedure code for imaging or SSAs, and a subsequent code for radionuclide therapy. The non-[177Lu]Lu-DOTA-TATE cohort included patients assigned with a diagnosis code relevant to GEP-NET who had an increased frequency of SSAs or switched from SSAs to chemotherapy or targeted therapies. Cohorts were matched on propensity scores with sex, age at disease progression, and Charlson Comorbidity Index as parameters. Healthcare Resource Group codes were used for costing. Results A total of 199 matched patients were included. The [177Lu]Lu-DOTA-TATE cohort had lower overall costs (£1,882,028 vs. £3,016,321; p < .0001), non-elective inpatient spells (289 vs. 611 days) and costs (£849,569 vs. £1,707,109; p < .0001 for both), Accident & Emergency costs (£41,978 vs. £62,480; p = .0013), and average length of stay for overall inpatient spells (14.2 vs. 23.3 days; p = .1092) compared with the non-[177Lu]Lu-DOTA-TATE cohort. Conclusions These analyses indicate significantly lower overall costs and HCRU for progressive GEP-NET patients treated with [177Lu]Lu-DOTA-TATE. Current research reveals that future real-world analyses would further benefit from using additional databases linked to the HES dataset such as the Clinical Practice Research Datalink and/or National Cancer Registration and Analysis Service database.

Clinicopathological and molecular profile of grade 3 gastroenteropancreatic neuroendocrine neoplasms.

The 2019Word Health Organization (WHO) subclassified grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) into neuroendocrine carcinoma (NEC) or tumours (G3NET) based on morphology and proliferation. Yet, few data exist on molecular profiles for G3NEN. We compared clinicopathological and molecular characteristics of these two groups. We retrospectively reviewed consecutive G3 GEP NEN patients and had their tumour tissues reviewed, reclassified as per the WHO 2019, and analyzed by a next-generation sequencing (NGS) panel. Between 2000 and 2019, 43 patients had pathology revision: 29 (67%) were NEC and 14 (33%) were G3NET, with a 23% change in diagnosis. Median overal survival for G3NET and NEC patients was 55.6 and 11.9months, respectively (hazard ratio=2.78 [95% confidence interval=1.09-7.11], p=.042), which was confirmed by an adjusted analysis (hazard ratio=2.90NEC vs. G3NET; p=.03). NGS was performed in 32 cases: 21NEC and 11 G3NET. Mutations in RB1 and PTEN were exclusively encountered in NEC. Median tumour mutational burden was 5 (0-67) mutations per megabase in NEC and 4.5 (0-9) among G3NET. Microsatellite instability was found in 3 (14.3%) NEC cases. In conclusion, pathology revision is essential to estimate prognosis and therapeutic plan. G3 GEP NEN generally harbour low tumor mutation burden and fewer actionable mutations, but 14% of NEC cases were microsatellite unstable and could benefit from immune checkpoint inhibitors.

A natural history of gastroenteropancreatic neuroendocrine tumors evaluated at a tertiary cancer center: An observational study of 2,067 cases.

508 Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are the second most prevalent digestive cancer and are increasing in incidence. With relatively indolent tumor growth, survival is often long, even for patients with metastatic disease. However, few studies have assessed long-term survival. Therefore, we analyzed the overall survival (OS) of a cohort of GEP-NET patients at a tertiary cancer center from 2000-2015. Methods: 2,707 patients with a pathologic diagnosis of GEP-NET were identified. 640 patients presented for second-opinion visits and were excluded, leaving 2,067 patients, of whom, 2,053 had vital status data for analysis. Primary sites included jejunum/ileum (small bowel), pancreas, gastric, colorectum, appendix, duodenum, and unknown. OS time was calculated from the date of pathologic diagnosis to the date of last follow-up or death. The reverse Kaplan-Meier method was used to calculate follow-up time. Vital status was identified through linkage to the Florida Cancer Registry. Kaplan-Meier (KM) curves and log-rank test were used for OS analyses. Results: The median age of the cohort was 60.7 years. The median follow-up time was 148.9 months (12.4 years). 1,431 (69.2%) patients presented with distant metastatic disease. Most patients, 1,351 (65.5%), underwent treatment at another facility before presentation. The median OS was 132.2 months (11.0 years) for the cohort and was 108.0 and 245.5 months for patients presenting with and without metastasis, respectively (p &lt; 0.001). For metastatic patients, unknown primary tumor site was associated with the worst median OS (55 months), followed by rectal (77 months), gastric (84 months) and pancreatic (85 months; p &lt; 0.001). Duodenal and small bowel had the longest median OS at 147 and 143 months, respectively. Surgery for metastatic disease had an OS benefit (155.7 months) compared to no surgery (98.3 months). Conclusions: In a large cohort of predominantly metastatic GEP-NET patients with extended follow-up time, median OS was over 11 years and 9 years for patients with metastatic disease. These results suggest that OS at a tertiary cancer center may be greater than historical national administrative analyses when given adequate follow-up time, which is important to avoid bias in survival estimates.[Table: see text]

Detection of Bone Metastases by 68Ga-DOTA-SSAs and 18F-FDG PET/CT: A Two-Center Head-to-Head Study of Gastroenteropancreatic Neuroendocrine Neoplasms.

This study aimed to assess the efficacy of dual-tracer [68Ga-DOTA-somatostatin receptor analogs (SSAs) and 18F-fluorodeoxyglucose (FDG)] positron emission tomography/computed tomography (PET/CT) imaging for detecting bone metastases (BMs) in patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). We retrospectively enrolled 74 GEP-NEN patients with BMs from two centers, who underwent dual-tracer PET/CT from January 2014 to March 2021. We compared and analyzed effectiveness of the dual PET/CT imaging techniques on the BMs, based on 18F-FDG and 68Ga-DOTA-SSAs. Specifically, we analyzed the imaging results using χ 2 tests for classification variables, paired-sample tests for number of BMs, Wilcoxon's signed rank test for number of lesions, and the Kruskal-Wallis test for standard uptake value (SUV) ratio comparison. The correlation of dual-tracer SUVmax with Ki-67 index was analyzed by Spearman's correlation coefficient. The detection efficiencies of dual-tracer PET/CT imaging in patients with different pathologies showed discordant for detecting liver metastases and BMs in group neuroendocrine tumor (NET) G3, 68Ga-DOTA-SSAs was better at detecting BMs for NET G3 (P=0.049 for SUVT/B and P=0.026 for the number of metastatic lesions). In addition, statistical significance was found among osteogenesis group, osteolysis group, and the no-change group (for bone SUVT/B value detected by 18F-FDG and Ki-67 index, osteogenesis group < osteolysis group; for bone SUVT/B detected by 68Ga-DOTA-SSAs, osteogenesis group > the no-change group). What is more, liver and bone SUVmax and Ki-67 index were positively correlated in 18F-FDG imaging (P < 0.001 for liver; P=0.002 for bone), and negatively correlated in 68Ga-DOTA-SSAs imaging (P < 0.001 for liver; P=0.039 for bone). 68Ga-DOTA-SSAs was superior to 18F-FDG for detecting BMs in NET G1/G2 (well and moderately differentiated NETs), as well as in NET G3 (poorly differentiated NETs). Relatively good differentiation was observed in the osteogenesis group. In addition, dual-tracer PET/CT imaging results were observably correlated with tumor differentiation.

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

Simple SummaryNeuroendocrine tumors of the gastrointestinal tract (GEP-NEN) are a rare type of tumor with considerable variability in the course of disease, which makes clinical management particularly challenging. Biomarkers that are able to guide personalized treatment decisions would be of importance, but are not yet available. In this study, we demonstrate that tissue expression, as well as circulating levels of the cytokine Flt3L in advanced and aggressive tumors, predict survival and time to progression. Increased tumoral Flt3L was also associated with upregulation of genes related to immune activation, suggesting Flt3L as a surrogate marker of host anti-tumor immunity. Therefore, Flt3L measurements in serum may hold promise as a biomarker of disease outcome that could support personalized treatment decisions in GEP-NEN patients, potentially guiding researchers towards viable immunotherapies.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.

Chronotype: what role in the context of gastroenteropancreatic neuroendocrine tumors?

BackgroundChronotype is defined as a trait determining the subject circadian preference in behavioral and biological rhythms relative to external light–dark cycle. Although individual differences in chronotype have been associated with an increased risk of developing some types of cancer, no studies have been carried out in gastroenteropancreatic neuroendocrine tumors (GEP-NET).MaterialsWe investigate the differences in chronotype between 109 GEP-NET and 109 healthy subjects, gender-, age-, and BMI-matched; and its correlation with tumor aggressiveness.ResultsGEP-NET patients have a lower chronotype score (p = 0.035) and a higher percentage of evening chronotype (p = 0.003) than controls. GEP-NET patients with morning chronotype had lower BMI, waist circumference, and higher percentage of MetS (p < 0.001) than evening type. Interestingly, considering the clinical pathological characteristics, patients with the presence of metastasis, grading G2, and in progressive disease presented the lower chronotype score (p = 0.004, p < 0.001, and p = 0.002; respectively) compared to other categories. Chronotype score was negatively associated with anthropometric measurements, metabolic profile, percentage of MetS, and Ki67 index (p < 0.001 for all).ConclusionsGEP-NET patients have an unhealthy metabolic profile and present more commonly an evening chronotype. These results support the importance of including the assessment of chronotype in an adjunctive tool for the prevention of metabolic alterations and tumor aggressiveness of GEP-NET.

The overriding role of surgery and tumor grade for long-term survival in patients with gastroenteropancreatic neuroendocrine neoplasms: A population-based cohort study.

BackgroundGastroenteropancreatic neuroendocrine neoplasms (GEP‐NENs) comprise a heterogeneous disease group. Factors that affect long‐term survival remain uncertain. Complete population‐representative cohorts with long‐term follow‐up are scarce.AimTo evaluate factors of importance for the long‐term survival.Methods and resultsAn Observational population‐based study on consecutive GEP‐NEN patients diagnosed from 2003 to 2013, managed according to national guidelines. Univariable and multivariable survival analyses were performed to evaluate overall survival (OS) and to identify independent prognostic factors. One hundred ninety eligible patients (males, 58.9%) (median age, 60.0 years; range, 10.0–94.2 years) were included. The small bowel, appendix, and pancreas were the most common tumor locations. The World Health Organization (WHO) tumor grade 1–3 distributions varied according to the primary location and disease stage. Primary surgery with curative intent was performed in 66% of the patients. The median OS of the study population was 183 months with 5‐ and 10‐year OS rates of 66% and 57%, respectively. Only age, WHO tumor grade, and primary surgical treatment were independent prognostic factors for OS.ConclusionThe outcomes of GEP‐NEN patients are related to several factors including age and primary surgical treatment. WHO tumor grading, based on the established criteria, should be routine in clinical practice. This may improve clinical decision‐making and allow the comparison of outcomes among different centers.

PCN236 A Retrospective Real-World Evidence Study of Patients with Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETS) in the US Using the Optum Database

The incidence and prevalence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has been growing over the last 40 years. 177Lu-DOTATATE (LUT) was approved by the FDA in 2018 for patients with GEP-NETs. We aim to describe the demographic and clinical characteristics of patients with GEP-NETs in the US, and the impact of LUT on healthcare resources using data from the Optum Electronic Health Records (EHR) database. Patients with GEP-NETs were identified from electronic health records using International Classification of Diseases (ICD) versions 9 and 10 diagnosis codes; medications were identified using National Drug Code (NDC) and Healthcare Common Procedure Coding System (HCPCS) codes. Data from January 2018 to March 2020 were included in the analysis. 40,834 patients with GEP-NETs were identified, of which 49.1% were female; 185 of these patients were treated with LUT. Mean (SD) age at diagnosis in overall GEP-NETs patients was 64.8 (14.2) years. 62.7% of patients on LUT had ≥3 co-morbidities (vs 64.9% in overall GEP-NETs). Treatment with LUT led to decreased use of various healthcare services (LUT vs overall GEP-NETS: inpatient visits, 35.1% vs 46.3%; GP visits, 53.5% vs 59.6%; ER visits, 8.6% vs 20.7%). The average length of stay was shorter for patients on LUT (3.9 days vs 7.1 days in overall GEP-NETs). For LUT-treated patients, some visit types increased when compared to the pre-treatment period (35.1% vs 13.0% for inpatient visits; 9.2% vs 1.6% for outpatient visits). Patients with GEP-NETs face a high burden of illness and substantial healthcare service use. In patients receiving LUT in the US, healthcare utilization appears reduced.

Sex-Based Differences in Prognosis of Patients With Gastroenteropancreatic-Neuroendocrine Neoplasms

The aim of this study was to assess sex-based differences in prognosis of a contemporary cohort of gastroenteropancreatic-neuroendocrine neoplasm (GEP-NEN) patients. Surveillance, Epidemiology, and End Results database was accessed, and cases with GEP-NENs were selected. Rates of GEP-NEN diagnosis from 1975 to 2016 for both male patients and female patients were reviewed. Survival outcomes of GEP-NEN patients diagnosed from 2010 to 2014 were determined through Kaplan-Meier estimates and multivariable Cox regression analysis. Overall survival analyses were stratified by stage and histology. A total of 20,836 GEP-NEN patients were diagnosed from 2010 to 2014, and they were included in the current analysis. These include 10,336 male patients and 10,500 female patients. Annual percent change for the age-adjusted rate for GEP-NENs in the United States (1975-2016) is 5.0 (95% confidence interval [CI], 4.8-5.2). When stratified by sex, annual percent change for male patients was 4.8 (95% CI, 4.6-5.1), whereas for female patients, it was 5.0 (95% CI, 4.8-5.3). Female patients have better overall survival compared with male patients among all substrata of patients (according to stage, histology, and differentiation) (P for all comparisons <0.01). Female sex seems to be associated with better overall survival among patients with GEP-NENs. It is unclear if this is the result of differences in noncancer mortality or is the result of inherent biological differences.

Autofluorescence Imaging of Treatment Response in Neuroendocrine Tumor Organoids.

Simple SummaryGastroenteropancreatic neuroendocrine tumors (GEP-NET) account for roughly 60% of all neuroendocrine tumors, and low/intermediate grade human GEP-NETs have relatively slow growth rates that many laboratory culture methods fail to capture. Patient-derived cancer organoids (PDCOs) are an attractive model to address this need for relevant 3D cultures of GEP-NETs for laboratory drug testing. However, traditional measurements of drug response are not effective in GEP-NET PDCOs due to the small volume of tissue and slow growth rates that are characteristic of the disease. Here, we test a label-free, non-destructive optical metabolic imaging (OMI) method to measure drug response in live GEP-NET PDCOs. OMI measured a response to the novel treatment combination of ABT-263 and everolimus in five out of seven PDCO lines, at 72 h post-treatment. Overall, this work shows that OMI provides single-cell metabolic measurements of drug response in PDCOs to guide drug development for GEP-NET patients.Gastroenteropancreatic neuroendocrine tumors (GEP-NET) account for roughly 60% of all neuroendocrine tumors. Low/intermediate grade human GEP-NETs have relatively low proliferation rates that animal models and cell lines fail to recapitulate. Short-term patient-derived cancer organoids (PDCOs) are a 3D model system that holds great promise for recapitulating well-differentiated human GEP-NETs. However, traditional measurements of drug response (i.e., growth, proliferation) are not effective in GEP-NET PDCOs due to the small volume of tissue and low proliferation rates that are characteristic of the disease. Here, we test a label-free, non-destructive optical metabolic imaging (OMI) method to measure drug response in live GEP-NET PDCOs. OMI captures the fluorescence lifetime and intensity of endogenous metabolic cofactors NAD(P)H and FAD. OMI has previously provided accurate predictions of drug response on a single cell level in other cancer types, but this is the first study to apply OMI to GEP-NETs. OMI tested the response to novel drug combination on GEP-NET PDCOs, specifically ABT263 (navitoclax), a Bcl-2 family inhibitor, and everolimus, a standard GEP-NET treatment that inhibits mTOR. Treatment response to ABT263, everolimus, and the combination were tested in GEP-NET PDCO lines derived from seven patients, using two-photon OMI. OMI measured a response to the combination treatment in 5 PDCO lines, at 72 h post-treatment. In one of the non-responsive PDCO lines, heterogeneous response was identified with two distinct subpopulations of cell metabolism. Overall, this work shows that OMI provides single-cell metabolic measurements of drug response in PDCOs to guide drug development for GEP-NET patients.

Cardio-Metabolic Indices and Metabolic Syndrome as Predictors of Clinical Severity of Gastroenteropancreatic Neuroendocrine Tumors.

BackgroundObesity, mainly visceral obesity, and metabolic syndrome (MetS) are major risk factors for the development of type 2 diabetes, cardiovascular diseases, and cancer. Data analyzing the association of obesity and MetS with gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) are lacking. Fatty liver index (FLI) is a non-invasive tool for identifying individuals with non-alcoholic fatty liver disease (NAFLD). Visceral adiposity index (VAI) has been suggested as a gender-specific indicator of adipose dysfunction. Both indexes have been proposed as early predictors of MetS. This study aimed to investigate the association of FLI VAI as early predictors of MetS with gastroenteropancreatic neuroendocrine tumors (GEP-NETs).MethodsA cross-sectional, case–control, observational study was carried out at the ENETS Centers of Excellence Multidisciplinary Group for Neuroendocrine Tumors, University “Federico II”. VAI and FLI were calculated.ResultsWe enrolled 109 patients with histologically confirmed G1/G2 GEP-NET (53 M; 57.06 ± 15.96 years), as well as 109 healthy subjects, age, sex- and body mass index-matched. Forty-four GEP-NET patients were G2, of which 21 were with progressive disease, and 27 patients had metastases. GEP-NET patients had a higher value of VAI (p < 0.001) and FLI (p = 0.049) and higher MetS presence (p < 0.001) compared with controls. VAI and FLI values and MetS presence were higher in G2 than in G1 patients (p < 0.001), in patients with progressive disease, and in metastatic vs non-metastatic patients (p < 0.001). In addition, higher values of VAI and FLI and higher MetS presence were significantly correlated with the worst clinical severity of NENs. The cut-off values for the FLI and MetS to predict high grading of GEP-NETs and the presence of metastasis were also provided.ConclusionsThis is the first study investigating an association between VAI and FLI as early predictors of MetS and GEP-NET. Our findings report that the worsening of clinicopathological characteristics in GEP-NET is associated with higher presence of MetS, NAFLD, evaluated by FLI, and visceral adiposity dysfunction, evaluated by VAI. Addressing the clinical evaluation of MetS presence, NAFLD, and visceral adiposity dysfunction might be of crucial relevance to establish targeted preventive and treatment interventions of NEN-related metabolic comorbidities.

Long-Term Survival and Value of 18F-FDG PET/CT in Patients with Gastroenteropancreatic Neuroendocrine Tumors Treated with Second Peptide Receptor Radionuclide Therapy Course with 177Lu-DOTATATE.

Peptide receptor radionuclide therapy (PRRT) has been recognized as a promising therapy against neuroendocrine tumors (NETs). The use of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in NETs has been a matter of controversy. The purpose of this study was to evaluate the long-term survival and efficacy of a second PRRT course with 177Lu-DOTATE in patients with advanced gastroenteropancreatic (GEP) NETs. Furthermore, the value of 18F-FDG PET/CT in these patients was evaluated. 40 patients with GEP NETs who underwent two PRRT courses with 177Lu-DOTATATE and combined examinations with 68Ga-DOTA-TOC and 18F-FDG PET/CT were evaluated. After the second PRRT course, two patients (5.0%) were in partial remission, 21 patients (52.5%) in stable disease and 17 patients (42.5%) had progressive disease. The median overall survival was 122.10 months. After the second PRRT course, the median overall survival was significantly higher (p = 0.033) in the 18F-FDG-negative group compared to the 18F-FDG-positive group (145.50 versus 95.06 months, respectively). The median time to progression was 19.37 months. In conclusion, a second PRRT course with 177Lu-DOTATE is an effective treatment approach for GEP NET patients with disease progression. A change in 18F-FDG status after PRRT may predict the disease course and survival. Patients who are 18F-FDG-negative have a significantly longer overall survival than those who are 18F-FDG-positive.

Surgical Feasibility, Determinants, and Overall Efficacy of Neoadjuvant 177Lu-DOTATATE PRRT for Locally Advanced Unresectable Gastroenteropancreatic Neuroendocrine Tumors.

We assessed 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in the neoadjuvant setting in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We also evaluated the variables associated with resectability of the primary tumor after PRRT. Methods: This study included 57 GEP-NET patients who had a primary tumor that was unresectable (because of vascular involvement as defined using the pancreatic ductal adenocarcinoma criteria of the National Comprehensive Cancer Network) and who underwent 177Lu-DOTATATE therapy without any prior surgery. They were categorized into 2 groups: 23 patients without liver metastases (group 1) and 34 patients with potentially resectable liver metastases (group 2). 177Lu-DOTATATE was administered with mixed amino acid-based renal protection at a dose of 7.4 GBq (200 mCi) per cycle. Surgical resectability was evaluated using triphasic contrast-enhanced abdominal CT imaging at 3 different time points during the PRRT course. Four broad categories of overall PRRT response were evaluated. The Kaplan-Meier product-limit method was used to calculate progression-free survival (PFS) and overall survival (OS). Associations between variables and a resectable primary tumor after PRRT were analyzed using the χ2 test, with a P value of less than 0.05 considered statistically significant. Results: After 177Lu-DOTATATE therapy, the unresectable primary tumor became resectable in 15 of 57 (26.3%) patients (7 patients in group 1 and 8 patients in group 2). A complete or partial response to PRRT was seen in 48 patients (84%), 23 patients (40%), 18 patients (31%), and 23 patients (40%) using symptomatic, biochemical, molecular imaging, and anatomic imaging criteria, respectively. Estimated rates of PFS were 95% and 90% at 2 y in groups 1 and 2, respectively. The 2-y OS of the 2 groups combined was 92.1%. The rate at which the primary tumor was resectable after PRRT was significantly higher in patients who had duodenal neuroendocrine tumors, patients who had GEP-NETs with no regional lymph node involvement, patients for whom the primary tumor was smaller than 5 cm, patients for whom liver metastases were no larger than 1.5 cm, patients for whom there were no more than 3 liver metastases, and patients for whom 18F-FDG uptake in the primary tumor had an SUVmax of less than 5. Conclusion: In a moderate fraction of GEP-NET patients, with or without liver metastases, whose primary tumor was unresectable because of vascular involvement, the primary tumor converted from unresectable to resectable after 177Lu-DOTATATE therapy, signifying that neoadjuvant PRRT can be considered in such patients. The effective control of symptoms, favorable morphologic and functional imaging response, and durable PFS and OS that we observed after 177Lu-DOTATATE PRRT may lead to less morbidity and mortality in these patients.

Effect of treatment center volume on outcomes in gastroenteropancreatic neuroendocrine tumor patients

BackgroundMedical centers with varying levels of expertise treat gastroenteropancreatic neuroendocrine tumors (GEP-NETs), which are relatively rare tumors. This study assesses the impact of center volume on GEP-NET treatment outcomes.MethodsWe used the Surveillance, Epidemiology, and End Results (SEER) registry linked to Medicare claims data. The data includes patients diagnosed between 1995 and 2010 who had no health maintenance organization (HMO) coverage, participated in Medicare parts A and B, were older than 65 at diagnosis, had tumor differentiation information, and had no secondary cancer. We identified medical centers at which patients received GEP-NET treatment (surgery, chemotherapy, somatostatin analogues, or radiation therapy) using Medicare claims data. Center volume was divided into 3 tiers – low, medium, and high – based on the number of unique GEP-NET patients treated by a medical center over 2 years. We used Kaplan-Meier curves and Cox regression to assess the association between volume and disease-specific survival.ResultsWe identified 899 GEP-NET patients, of whom 37, 45, and 18% received treatment at low, medium volume, and high-volume centers, respectively. Median disease-specific survival for patients at low and medium tiers were 1.4 years and 5.3 years, respectively, but was not reached for patients at high volume centers. Results showed that patients treated at high volume centers had better survival than those treated in low volume centers (HR: 0.63, 95% CI: 0.4–0.9), but showed no difference in outcomes between medium and high-volume centers.ConclusionsOur results suggest that for these increasingly common tumors, referral to a tertiary care center may be indicated. Physicians caring for GEP-NET patients should consider early referral to high volume centers.

Copy number alterations in plasma cell-free DNA from metastatic gastroenteropancreatic neuroendocrine neoplasms.

372 Background: Recent studies, including our proof-of-concept study, demonstrated the possibility to detect tumor-derived molecular alterations in cell-free DNA (cfDNA) from plasma of patients with a gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN). More in-depth evaluation of the biomarker potential of cfDNA in GEP-NENs is warranted, since highly sensitive and specific blood-based biomarkers are an important unmet need for this tumor type. The aim of our study was to detect tumor-associated copy number alterations (CNAs) in cfDNA from GEP-NEN patients to molecularly characterize the tumor and to estimate tumor fraction, as a measure of tumor burden, and to evaluate changes in these parameters over time. Methods: Metastatic GEP-NEN patients were included within NETwerk, a multi-institutional network of nine hospitals in Belgium. Clinicopathological data were collected to correlate experimental and clinical findings. Plasma samples were collected from all patients and cfDNA was extracted and subjected to shallow whole-genome sequencing (WGS). Detection of CNAs and estimation of tumor fraction, based on the sequencing data, were performed using the R-based tool ichorCNA. Results: In total, 80 samples of 29 metastatic GEP-NEN patients were analyzed using shallow WGS. All patients had a well-differentiated GEP-NEN of Grade 1/2 and primary sites were pancreas (N = 15), small intestine (N = 9), colon (N = 1), caecum (N = 1), ileocaecal valve (N = 1), pylorus (N = 1) and unknown (N = 1). Median number of samples per patient was two, with a median time between first and last sampling of six months. In 25 cfDNA samples from nine patients (31%), CNAs with tumor fractions higher than 3% could be detected. The primary tumor site of all CNA-positive patients was pancreas, corresponding to 60% of included pancreatic NEN (PNEN) patients. Six of the CNA-positive patients were included at initiation of everolimus treatment. The detected CNA patterns were similar to the copy number profiles of PNENs described in literature, e.g. whole-chromosome gains of chromosomes 5, 7, 9, 12, 13, 14, 19 and 20. CNA profiles were relatively stable over time, although in two patients new alterations did arise. Tumor fractions changed over time, which could be linked to changes in tumor burden, tumor progression and treatment response according to RECIST1.1 criteria and will be further examined, including in additional samples that are being collected. Conclusions: Cell-free DNA of metastatic GEP-NEN patients contains CNAs that correspond to CNA profiles seen in tumor tissue samples. CNAs can be used to quantify the tumor fraction in cfDNA over time, which will be linked to tumor progression in our ongoing study, particularly in the promising subgroup of PNEN patients.