Bronchopulmonary Neuroendocrine Tumors Research Articles

Diagnostic issues in neuroendocrine neoplasms ofthe lung.

Bronchopulmonary neuroendocrine neoplasms (BP-NENs) account for approximately 30% of all NENs. Although BP-NENs and NENs of the gastroenteropancreatic organs (GEP-NENs) share morphological and molecular features, they differ in terms of their terminology and classification. Bronchopulmonary neuroendocrine tumors (BP-NETs) have classically been termed as carcinoid and grouped into typical (TC) and atypical carcinoid (AC) based on the presence or absence of necrosis and mitotic count. In the most recent World Health Organization (WHO) classification for NENs of endocrine organs (WHO 2022), BP-NETs-NET G1 and G2-are introduced as synonyms of TC and AC, respectively. However, the Ki-67 index, which defines the grade of NETs in digestive organs, is only discussed in the descriptive text and not included into the criteria for classification of BP-NENs. In addition, well-differentiated NENs with high mitotic counts which correspond toNET G3 in the GEP organ system are not defined. This review discusses the role of Ki-67 for aproper classification of BP-NETs/carcinoids.

Adipokines in Neuroendocrine Tumors: An Evaluation of the Serum Levels of Ghrelin and Leptin.

Neuroendocrine tumors (NETs) are a heterogeneous group of tumors that are characteristically different from other malignancies. The difference is not only in the prognosis, which is usually more favorable in such patients, but also in the high clinical progression of the disease, where NET patients do not experience the cachexia typical of other malignancies. The purposes of this study were to evaluate the ghrelin and leptin levels in a group of patients diagnosed with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and bronchopulmonary neuroendocrine tumors (BP-NETs) and to analyze the relationship between the body mass index (BMI), cachexia and selected NET markers. The study group comprised 52 patients with GEP-NETs and BP-NETs, while the controls comprised 67 healthy volunteers. The ghrelin and leptin concentrations were determined in both groups. The concentrations of chromogranin A, serotonin, 5-hydroxyindoleacetic acid (5-HIAA), total cholesterol, triglycerides and glucose were determined in the study group. Characteristics of the study group and of the controls were defined by age, sex and BMI, and the effects of these factors on the ghrelin and leptin concentrations were assessed. The data obtained were subject to statistical analysis. The study cohort showed higher levels of ghrelin as compared to the controls (142.31 ± 26.00 vs. 121.49 ± 35.45, p = 0.016), and no statistical difference in the levels of leptin (11.15 ± 9.6 vs. 12.94 ± 20.30, p = 0.439) were observed. Significantly lower levels of leptin were found in patients with the small intestine primary location, as compared to individuals with primary locations in the lungs and the pancreas (4.9 ± 6.49 vs. 16.97 ± 15.76, p = 0.045, and 4.9 ± 6.49 vs. 12.89 ± 8.56, p = 0.016, respectively). A positive correlation was observed between the leptin levels and the BMIs in both the study group (rS = 0.33, p = 0.016) and the controls (rS = 0.41, p = 0.001). The study group showed a negative correlation between the leptin levels and 5-HIAA (rS = -0.32, p = 0.026) and a negative correlation between the leptin levels and Ki-67 (rS = -0.33, p = 0.018). The control group showed negative correlations between the ghrelin and the volunteer age (rS = -0.41, p = 0.008), the leptin and the volunteer age (rS = -0.44, p < 0.001), the leptin and total cholesterol (rS = -0.24, p < 0.049) as well as the leptin and triglycerides (rS = -0.33, p < 0.006). The current study emphasized the importance of the markers' determination, where ghrelin appears as a valuable diagnostic biomarker in NETs, probably responsible for maintaining a normal BMI, despite the progression of the disease.

Treatment of advanced BP-NETS with lanreotide autogel/depot vs placebo: the phase III SPINET study.

Prospective data are lacking on early somatostatin analog (SSA) therapy in bronchopulmonary neuroendocrine tumors (BP-NETs; typical carcinoids and atypical carcinoids (TCs and ACs)). SPINET (EudraCT: 2015-004992-62; NCT02683941) was a phase III, double-blind study of lanreotide autogel/depot (LAN; 120 mg every 28 days) plus best supportive care (BSC) vs placebo plus BSC, with an optional open-label treatment phase (LAN plus BSC). Patients had metastatic/unresectable, somatostatin receptor (SSTR)-positive TCs or ACs. Recruitment was stopped early owing to slow accrual; eligible patients from the double-blind phase transitioned to open-label LAN. The adapted primary endpoint was progression-free survival (PFS) during either phase for patients receiving LAN. Seventy-seven patients were randomized (LAN, n = 51 (TCs, n = 29; ACs, n = 22); placebo, n = 26 (TCs, n = 16; ACs, n = 10)). Median (95% CI) PFS during double-blind and open-label phases in patients receiving LAN was 16.6 (11.3; 21.9) months overall (primary endpoint), 21.9 (12.8, not calculable (NC)) months in TCs, and 13.8 (5.4; 16.6) months in ACs. During double-blind treatment, median (95% CI) PFS was 16.6 (11.3; 21.9) months for LAN vs 13.6 (8.3; NC) months for placebo (not significant); corresponding values were 21.9 (13.8; NC) and 13.9 (13.4; NC) months, respectively, in TCs and 13.8 (5.4; 16.6) and 11.0 (2.8; 16.9) months, respectively, in ACs. Patients' quality of life did not deteriorate and LAN was well tolerated. Although recruitment stopped early and the predefined sample size was not met, SPINET is the largest prospective study to date of SSA therapy in SSTR-positive TCs and ACs and suggests clinical benefit in TCs.

Concomitant inhibition of PI3K/mTOR signaling pathways boosts antiproliferative effects of lanreotide in bronchopulmonary neuroendocrine tumor cells.

Introduction: Somatostatin analogues (SSAs) are commonly used in the treatment of hormone hypersecretion in neuroendocrine tumors (NETs), however the extent to which they inhibit proliferation is much discussed. Objective: We studied the antiproliferative effects of novel SSA lanreotide in bronchopulmonary NETs (BP-NETs). We focused on assessing whether pretreating cells with inhibitors for phosphatidylinositol 3-kinase (PI3K) and mammalian target for rapamycin (mTOR) could enhance the antiproliferative effects of lanreotide. Methods: BP-NET cell lines NCI-H720 and NCI-H727 were treated with PI3K inhibitor BYL719 (alpelisib), mTOR inhibitor everolimus and SSA lanreotide to determine the effect on NET differentiation markers, cell survival, proliferation and alterations in cancer-associated pathways. NT-3 cells, previously reported to express somatostatin receptors (SSTRs) natively, were used as control for SSTR expression. Results: SSTR2 was upregulated in NCI-H720 and NT-3 cells upon treatment with BYL719. Additionally, combination treatment consisting of BYL719 and everolimus plus lanreotide tested in NCI-H720 and NCI-H727 led to diminished cell proliferation in a dose-dependent manner. Production of proteins activating cell death mechanisms was also induced. Notably, a multiplexed gene expression analysis performed on NCI-H720 revealed that BYL719 plus lanreotide had a stronger effect on the downregulation of mitogens than lanreotide alone. Discussion/Conclusion: We report a widespread analysis of changes in BP-NET cell lines at the genetic/protein expression level in response to combination of lanreotide with pretreatment consisting of BYL719 and everolimus. Interestingly, SSTR expression reinduction could be exploited in therapeutic and diagnostic applications. The overall results of this study support the evaluation of combination-based therapies using lanreotide in preclinical studies to further increase its antiproliferative effect and ultimately facilitate its use in high-grade tumors.

Angiogenic biomarkers of response to treatment with peptide receptor radionuclide therapy in neuroendocrine tumours.

Neuroendocrine tumours (NETs) are a heterogeneous group of tumours, which is characterized by rich vascularization. The role of angiogenesis in NETs has been widely researched. Peptide receptor radionuclide therapy (PRRT) is an effective treatment method for patients with disease progression in NETs. Due to the heterogeneousness of NETs, the response to treatment varies. Currently, the finding of efficient markers helpful in assessing the response to treatment in NETs is crucial. The aim of this study was to assess chromogranin A (CgA) and angiogenic factors in gastro-entero-pancreatic (GEP) and broncho-pulmonary (BP) NET patients treated with PRRT. The study group included 40 patients with GEP NETs and BP NETs who completed four cycles of PRRT. Serum levels of CgA and angiogenic factors such as vascular endothelial growth factor (VEGF), its receptors (VEGF-R1, VEGF-R2, VEGF-R3), were assessed before and after four cycles of PRRT. All tests were determined using ELISA. The concentration of CgA, VEGF-R1 and VEGF-R2 decreased significantly, whereas VEGF-R3 increased significantly after PRRT. PRRT did not affect VEGF, it was similar before and after the radioisotope treatment. Based on AUROC, only for VEGF-R1 AUC was a consequence of 0.7 which can be considered as a good response to PRRT treatment. VEGF-R1 may be a potential biomarker useful in assessing the effectiveness of PRRT in NET patients.

Progression-Free Survival in Patients with Bronchopulmonary Neuroendocrine Tumors Treated with Lanreotide or Placebo: Adjustment for Crossover Effects in Placebo Arm

Progression-Free Survival in Patients with Bronchopulmonary Neuroendocrine Tumors Treated with Lanreotide or Placebo: Adjustment for Crossover Effects in Placebo Arm

BRONCHOPULMONARY CARCINOID AND TYPE 1 MULTIPLE ENDOCRINE NEOPLASIA (MEN)

BRONCHOPULMONARY CARCINOID AND TYPE 1 MULTIPLE ENDOCRINE NEOPLASIA (MEN)

Neuroendocrine tumor G3 of bronchopulmonary origin and its classification.

Neuroendocrine tumors (NET) with high proliferative activity (Ki-67 index >20% and/or mitotic counts >2 mm2 ) are defined as NET G3 in the 2019 World Health Organization (WHO) classification of digestive system neuroendocrine neoplasms (NENs). NETs G3 occur mostly in the pancreas, colon, rectum, and stomach and only rarely in the small intestine and the appendix. In the bronchopulmonary system, similar tumors have also been recognized and were mostly classified as atypical carcinoid (AC) or large cell neuroendocrine carcinoma. Bronchopulmonary NENs that were classified as NETs G3 are characterized by histological and immunohistochemical similarities with carcinoids/NETs, and a clinical course that is more aggressive than with ACs and similar to that of neuroendocrine carcinomas. The morphomolecular and clinical features of bronchopulmonary neoplasms with a high proliferative activity were reviewed and a future classification system that is applicable for both digestive and bronchopulmonary NETs is proposed.

Management of bronchopulmonary neuroendocrine tumors

Bronchopulmonary neuroendocrine tumors (BPNETs) are the second most common subset of NETs after gastroenteropancreatic NETs. Historically, most clinical studies have excluded BPNETs during drug development and the data is often extrapolated from non-BPNETs. However, growing burden of BPNETs and the development of novel treatment strategies including targeted therapies and radiopharmaceuticals have paved the way for revisiting treatment strategies. In this review, we go over recent advances in the management of BPNETs and summarize consensus guidelines with the help of research data and clinical scenarios.

Randomized, parallel arm, phase II study of telotristat (Xermelo) in combination with lutetium Lu 177 dotatate (Lutathera) in well-differentiated neuroendocrine tumors (NETs).

TPS516 Background: PRRT using Lutetium Lu 177 Dotatate, has been approved by the FDA for metastatic, progressive gastroenteropancreatic neuroendocrine tumors (GEPNETs). Despite an impressive progression-free survival noted in NETTER-1 study, most patients will eventually progress after PRRT treatment. Increased serotonin secretion is found in a number of slow-growing NETs of the diffuse neuroendocrine system. Serotonin stimulates proliferation in cell lines of a typical (NCI-H727), an atypical (NCI-H720) bronchopulmonary NET, a small intestinal NET (KRJ-I), and a functioning human pancreatic carcinoid cell line (BON). This stimulation of growth by serotonin can be performed in an autocrine manner. Telotristat ethyl is a novel oral inhibitor of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis. In 2017, results of placebo-controlled phase III study (Telestar) evaluating Telotristat ethyl confirmed that among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with Telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in bowel movement frequency and urinary 5- hydroxy indoleacetic acid (u5-HIAA). Based on results of the Telestar trial, FDA approved 250 mg PO TID dosage of Telotristat for control of carcinoid syndrome diarrhea. Of note, 500 mg TID arm showed increased decline in urinary 5-HIAA as compared to 250 mg TID arm. Study Hypotheses: We hypothesize that inhibition of serotonin production will lead to cytostatic effect on neuroendocrine tumors and will complement anti-tumor activity of lutetium 177 dotatate. We anticipate our proposed combination will result in improved treatment efficacy as reflected by improved 20-month PFS as compared to historical control (NETTER-1). Methods: This is a single center, open label, randomized, parallel arm, phase II study evaluating two dose levels of Telotristat (Xermelo; 250 mg vs 500 mg) in combination with Lutetium Lu 177 Dotatate (Lutathera) in 70 well-differentiated neuroendocrine tumor patients. Study is currently enrolling patients and is expected to complete accrual in 3 years. Clinical trial information: NCT04543955.

1109P The psychological impact of COVID-19 pandemic on patients with NETs: Between resilience and vulnerability

The COVID-19 pandemic has dramatically changed lifestyles and quality of life (QoL) of the global population. Little is known regarding the psychological impact of the COVID-19 outbreak on patients with gastroenteropancreatic (GEP) or bronchopulmonary (BP) neuroendocrine tumors (NETs).

1096O Lanreotide autogel/depot (LAN) in patients with advanced bronchopulmonary (BP) neuroendocrine tumors (NETs): Results from the phase III SPINET study

Well-differentiated BP-NETs (typical and atypical carcinoid; TC and AC) account for ∼25% of all NETs. However, there is a lack of prospective data with somatostatin analogs (SSAs) in BP-NETs. SPINET evaluated LAN in advanced somatostatin receptor (SSTR)-positive TC and AC BP-NETs. SPINET (EudraCT 2015-004992-62; NCT02683941) was a phase 3, randomized (2 LAN: 1 PBO, stratified by TC vs AC), double-blind (DB) study of LAN (120 mg/28 days), with optional open-label LAN treatment phase (OL-LAN). Enrollment was stopped due to slow accrual and ongoing patients in the DB phase could transition to open-label LAN. The primary endpoint was adapted: centrally assessed (RECIST 1.1) PFS during the DB/OL-LAN phases in patients randomized to LAN. Secondary endpoints included PFS and objective response rate (ORR) [central] and time to treatment failure (TTF) [local/central] in each treatment arm during DB phase, and safety. Overall, 77 patients were randomized and treated (intention-to-treat set: LAN, n=51; PBO, n=26; [OL-LAN, n=40]). Mean (SD) age was 66.2 (12.5) years and 42 (54.5%) were male; 45 (58.4%) and 32 (41.6%) patients had TC and AC respectively, all (Octreoscan) patients had a Krenning score ≥2, 6 (7.8%) had received prior cytotoxic chemotherapy, 71 (92.2%) had hepatic tumor load ≤25%, and 28 (57.1%) and 19 (38.8%) patients had liver and bone metastases, respectively. Median (95% CI) PFS in the LAN randomized group was 16.6 (12.8–21.9) months (TC 21.9 [12.8–not calculable (NC)] months; AC 14.1 [5.6–16.6] months). Key secondary endpoints are shown in the table. In the DB phase, PFS for LAN and PBO, respectively, was 21.9 (13.8–NC) vs 13.9 (13.4–NC) months in TC and 13.8 (5.6–16.6) vs 11.0 (2.8–16.9) months in AC.Table: 1096ODBLAN (n=51)PBO (n=26)HR [95% CI]aPFS (TC & AC), median (95% CI), mths16.6 (11.3–21.9)13.6 (8.3–NC)0.90 [0.46–1.88]ORR, % (95% CI)14.0 (5.8–26.7)0 (0.0–13.7)–TTF, median (95% CI), mths13.3 (5.6–14.1)9.8 (5.4–13.6)0.86 [0.50–1.50]DBOL-LANTEAEs, n (%)bLAN (n=51)PBO (n=26)All pts (n=40)Any49 (96.1)25 (96.2)26 (65.0)Related38 (74.5)14 (53.8)13 (32.5)Grade1234544 (86.3)37 (72.5)13 (25.5)1 (2.0)1 (2.0)23 (88.5)19 (73.1)8 (30.8)0025 (62.5)14 (35.0)3 (7.5)00Leading to study treatment withdrawal2 (3.9)3 (11.5)0Serious AEs10 (19.6)7 (26.9)1 (2.5)Related2 (3.9)1 (3.8)0aLAN vs PBO; bExcludes death/progression (part of PFS assessment) TEAE, treatment-emergent adverse event. Open table in a new tab aLAN vs PBO; bExcludes death/progression (part of PFS assessment) TEAE, treatment-emergent adverse event. SPINET, the largest prospective study to date with a SSA in SSTR-positive BP-NETs, suggests that LAN 120 mg could be an appropriate treatment option, especially for TC.

Targeted inhibition of the WEE1 kinase as a novel therapeutic strategy in neuroendocrine neoplasms

Neuroendocrine neoplasms (NENs) represent a rare and heterogeneous group of malignancies, sharing features of both neural and endocrine cells. NENs G3 appear as a highly aggressive subset with a poor prognosis and limited therapeutic options. The small-molecule inhibitor of the WEE1 tyrosine kinase, adavosertib (AZD1775), has previously demonstrated potent anti-tumor effects on various types of cancer in preclinical and clinical studies. However, the role of adavosertib in NENs G3 had remained elusive. We evaluated the effects of adavosertib on pancreatic (BON-1, QGP-1) and bronchopulmonary (NCI-H720) neuroendocrine tumor cell lines applying 2D and 3D spheroid models. We newly demonstrated that adavosertib is sufficient to reduce cell viability and proliferation in neuroendocrine cell lines with features of high-grade NENs. As underlying mechanisms, we identified adavosertib-mediated DNA double-strand breaks and a G2/M cell cycle checkpoint abrogation leading into mitotic catastrophe and cancer cell apoptosis. Silencing of WEE1 via siRNA transfection resulted in a phenotype similar to adavosertib treatment. Together, inhibition of the WEE1 tyrosine kinase applying adavosertib on NENs G3 outlines a promising novel therapeutic strategy.

Well-Differentiated Bronchopulmonary Neuroendocrine Tumors: More Than One Entity

IntroductionUntil now, well-differentiated bronchopulmonary neuroendocrine tumors (bpNET) occurring either sporadically (sp-bpNET) or in the context of multiple endocrine neoplasia type 1 (MEN1) and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) are regarded as similar entities. However, in contrast to sp-bpNET: MEN1-related and DIPNECH-related bpNET rarely metastasize or lead to bpNET-related death. We aimed to describe and compare the course of the disease of sp-bpNET, DIPNECH- and MEN1-related bpNET. MethodsAll patients with histologically confirmed MEN1-related bpNET from the DutchMEN Study Group database (1990-2017), patients with resected sp-bpNET and DIPNECH patients referred to a Dutch European Neuroendocrine Tumor Society center between 2000 and 2018 were included. Fisher’s exact test was used for comparison between groups. The primary end point was disease-specific mortality (DSM). Kaplan-Meier and logrank test were used to compare survival. Cox regression was used to identify risk factors for DSM in the sp-bpNET subgroup. ResultsWe included 112 sp-bpNET, 29 MEN1, and 27 DIPNECH patients. Tumor classification was similar across subgroups. A total of 20 patients (18%) with sp-bpNET died because of bpNET, compared with none in the MEN1 group and DIPNECH group. Median disease-specific survival was 12.3 (confidence interval: 6.3–18.3) years for patients with sp-bpNET, and not estimable for the other subgroups (p < 0.001). Differences in baseline characteristics did not explain worse survival in sp-bpNET. Tumor classification and age at diagnosis were independent risk factors for DSM in sp-bpNET. ConclusionsPatients with sp-bpNET have a significantly higher DSM compared with MEN1 or DIPNECH-related bpNET, unexplained by differences in baseline characteristics. This implies that not all bpNET are similar entities.

Radiation treatment for adult rare cancers: Oldest and newest indication.

Aim of this analysis is to review the role of RT in the management of several rare tumors for adult patients. Collection data regarding RT and rare tumors was made by Pubmed. For mucosal melanomas, RT is prescribed, being associated with lower local recurrence rate. For trachea tumors, RT was used as adjuvant or salvage treatment for unresectable disease. For pNET, RT can be a suitable option for post-surgical or unresectable/borderline. For bronchopulmonary neuroendocrine tumors the role of adjuvant treatments is uncertain. For hepatobiliary and ovarian malignancy, stereotactic body RT (SBRT) is a promising approach. For soft tissue sarcoma, perioperative treatments are indicated, and a growing role of SBRT in oligometastatic disease is recognized. For endocrine tumors, adjuvant RT has demonstrated benefits through reducing recurrence risk. The radiotherapy is a frequent indication in adult rare cancers; thus the role of Radiation Oncologist must not be neglected.

Unexpected Detection of Abscessualized Lung Carcinoma on Tc-99m-HMPAO-labeled Leukocytes Scintigraphy Misdiagnosed on Chest Computed Tomography.

Technetium-99m (Tc-99m)-hexamethylpropylene amine oxime (HMPAO)-labeled leukocytes scintigraphy is well established for investigating and diagnosing infections in bone and soft tissue, as well as for the detection of occult infection. A 71-year-old female who was recently diagnosed with bronchopulmonary neuroendocrine tumor of the right lung was referred for an intermittent fever of unknown origin associated with chill at night for the last month. Chest computed tomography (CT) scan showed a thrombotic widespread of the superior vena cava and a solid pathological tissue in the superior segment of the inferior lobe of the right lung with consensual atelectasis. Being a carrier of port-a-cath, an infection of this device was suspected. Therefore, Tc-99m-HMPAO-labeled leukocytes single-photon emission computed tomography (SPECT) was performed, and matching pairs of CT scan and Tc-99m-HMPAO-labeled white blood cell SPECT images were fused. Through this means, it was found that the area of the radiotracer increased uptake corresponded with the soft tissue density mass detected by CT scan localized at the inferior lobe of the right lung. The hybrid SPECT/CT fused imaging was crucial for diagnosis of the presence of a lung abscess localized in correspondence with the known lung cancer region.

Clinical significance of brain metastases in patients with bronchopulmonary neuroendocrine tumors: A population-based analysis.

e21575 Background: The clinical significance of brain metastases in patients with bronchopulmonary neuroendocrine (NE) tumors is unknown; we therefore conducted a population based analysis to evaluate the implications of brain metastases in these patients. Methods: The NCDB database was queried to identify patients with stage IV bronchopulmonary NE tumors treated between the years of 2004-2012. Patients were split into two groups based on the presence of brain metastases at diagnosis and survival probabilities with multivariate models were performed. Results: A total of 7,725 patients with Stage IV bronchopulmonary NE tumors were identified. The histological subtypes studied in this cohort were NE carcinoma (65.4%), large cell NE carcinoma (30.5%), typical carcinoid (2.8%) and atypical carcinoid (1.3%) . The patients included in this study were mainly white (86.4%) men (56.8%) with a median age of 67 years who had liver (9.5%), bone (6.2%) and brain (5.9%) metastases at diagnosis. The median overall survival (OS) of the cohort was 5.59 (95% CI: 5.4-5.8) months, but when OS was stratified by histological subtype it was significantly better in patients with typical carcinoid (table). In the whole cohort, the median OS did not differ between patients with and without brain metastases (5.55 vs. 5.68; p = 0.24). However, a sensitivity analysis by histology showed that the presence of brain metastases worsen the median OS of patients with typical carcinoid only (15.1 vs 4.6, p = 0.04). An adjusted multivariate analysis restricted to patients with brain metastases showed that administration of systemic chemotherapy (HR:0.5; 95% CI:0.35-0.72, p &lt; 0.001) and resection of distant metastases (HR:0.5; 95% CI:0.29-0.88, p = 0.017) were the two most powerful independent prognostic factors. Conclusions: The presence of brain metastases negatively impact survival of patients with typical carcinoids but not in those with the other histological subtypes included in this study. Staging MRI should be strongly considered at diagnosis in patients with bronchopulmonary NE tumors, due to the sizable proportion of these patients presenting with brain metastases and also due to its prognostic value in a subset of this population. [Table: see text]

Prospective Evaluation of the NETest as a Liquid Biopsy for Gastroenteropancreatic and Bronchopulmonary Neuroendocrine Tumors: An ENETS Center of Excellence Experience

Background: There is a substantial unmet clinical need for an accurate and effective blood biomarker for neuroendocrine neoplasms (NEN). We therefore evaluated, under real-world conditions in an ENETS Center of Excellence (CoE), the clinical utility of the NETest as a liquid biopsy and compared its utility with chromogranin A (CgA) measurement. Methods: The cohorts were: gastroenteropancreatic NEN (GEP­NEN; n = 253), bronchopulmonary NEN (BPNEN; n = 64), thymic NEN (n = 1), colon cancer (n = 37), non-small-cell lung cancer (NSCLC; n = 63), benign lung disease (n = 59), and controls (n = 86). In the GEPNEN group, 164 (65%) had image-positive disease (IPD, n = 135) or were image-negative but resection-margin/biopsy-positive (n = 29), and were graded as G1 (n = 106), G2 (n = 49), G3 (n = 7), or no data (n = 2). The remainder (n = 71) had no evidence of disease (NED). In the BPNEN group, 43/64 (67%) had IPD. Histology revealed typical carcinoids (TC, n = 14), atypical carcinoids (AC, n = 14), small-cell lung cancer (SCLC, n = 11), and large-cell neuroendocrine carcinoma (LCNEC, n = 4). Disease status (stable or progressive) was evaluated according to RECIST v1.1. Blood sampling involved NETest (n = 563) and NETest/CgA analysis matched samples (n = 178). NETest was performed by PCR (on a scale of 0–100), with a score ≥20 reflecting a disease-positive status and >40 reflecting progressive disease. CgA positivity was determined by ELISA. Samples were deidentified and measurements blinded. The Kruskal-Wallis, Mann-Whitney U, and McNemar tests, and the area under the curve (AUC) of the receiver-operating characteristics (ROC) were used in the statistical analysis. Results: In the GEPNEN group, NETest was significantly higher (34.4 ± 1.8, p < 0.0001) in disease-positive patients than in patients with NED (10.5 ± 1, p < 0.0001), colon cancer patients (18 ± 4, p < 0.0004), and controls (7 ± 0.5, p < 0.0001). Sensitivity for detecting disease compared to controls was 89% and specificity was 94%. NETest levels were increased in G2 vs. G1 (39 ± 3 vs. 32 ± 2, p = 0.02) and correlated with stage (localized: 26 ± 2 vs. regional/distant: 40 ± 3, p = 0.0002) and progression (55 ± 5 vs. 34 ± 2 in stable disease, p = 0.0005). In the BPNEN group, diagnostic sensitivity was 100% and levels were significantly higher in patients with bronchopulmonary carcinoids (BPC; 30 ± 1.3) who had IPD than in controls (7 ± 0.5, p < 0.0001), patients with NED (24.1 ± 1.3, p < 0.005), and NSCLC patients (17 ± 3, p = 0.0001). NETest levels were higher in patients with poorly differentiated BPNEN (LCNEC + SCLC; 59 ± 7) than in those with BPC (30 ± 1.3, p = 0.0005) or progressive disease (57.8 ± 7), compared to those with stable disease (29.4 ± 1, p < 0.0001). The AUC for differentiating disease from controls was 0.87 in the GEPNEN group and 0.99 in BPC patients (p < 0.0001). Matched CgA analysis was performed in 178 patients. In the GEPNEN group (n = 135), NETest was significantly more accurate for detecting disease (99%) than CgA positivity (53%; McNemar test χ² = 87, p < 0.0001). In the BPNEN group (n = 43), NETest was significantly more accurate for disease detection (100%) than CgA positivity (26%; McNemar’s test χ² = 30, p < 0.0001). Conclusions: The NETest is an accurate diagnostic for GEPNEN and BPNEN. It exhibits tumor biology correlation with grading, staging, and progression. CgA as a biomarker is significantly less accurate than NETest. The NETest has substantial clinical utility that can facilitate patient management.

Blood Chromogranin A Is Not Effective as a Biomarker for Diagnosis or Management of Bronchopulmonary Neuroendocrine Tumors/Neoplasms

Background: Identification of circulating tumor markers for clinical management in bronchopulmonary (BP) neuroendocrine tumors/neoplasms (NET/NEN) is of considerable clinical interest. Chromogranin A (CgA), a “universal” NET biomarker, is considered controversial as a circulating biomarker of BPNEN. Aim: Assess utility of CgA in the diagnosis and management of BPNEN in a multicentric study. Material and Methods: CgA diagnostic metrics were assessed in lung NET/NENs (n = 200) and controls (n = 140), randomly assigned to a Training and Test set (100 BPC and 70 controls in each). Assay specificity was evaluated in neoplastic lung disease (n = 137) and nonneoplastic lung disease (n = 77). CgA efficacy in predicting clinical status was evaluated in the combined set of 200 NET/NENs. CgA levels in bronchopulmonary neuroendocrine tumor (BPNET) subtypes (atypical [AC] vs. typical [TC]) and grade was examined. The clinical utility of an alteration of CgA levels (±25%) was evaluated in a subset of 49 BPNET over 12 months. CgA measurement was by NEOLISA^TM kit (EuroDiagnostica). Results: Sensitivity and specificity in the training set were 41/98%, respectively. Test set data were 42/87%. Training set area under receiver operator characteristic analysis differentiated BPC from control area under the curve (AUC) 0.61 ± 0.05 p = 0.015. Test set the data were AUC 0.58 ± 0.05, p = 0.076. In the combined set (n = 200), 67% BPNET/NEN (n = 134) had normal CgA levels. CgA levels did not distinguish histological subtypes (TC vs. AC, AUC 0.56 ± 0.04, p = 0.21), grade (p = 0.45–0.72), or progressive from stable disease (AUC 0.53 ± 0.05 p = 0.47). There was no correlation of CgA with Ki-67 index (Pearson r = 0.143, p = 0.14). For nonneoplastic diseases (chronic obstructive pulmonary disorder and idiopathic pulmonary fibrosis), CgA was elevated in 26–37%. For neoplastic disease (NSCLC, squamous cell carcinoma), CgA was elevated in 11–16%. The neuroendocrine SCLC also exhibited elevated CgA (50%). Elevated CgA was not useful for differentiating BPNET/NEN from these other pathologies. Monitoring BPNET/NEN over a 12-month period identified neither CgA levels per se nor changes in CgA were reflective of somatostatin analog treatment outcome/efficacy or the natural history of the disease (progression). Conclusions: Blood CgA levels are not clinically useful as a biomarker for lung BPNET/NEN. The low specificity and elevations in both nonneoplastic as well as other common neoplastic lung diseases identified limited clinical utility for this biomarker.

MON-330 Cushing Syndrome Secondary to Neuroendocrine Lung Carcinoma: To X-Ray or Not to X-Ray?

Introduction Adrenocorticotropic hormone (ACTH) overproduction leads to hypercortisolism and Cushing syndrome (CS). We describe a rare case of ectopic ACTH secretion (EAS) secondary to a primary lung neuroendocrine tumor (NET). Case description A 30-year-old female presented with fatigue, muscle weakness and poor memory. She had associated weight gain, hair loss and amenorrhea. She had a history of recent microprolactinoma treated with Cabergoline. Vital signs were normal aside from mild hypertension. Physical examination revealed facial acne, posterior neck fullness, hirsutism and abdominal striae. Morning cortisol was 53.6 (4.3-22.4mcg/dl) and ACTH was 147 (0-46pg/ml). A midnight salivary cortisol level was 2.54 (<0.09mcg/dL), urine 24-hour cortisol was 4405 (4-55mcg/24h) and potassium was 3.3 (3.5-4.5mmol/L). Her glycosylated hemoglobin was 6.4% and insulin like growth factor was 163 (53-331 ng/ml). A low-dose 1mg and a high-dose 8mg dexamethasone suppression test failed to suppress cortisol confirming EAS. A review of brain magnetic resonance imaging (MRI) from Vietnam at the time of diagnosis and post treatment did not reveal a microprolactinoma indicating possible misdiagnosis. Given the high clinical suspicion for EAS, a chest x-ray was obtained first which identified two left upper lobe lung masses. As such, inferior petrosal sinus sampling (IPSS) was avoided. A computed tomography guided lung biopsy confirmed well-differentiated NET, staining positive for synaptophysin, chromogranin and pancytokeratin. The Ki-67 proliferation index was low <2%. Positron emission tomography showed hypermetabolic activity within the lung masses, left hilum and mediastinal lymph nodes. Octreotide scan showed increased radiotracer uptake within the lung masses and corresponding lymph nodes. She underwent wedge resection of her left upper lobe and was treated with a steroid taper perioperatively. She required intermittent insulin therapy for hyperglycemia. Post-operatively, her ACTH, blood glucose and cortisol normalized. She remains asymptomatic at 6-month follow up. Conclusion ACTH-producing pituitary adenomas result in most cases of ACTH-dependent CS and 10-15% result from EAS. EAS must be suspected if a pituitary adenoma is not visible on MRI. Challengingly, up to 40% of ACTH-dependent CS from a pituitary source may not have a visualizable adenoma and IPSS is invasive. Although bronchopulmonary NETs are usually non-functional and 1-2% cause CS, studies have shown that pulmonary NETs are up to 4cm in size. As such, we began with a simple chest-xray looking for an ectopic source rather than subjecting our patient to IPSS as guidelines suggest. Hypokalemia can be a clue to EAS causing mineralocorticoid receptor activation. Our diagnosis was made and fortunately a well-differentiated localized tumor with low Ki-67 mitotic index yielded the positive outcome seen in our patient.