Unmet Medical Needs in Metastatic Lung and Digestive Neuroendocrine Neoplasms

Capdevila, Jaume; Bodei, Lisa; Davies, Philippa; Gorbounova, Vera; Jensen, Robert T.; Knigge, Ulrich; Krejs, Guenter J.; Krenning, Eric P.; O’Connor, Juan Manuel; Peeters, Marc; Rindi, Guido; Salazar, Ramón; Vullierme, Marie‐Pierre; Pavel, Marianne

doi:10.1159/000493319

Cited by 9 publications

(5 citation statements)

References 21 publications

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“…Diagnosis is difficult since symptomatology is protean and often evanescent while functional imaging requires sophisticated technology and is expensive and not widely available. Tissue pathology involves invasive biopsy and provides a random, one-time assessment of a heterogeneous neoplasm (2). Given these limitations, there remains a critical unmet need to identify an accurate circulating general NEN tumour biomarker.…”

Section: Introductionmentioning

confidence: 99%

“…Given these limitations, there remains a critical unmet need to identify an accurate circulating general NEN tumour biomarker. This would facilitate diagnosis, establish recurrence or residual disease after surgery, enable accurate monitoring of disease progression, evaluate response to therapy and refine prognosis (2). Although CgA in blood has been considered "effective" for more than four decades, it is now known to have significant limitations in clinical utility due to assay variability, non-specific elevations and low specificity (1).…”

Section: Introductionmentioning

confidence: 99%

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NETest is superior to chromogranin A in neuroendocrine neoplasia: a prospective ENETS CoE analysis

Malczewska

Öberg

Kos–Kudła

2021

Endocrine Connections

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Introduction: The absence of a reliable, universal biomarker is a significant limitation in neuroendocrine neoplasia (NEN) management. We prospectively evaluated two CgA assays, (NEOLISA, EuroDiagnostica,) and (CgA ELISA, Demeditec Diagnostics (DD)) and compared the results to the NETest. Methods: NEN cohort (n=258): pancreatic, n=67; small intestine, n=40; appendiceal, n=10; rectal, n=45; duodenal, n=9; gastric, n=44; lung, n=43. Image-positive disease (IPD) (n=123), image and histology negative (IND) (n=106), and image negative and histology positive (n=29). CgA metrics: NEOLISA, ULN: 108ng/mL, DD: ULN: 99ng/mL. Data: mean ±SEM. NETest: qRT-PCR - multianalyte analyses, ULN: 20. All samples de-identified and assessed blinded. Statistics: Mann-Whitney U-test, Pearson correlation and McNemar-test. Results: CgA positive in 53/258 (NEOLISA), 32 (DD) and NETest-positive in 157/258. In image positive disease (IPD, n=123), NEOLISA-positive: 33% and DD: 19%. NETest-positive: 122/123 (99%; McNemar’s Chi2=79-97, p<0.0001). NEOLISA was more accurate than DD (p=0.0003). In image negative disease (IND), CgA was NEOLISA-positive (11%), DD (8%), p=NS, and NETest (33%). CgA assays could not distinguish progressive (PD) from stable disease (SD) or localized from metastatic disease (MD). NETest was significantly higher in PD (47±5) than SD (29±1, p=0.0009). NETest levels in MD (35±2) were elevated versus localized disease (24±1.3, p=0.008). Conclusions: NETest, a multigenomic mRNA biomarker, was ~99% accurate in the identification of NEN disease. The CgA assays detected NEN disease in 19-33%. Multigenomic blood analysis using NETest is more accurate than CgA and should be considered the biomarker standard of care.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NETest is superior to chromogranin A in neuroendocrine neoplasia: a prospective ENETS CoE analysis

Malczewska

Öberg

Kos–Kudła

2021

Endocrine Connections

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“…It is an unfortunate reality that neuroendocrine tumor (NET) disease is an underserved division of oncology due to its relatively low incidence and the limited number of therapeutic strategies that have been developed for its treatment [1]. In general, NETs are difficult to manage since they are usually identified late in their natural history and thus present the challenges associated with treating metastatic disease [2, 3].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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...

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“…Established systemic treatment strategies include biotherapy with somatostatin analogs, chemotherapy with streptozotocin/5-fluorouracil or 2 of 20 capecitabine/temozolomide in pancreatic NETs, peptide receptor-based radionuclide therapy (PRRT) with 177Lutetium-DOTA-TATE, and molecular targeted therapy with everolimus or sunitinib [3][4][5]. Despite our increasing understanding of the genetics and molecular biology of NETs [6,7], and growing preclinical and clinical data of novel molecular targeted therapy strategies and precision oncology approaches in NETs [8,9], there is still an unmet medical need for further novel systemic treatment strategies in advanced NETs [9,10]. In the current in vitro study, we aimed to investigate the potential role of Wnt/β-catenin signaling as a novel strategy of molecular targeted therapy in neuroendocrine tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Wnt/β-Catenin Signaling in Neuroendocrine Tumors In Vitro: Antitumoral Effects

Jin

Spoettl

Maurer

et al. 2020

Cancers

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Background and aims: Inhibition of Wnt/β-catenin signaling by specific inhibitors is currently being investigated as an antitumoral strategy for various cancers. The role of Wnt/β-catenin signaling in neuroendocrine tumors still needs to be further investigated. Methods: This study investigated the antitumor activity of the porcupine (PORCN) inhibitor WNT974 and the β-catenin inhibitor PRI-724 in human neuroendocrine tumor (NET) cell lines BON1, QGP-1, and NCI-H727 in vitro. NET cells were treated with WNT974, PRI-724, or small interfering ribonucleic acids against β-catenin, and subsequent analyses included cell viability assays, flow cytometric cell cycle analysis, caspase3/7 assays and Western blot analysis. Results: Treatment of NET cells with WNT974 significantly reduced NET cell viability in a dose- and time-dependent manner by inducing NET cell cycle arrest at the G1 and G2/M phases without inducing apoptosis. WNT974 primarily blocked Wnt/β-catenin signaling by the dose- and time-dependent downregulation of low-density lipoprotein receptor-related protein 6 (LRP6) phosphorylation and non-phosphorylated β-catenin and total β-catenin, as well as the genes targeting the latter (c-Myc and cyclinD1). Furthermore, the WNT974-induced reduction of NET cell viability occurred through the inhibition of GSK-3-dependent or independent signaling (including pAKT/mTOR, pEGFR and pIGFR signaling). Similarly, treatment of NET cells with the β-catenin inhibitor PRI-724 caused significant growth inhibition, while the knockdown of β-catenin expression by siRNA reduced NET tumor cell viability of BON1 cells but not of NCI-H727 cells. Conclusions: The PORCN inhibitor WNT974 possesses antitumor properties in NET cell lines by inhibiting Wnt and related signaling. In addition, the β-catenin inhibitor PRI-724 possesses antitumor properties in NET cell lines. Future studies are needed to determine the role of Wnt/β-catenin signaling in NET as a potential therapeutic target.

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Unmet Medical Needs in Metastatic Lung and Digestive Neuroendocrine Neoplasms

Cited by 9 publications

References 21 publications

NETest is superior to chromogranin A in neuroendocrine neoplasia: a prospective ENETS CoE analysis

NETest is superior to chromogranin A in neuroendocrine neoplasia: a prospective ENETS CoE analysis

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

Inhibition of Wnt/β-Catenin Signaling in Neuroendocrine Tumors In Vitro: Antitumoral Effects

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