TEST:

NETest®

P1/2, N=27, Not yet recruiting, University Hospital, Basel, Switzerland | Initiation date: Jun 2024 --> Jan 2025

NETest 2.0 simplified the disease scoring system exhibiting improved diagnostic and prognostic capabilities over NETest 1.0. This optimized, validated blood-based molecular tool provides a powerful approach for diagnostic, prognostic and patient monitoring.

Advances in sequencing technologies may enhance the clinical utility of LB in NENs. Future research should focus on refining LB methods, standardising protocols and exploring applications in high-grade NENs.

P2; Not yet recruiting --> Recruiting | Trial completion date: Dec 2028 --> Mar 2029 | Trial primary completion date: Mar 2028 --> Sep 2028

Among three patients who underwent R0 resection and four treated with peptide receptor radionuclide therapy, the changes in NETest scores closely correlated with disease progression. The NETest demonstrated high diagnostic efficacy and accurate therapeutic monitoring capabilities in a Japanese population.

In Group 2, ROC analysis identified an AUC of 0.909 (95% CI: 0.75-0.100) for prediction of local or metastatic recurrence. Blood NETest scores were associated with PFS and OS in patients with metastatic Si-NENs, along with TGR, CgA > 10 × ULN, and presence of lung metastases.

The NETest was also frequently elevated in NET G3 and MiNEN, however cases were limited. Baseline NETest was not predictive for benefit of chemotherapy, however a NETest >60 was prognostic with a shorter survival for patients receiving chemotherapy.

P1/2; N=27; Not yet recruiting; Sponsor:University Hospital, Basel, Switzerland

Diagnosis in NEN still represents a challenge due to their complex biology and variable presentation. Further advancements are necessary to obtain early and minimally invasive diagnosis to improve patients' outcomes.

NETest was a weak indicator of AJCC staging, Ki-67, and CgA, inconsistent with previously reported superiority. NETest was weakly correlative with CgA, showing improved accuracy with advanced disease. Further studies are needed to better understand the true value of this test.

Given the promising results, the development and implementation of these multianalyte markers are expected to usher in a new era of NEN biomarkers in the clinic. In this review, we will outline both clinically implemented and more experimental circulating markers to provide an update on developments in this rapidly evolving field.

Trials primarily focusing on targeted therapy and radionuclides are currently active. A multidisciplinary approach, correct timing, and personalization are key for successful PPGL management.

"Wren’s PPQ, a companion test to Wren Laboratories’ NETest®, classifies patients as either a 'Responder' who will experience disease stabilization and have a longer time to disease progression (usually greater than 18 months after the end of PRRT treatment), or as a 'Non-responder,' who will have a shorter time until the disease progresses (usually less than 12 months after the start of PRRT)."

In contrast, multi-analytical circulating biomarkers (including NETest) are emerging as more effective tools to determine the real-time profile of the disease, both in terms of accurate diagnosis and effective treatment. In this review, we will analyze the capabilities and limitations of different circulating biomarkers focusing on three relevant questions: (1) accurate and early diagnosis; (2) monitoring of disease progression and response to therapy; and (3) detection of early relapse.

"Wren Laboratories announced...that it finalized a distribution agreement with Kindstar Globalgene Technology to distribute Wren's blood-based neuroendocrine tumor NETest throughout China...Under the five-year agreement, Kindstar Global plans to conduct a pilot study at Peking Union Medical College and use the data in a nationwide educational campaign about the benefits and diagnostic efficacies of the NETest."

However, the diagnostic accuracy as well as the prognostic and predictive value of these biomarkers are limited and novel techniques of multianalyte analysis of regulators of tumor biology have been developed. The NETest has been most extensively studied and proved to be useful in NET diagnosis, early detection of post-operative recurrence and prediction of response to treatment but further investigation establishing higher level of evidence is required for implementation in clinical practice.

Tissue-based molecular genetic information had little value in PRRT-prediction. Blood-based gene signatures may improve management of patients undergoing Lu-DOTATATE, by providing information regarding tumor radiosensitivity and disease course, thus allowing possible individualized strategies.

For the diagnosis and clinical monitoring of NEN, there still exists a considerable need for better biomarkers. Novel technology has resulted in a promising liquid biopsy for the detection and monitoring of GEP-NENs. The search for improved tissue biomarkers has resulted in identification of one potential candidate whereas several others remain in the investigatory phase.

Management includes wait and watch approach, surgical resection, somatostatin analogs, Lu DOTATATE therapy, chemotherapy, radiotherapy or immunotherapy combinations. Further clinical trials are necessary for determining the appropriate sequencing.

A biologically plausible panel of cytokines might be added to the diagnostic and prognostic tools currently employed in patients with NETs. Combining different markers into a score would elevate diagnostic accuracy compared to single markers.

In this literature review, we describe the analytes used over the years and cover novel biomarkers that could find a use in the future. We discuss their pros and cons while showcasing recent advances in the field of neuroendocrine tumor biomarkers.

Pharmacological management including biotherapy, radioisotope therapy, targeted molecular therapy and chemotherapy are important methods of systemic therapy. Treatment of PanNENs requires a multidisciplinary team of specialists in the field of neuroendocrine neoplasms.

In patients not undergoing treatment consecutive low NETest scores are associated with indolent behavior. Patients who develop PD exhibit elevated scores. Elevated results have important predictive value for treatment responsiveness and could be used for individualizing decisions on systemic therapy. The clinical value of follow-up NETest scores for patients who choose to watch-and-wait requires further study.

There are new promising alternatives to chromogranin A, which has been clinically widespread since the 1970s despite several drawbacks, to map the extent, risk of recurrence, prognosis and response to treatment of pancreatic pNENs. In terms of personalized medicine, modern molecular and radiological diagnostics should play an increasing role for indicating and planning surgical treatment and for follow-up in the future.

In patients with SI-NET, the NETest was the only predictor of PFS but did not improve prediction of DSS over currently established clinical parameters. References: 1. Modlin, et al.

Although, low scores are associated with an indolent tumor behaviour in the follow up of individuals, NETest scores fluctuate over time in patients with NED and SD. Elevated NETest scores – measured before treatment initiation – predicted treatment response and might therefore be used for individualizing decisions on starting systemic therapy.

The NETest is characterized by high sensitivity and is able to capture disease recurrence in the post-operative setting. A longer follow-up is needed to draw reliable conclusions on the prognostic impact of the NETest.

Despite these recent findings yielding promising observations, further research is necessary. The present review therefore summarizes the existing knowledge and recent advancements in the exploration of biochemical markers for NENs, with focus on gastroenteropancreatic-neuroendocrine tumors.

"NETest decreased during 177Lu-DOTATATE in responders, increased in non-responders and can be used as an early monitor of response. PPQ predicted response in 97%. RAD-TOX correlated with hematological toxicity and pre-PRRT scores predicted toxicity with 75% accuracy."

The development of new molecular multianalyte biomarkers, especially the mRNA transcript based "NETest", has rapidly evolve the field and gives the ability for a "liquid biopsy" which can reliably assess disease status in real time. In this review we discuss the use of established and novel biomarkers in the diagnosis and management of small intestine NETs and carcinoid heart disease.

No abstract available

The PHEOs/PGLs in the pediatric cohort (n=10) were all NETest-positive (81±8) and exhibited a gene expression profile spectrum analogous to adults. Circulating NET transcript analysis identifies PHEOs/PGLs with 100% efficacy and is likely to have clinical utility in the diagnosis and management of PHEO/PGL patients.

NETest accurately diagnoses NETs and is an effective surrogate marker for imaging, grade, metastases and disease status compared to CgA. A multigenomic liquid biopsy is an accurate biomarker of NET disease.

NETest diagnosis is more accurate than CgA (100% vs. 22%). Surgery significantly decreased NETest. An elevated POD30 NETest predicted recurrence with 94% accuracy and post-surgical POD30 NETest follow-up stratification decreased costs by 42%. CgA had no surgical utility. Further studies would define the accuracy and cost-effectiveness of the NETest in the detection of post-operative recurrent disease.

The preoperative NETest accurately identified all NETs (100%). All resections decreased NETest levels and a POD30 NETest score >20 predicted radiologically recurrent disease with 94% accuracy and 100% sensitivity. R0 resection appears to be ineffective in approximately 30% of patients. NET mRNA blood levels provide early objective genomic identification of residual disease and may facilitate management.

"New response criteria for NET patients undergoing PRRT will comprise multiparametric hybrid imaging and blood-based multianalyte markers. This represents tumor biology and heterogeneity."

Surgery combined with Lu PRRT is safe and provides favourable PFS and OS in selected patients with advanced SBNEN. Liquid biopsy (NETest) has the potential to accurately delineate disease status.

Several molecular-targeted therapies are considered second line to somatostatin analogues. This review is a clinical update on the pathophysiological aspects, diagnostic algorithm, and management of GEP NENs.

NETest is a NET multigenomic blood biomarker that accurately diagnoses NET disease. In addition, it correlates with clinical parameters (imaging, grade, metastases, disease status). Liquid biopsy with NETest provides an accurate, non-invasive strategy to real-time assess disease status and surgical treatment efficacy.

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

We are also evaluating NETEST, a novel blood based predicting as well as prognosticating test. In addition, the study will evaluate baseline somatostatin receptor density, somatic tumor mutations and germline mutations and correlate with clinical outcome.ClinicalTrials.gov Identifier: NCT04234568

P=N/A; Active, not recruiting --> Completed | N=200 --> 105