Multi-dimensional Fragmentomic Assay for Early Detection of Pancreatic Neuroendocrine Tumors

Study Overview
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Brief Summary
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This prospective study aims to evaluate the sensitivity and specificity of an integrated model using fragmentomic profiles of plasma cell-free DNA for early detection of pancreatic neuroendocrine tumors.

Detailed Description
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Pancreatic neuroendocrine tumors (pNETs) are insidious and difficult to diagnose early. Approximately 36.8% of pNET patients have lymph node metastasis[1], and 20% -64% of patients have liver metastasis at the time of diagnosis[2]. The prognosis of pNETs is closely related to tumor grade and the American Joint Committee on Cancer (AJCC) staging. Among patients with known pathological grades in the United States, well-differentiated NETs had the highest median overall survival (OS, 16.2 years), moderately differentiated NETs had the worse OS (8.3 years), and poorly differentiated or undifferentiated NETs had the worst OS (10 months)[3]. The 5-year overall survival rates of localized, locally advanced, and metastatic pNETs were 93%, 77%, and 27%, respectively[4]. Given that the prognosis of early-stage pNETs is significantly better than that of advanced pNETs, early detection of pNETs can provide a cure opportunity and significantly improve survival. In the past few decades, the application of 68Ga-DOTANOC PET/CT, magnetic resonance imaging (MRI), computed tomography (CT), and endoscopic ultrasound (EUS) has improved the detection rate of pNETs. But their application is limited by high costs, lack of sufficient sensitivity or specificity, and radiation exposure. Therefore, there is an urgent need for accurate and less invasive approaches to use in clinical practice for the early detection of pNETs. Recently, the study of cell-free DNA (cfDNA) has provided a noninvasive approach for the diagnosis of solid malignancies. cfDNAs represent extracellular DNA fragments released from cell apoptosis and necrosis into human body fluids like plasma, thus carrying the genetic and epigenetic information from the cell and tissue of origin[5]. Among them, circulating tumor DNA (ctDNA), as a part of the total cfDNA, is released into the blood by tumor cells[6]. cfDNA fragmentomics depends on whole genome sequencing, and its characteristics mainly include copy number variation (CNV), nucleosome footprint, fragment length and motif[5, 7, 8], with targets covering the entire genome level. cfDNA fragmentomics has shown excellent predictive performance in multiple studies[5, 9-11]. Therefore, this prospective study aims to evaluate the sensitivity and specificity of an integrated model using fragmentomic profiles of plasma cell-free DNA (cfDNA) for early detection of pancreatic neuroendocrine tumors.

Official Title
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Multi-dimensional Fragmentomic Assay for Early Detection of Pancreatic Neuroendocrine Tumors: a Prospective Study

Conditions
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Pancreatic Neuroendocrine Tumor

Intervention / Treatment
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* Diagnostic Test: Fragmentomic profiles of plasma cfDNA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 and above, regardless of gender; Histopathological diagnosis with pancreatic neuroendocrine tumor before surgery; Not receiving any anti-tumor treatment before surgery, including chemotherapy, embolization, ablation, radiotherapy, and molecular targeted therapy; No obvious surgical contraindications; Able to comply with research plans, follow-up plans, and other protocol requirements; Voluntary participation and signed informed consent. Exclusion Criteria: Pathological diagnosis was nonpancreatic neuroendocrine tumor; Currently diagnosed with other types of tumors or any cancer history; Diagnosed with familial syndromes; Receiving anti-tumor treatment before surgery, including chemotherapy, embolization, ablation, radiotherapy, and molecular targeted therapy; Ongoing fever or recipient of anti-inflammation therapy within 14 days prior to study blood draw; Recipient of blood transfusion within 30 days prior to study blood draw; Recipient of organ transplant or prior non-autologous (allogeneic) bone marrow or stem cell transplant; Poor health condition and not suitable for blood draw; Any other disease/condition deemed not suitable for study enrollment by researcher.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| pNETs<br>Patients with pancreatic neuroendocrine tumors (pNETs). | Diagnostic Test: Fragmentomic profiles of plasma cfDNA<br>* Blood collection and early detection testing based on fragmentomic profiles of plasma cfDNA<br>|
| Healthy<br>Healthy volunteers. | Diagnostic Test: Fragmentomic profiles of plasma cfDNA<br>* Blood collection and early detection testing based on fragmentomic profiles of plasma cfDNA<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensitivity and specificity | Sensitivity and specificity of the integrated model using fragmentomic profiles of plasma cfDNA for early detection of pNETs | From date of first blood draw until first documented pNETs diagnosis, assessed up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Positive predictive value and negative predictive value | Positive predictive value (PPV) and negative predictive value (NPV) of the integrated model using fragmentomic profiles of plasma cfDNA for early detection of pNETs | From date of first blood draw until first documented pNETs diagnosis, assessed up to 3 years | 
| Sensitivity and specificity in distinguishing different AJCC stages | Sensitivity and specificity of the integrated model using fragmentomic profiles of plasma cfDNA in distinguishing different AJCC stages | From date of first blood draw until first documented pNETs diagnosis, assessed up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreatic neuroendocrine tumor, cell-free DNA, fragmentomics, early detection