Optimizing Risk Assessment Through cfDNA in Pancreatic Neuroendocrine Tumors for Clinical Evaluation: a Retrospective Study (ORACLE)

September 8, 2026 updated by: Massimo Falconi

Non-functioning pancreatic neuroendocrine tumors (NF-PanNETs) are heterogeneous neoplasms of the pancreatic endocrine tissue, displaying variable clinical behavior from indolent to highly aggressive forms. Their often asymptomatic nature and lack of reliable preoperative biomarkers make clinical management particularly challenging.

This exploratory study will investigate cell-free DNA (cfDNA) as a potential non-invasive biomarker in NF-PanNETs. cfDNA samples from approximately 30 patients, representing distinct clinical courses (active surveillance, indolent post-surgical, and aggressive post-surgical cases), will be analyzed using advanced methylome and nucleosome footprinting techniques.

The aim is to evaluate cfDNA's diagnostic and prognostic potential to improve disease monitoring and support personalized therapeutic strategies in NF-PanNET patients.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Pancreatic neuroendocrine tumors (PanNETs) are rare, heterogeneous neoplasms arising from the endocrine tissue of the pancreas. Non-functioning pancreatic neuroendocrine tumors (NF- PanNETs) have traditionally been considered rare; however, their reported incidence has significantly increased over the past two decades [1]. Current estimates suggest that approximately 1-5% of the general population may harbor undiagnosed NF-PanNETs [2]. Given this prevalence, there is an increasing need for reliable diagnostic tools to distinguish high-risk, aggressive tumors from benign, indolent lesions.

NF-PanNETs exhibit a wide spectrum of biological behavior, ranging from slow-growing, indolent tumors to highly aggressive variants prone to local invasion and distant metastases. However, due to their frequent asymptomatic presentation and the absence of reliable preoperative markers for tumor aggressiveness, clinical management remains challenging. Current diagnostic methods rely on imaging and invasive biopsies. However, this approach has limitations in detecting early-stage disease and assessing tumor dynamics. Indeed, it often leads to overtreatment in low-risk patients through unnecessary surgical interventions, while potentially undertreating those who might benefit from more aggressive therapeutic strategies, such as neoadjuvant therapy [3].

In recent years, cell-free DNA (cfDNA) has emerged as a promising non-invasive biomarker in the oncology setting, proving to be extremely useful for diagnosis, prognosis and therapeutic purposes.

In the specific context of PanNETs, there is limited research on the value of cfDNA. Despite showing encouraging results, the few existing investigations on this subject, have included only small and heterogeneous cohorts, varying primary tumor sites, stages and differentiation status [4-6].

This exploratory study will analyze cfDNA profiles from approximately 30 NF-PanNET patients (10 under active surveillance, 10 with indolent tumors post-surgery, and 10 with aggressive tumors post-surgery) using advanced methylome and nucleosome footprinting technologies [7,8]. Analyses in the three patient subgroups will be compared with data from a previously characterized cohort of healthy subjects.

The goal is to assess cfDNA's diagnostic and prognostic utility, potentially offering a non-invasive tool for better disease management, monitoring and personalized patient care.

Study Type

Observational

Enrollment (Actual)

30

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
    • MI
      • Milan, MI, Italy, 20132
        • IRCCS San Raffaele

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

The study population will include approximately 30 adult patients diagnosed with non-functioning pancreatic neuroendocrine tumors (NF-PanNETs) whose biological samples are available through the HSR NETBank biobank. Participants will represent three distinct clinical subgroups: patients under active surveillance and patients who underwent surgical resection with a histopathological diagnosis of either indolent or aggressive disease. All included patients have provided informed consent for the use of their biological material and clinical data for research purposes.

Description

Inclusion Criteria:

  • Age ≥18 years.
  • Diagnosis of sporadic, well-differentiated, non-functioning PanNET (NF-PanNET).
  • Signed informed consent for the use of plasma samples stored in the NETbank biobank.
  • Availability of pre-operative or surveillance plasma samples.

Exclusion Criteria:

  • Genetic syndromes associated with NF-PanNETs (e.g., MEN1, VHL).
  • Functioning PanNETs.
  • Inadequate quality or quantity of cfDNA extracted from plasma samples.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
histological indolent PanNET
patients submitted to surgical resection for PanNET with histopathological diagnosis of indolent disease
Other: cfDNA molecular profiling
cfDNA will be extracted from plasma samples previously collected and currently stored at the HSR NETBank biobank. cfDNA profiling will be performed using methylome and nucleosome footprinting techniques. No therapeutic or experimental intervention will be performed.
histological aggressive PanNET
patients submitted to surgical resection for PanNET with histopathological diagnosis of aggressive disease
Other: cfDNA molecular profiling
cfDNA will be extracted from plasma samples previously collected and currently stored at the HSR NETBank biobank. cfDNA profiling will be performed using methylome and nucleosome footprinting techniques. No therapeutic or experimental intervention will be performed.
PanNET under active surveillance
patients currently under active surveillance for small indolent PanNET
Other: cfDNA molecular profiling
cfDNA will be extracted from plasma samples previously collected and currently stored at the HSR NETBank biobank. cfDNA profiling will be performed using methylome and nucleosome footprinting techniques. No therapeutic or experimental intervention will be performed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
cfDNA Molecular Profiling
Time Frame: From enrollment until the day before surgery, or during scheduled visits for patients under active surveillance.
To investigate the feasability of cfDNA assessment as a non- invasive biomarker for NF- PanNETs. cfDNA concentrations and cfDNA epigenetic and fragmentomic signatures in plasma samples will be analysed.
From enrollment until the day before surgery, or during scheduled visits for patients under active surveillance.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Predictive Value of cfDNA for Tumor Aggressiveness
Time Frame: From enrollment until the day before surgery, or during scheduled visits for patients under active surveillance.
To correlate cfDNA levels with tumor aggressiveness and clinical outcomes, and to identify tissue-of-origin insights using cfDNA methylation and nucleosomal footprints.
From enrollment until the day before surgery, or during scheduled visits for patients under active surveillance.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Massimo Falconi

Investigators

  • Principal Investigator: Stefano Partelli, MD, PhD, IRCCS San Raffaele
  • Principal Investigator: Daniela Cesana, PhD, San Raffaele Telethon Institute for Gene Therapy

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2017

Primary Completion (Estimated)

September 1, 2027

Study Completion (Estimated)

December 1, 2027

Study Registration Dates

First Submitted

September 8, 2026

First Submitted That Met QC Criteria

September 8, 2026

First Posted (Actual)

September 14, 2026

Study Record Updates

Last Update Posted (Actual)

September 14, 2026

Last Update Submitted That Met QC Criteria

September 8, 2026

Last Verified

October 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ORACLE

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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