ATRX/DAXX in EUS-FNB Specimens of Pan-NETs

Pancreatic Neuroendocrine Tumor Clinical Trial

— FORESEE  

Official title:

Association Between Endoscopic Ultrasound Based Preoperative ATRX/DAXX Immunohistochemistry Expression and Prognosis of Sporadic, Non-FunctiOnal pancREatic Neuroendocrine tumorS: a prospEctivE Cohort Study

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06406387
• Other study ID #: FORESEE
• Status: Not yet recruiting
• Start date: June 1, 2024
• Est. completion date: November 30, 2029

Study information

• Verified date: May 2024
• Source: Azienda Ospedaliera Universitaria Integrata Verona
• Contact: Stefano Francesco Crinò, MD, PhD
• Phone: 00390458126191
• Email: stefanofrancesco.crino[@]aovr.veneto.it
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

P-NENs are classified as functional (F-) or non-functional (NF-) depending on the presence or absence of a clinical hormonal hypersecretion syndrome. Moreover, the WHO 2017 classification of pNENs distinguishes between well-differentiated pancreatic neuroendocrine tumors (pNETs) and poorly differentiated pancreatic neuroendocrine carcinomas (pNECs). pNETs are then divided according to a grading scheme based on Ki67 index in pNETs-G1 (Ki67 index ≤3%) and pNETs-G2 (Ki67 index between 4% and 20%). pNECs are all G3, with a Ki67 index >20%. Endoscopic ultrasound with fine-needle biopsy (EUS-FNB) demonstrated safe and effective preoperative grading based on the Ki-67 proliferative index. However, downstaging rate is not neglectable, reaching 15% in a recent metanalysis. Moreover, recent whole-exome and whole genome sequencing studies revealed that the mutually exclusive inactivating mutations in death domain-associated protein (DAXX) and/or in α-thalassemia/mental retardation X-linked (ATRX) chromatin remodeling genes are associated with more aggressive disease. In a retrospective study, the investigators recently evaluated the correspondence of DAXX/ATRX expression on 41 EUS-FNB samples with corresponding surgical specimens demonstrating a 95.1% (almost perfect agreement, κ = 0.828; p < 0.001) and 92.7% (substantial agreement, κ = 0.626; p < 0.001) concordance for DAXX and ATRX expression, respectively. This study aims to evaluate the potential clinical/prognostic role of DAXX/ATRX expression as implementation of the currently used Ki67-based grading, evaluated on EUS-FNB samples in a prospective cohort of patients with NF-pNETs

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 100
• Est. completion date: November 30, 2029
• Est. primary completion date: November 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age =18 years
• Cyto/histologic diagnosis of pNETs
• Signed informed consent

Exclusion Criteria:

• Functional pNETs
• Multiple pancreatic nodules
• Diagnosis of MEN-1 or Von-Hippel Lindau
• Mixed types (e.g., mixed neuroendocrine-acinar/adenocarcinoma) or neuroendocrine carcinomas
• Predominantly cystic lesions (more than 50% of the volume).
• Metastatic tumors at the time of diagnosis
• Known bleeding disorder that cannot be sufficiently corrected with co-fact or fresh frozen plasma
• Use of anticoagulants that cannot be discontinued
• INR >1.5 or platelet count <50.000
• Pregnancy or breastfeeding
• Failure to sign the patient's or closest relative's informed consent

Related Conditions & MeSH terms

• Neuroendocrine Tumors
• Pancreatic Neuroendocrine Tumor

Intervention

Diagnostic Test:
• ATRX/DAXX immunohistochemistry
Immunohistochemistry will be performed using an Autostainer Leica (Leica Biosystems) according to the manufacturer's instructions. Four µm formalin-fixed paraffin-embedded sections will be immunostained with antibodies for Cytokeratin AE1/AE3 (AE1-AE3, 1:100 dilution, Novocastra/United Kingdom) Chromogranin A (DAK-A3, 1:2500, Dako/Denmark), and Synaptophysin (27G12, 1:100, Novocastra), Ki67 (MIB1, 1:100, Dako/Denmark), ATRX (1:400, Sigma-Aldrich), DAXX (1:200, Sigma-Aldrich). After antigen retrieval, immunostaining will be performed in an automated Bond instrument (Vision-Biosystem, Leica, Milan, Italy) using a sensitive peroxidase-based 'Bond polymer Refine' detection system.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Azienda Ospedaliera Universitaria Integrata Verona

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	ATRX/DAXX loss-tumor aggressiveness association	To assess the association between ATRX/DAXX loss of expression assessed on endoscopic ultrasound biopsy specimens and pathological features indicative of tumor aggressiveness evaluated on surgical pathology	18 months
Secondary	Ki-67 concordance	To evaluate the concordance rate of Ki67-based tumor grade between endoscopic ultrasound biopsy samples and surgical specimens.	18 months
Secondary	DAXX/ATRX concordance	To evaluate the concordance rate of DAXX/ATRX expression between endoscopic ultrasound biopsy samples and surgical specimens	18 months
Secondary	Ki-67-tumor aggressiveness association	To assess the association between preoperative Ki67-based grade 2/3 on endoscopic ultrasound samples and pathological features indicative of tumor aggressiveness evaluated on surgical pathology	18 months
Secondary	Preoperative prognosis assessment	To evaluate the association between DAXX/ATRX expression on endoscopic ultrasound biopsy samples, Ki67-based grade 2/3 on endoscopic ultrasound biopsy samples, and tumor size on endoscopic ultrasound and progression-free survival and relapse-free survival.	60 months