Blood-Based Liquid Biopsy Biomarkers in Pancreatic Neuroendocrine Tumors: A Systematic Review and Narrative Synthesis of Diagnostic, Prognostic, Molecular Profiling, and Monitoring Utility

Abstract

Introduction: Pancreatic neuroendocrine tumors (PNETs) are biologically heterogeneous neoplasms for which reliable non-invasive biomarkers remain limited. Although tissue-based genomic studies have identified recurrent molecular alterations, the clinical utility of blood-based liquid biopsy in PNETs remains uncertain.

Methods: A PubMed-based systematic review was conducted following PRISMA 2020 guidelines, with the final search performed on 20 February 2026. Eligible studies investigated blood-based biomarkers in PNETs, including circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), plasma next-generation sequencing (NGS), copy-number alterations (CNAs), and transcript-based multigene assays. Given methodological and clinical
heterogeneity, findings were synthesized narratively. One pancreatic neuroendocrine carcinoma case report was included solely as illustrative evidence.

Results: Six reports were included, comprising five studies providing PNET-specific evidence and one illustrative case report. CNA-based ctDNA analysis demonstrated the strongest
prognostic associations, with detectable tumor fraction associated with poorer overall and progression-free survival. Mutation-based plasma NGS identified potentially actionable genomic alterations, although clinical validation remained limited. Total cfDNA showed inconsistent clinical utility. Transcript-based assays, particularly NETest, demonstrated promising diagnostic performance and concordance with imaging-based disease assessment but lacked tumor-specific genomic information for treatment selection.

Conclusions: Blood-based liquid biopsy biomarkers in PNETs demonstrate promising but heterogeneous clinical utility. CNA-Blood-based liquid biopsy approaches show potential for improving PNET management, although their clinical applications differ. CNA-based ctDNA appears promising for prognostication and disease monitoring, while transcript-based assays may support diagnosis and assessment of disease activity. Plasma NGS could provide complementary molecular information in selected patients with advanced disease. However, small study populations, single-database retrieval, assay heterogeneity, and limited prospective validation restrict clinical applicability. Larger multicenter prospective studies with standardized methodologies and clinically relevant endpoints are required before routine implementation.