Neuroendocrine neoplasms: current and potential diagnostic, predictive and prognostic markers

Abstract

Some biomarkers for functioning and non-functioning neuroendocrine neoplasms (NENs) are currently available. Despite their application in clinical practice, results should be interpreted cautiously. Considering the variable sensitivity and specificity of these parameters, there is an unmet need for novel biomarkers to improve diagnosis and predict patient outcome. Nowadays, several new biomarkers are being evaluated and may become future tools for the management of NENs. These biomarkers include (1) peptides and growth factors; (2) DNA and RNA markers based on genomics analysis, for example, the so-called NET test, which has been developed for analyzing gene transcripts in circulating blood; (3) circulating tumor/endothelial/progenitor cells or cell-free tumor DNA, which represent minimally invasive methods that would provide additional information for monitoring treatment response and (4) improved imaging techniques with novel radiolabeled somatostatin analogs or peptides. Below we summarize some future directions in the development of novel diagnostic and predictive/prognostic biomarkers in NENs. This review is focused on circulating and selected tissue markers.

Blood-based next-generation sequencing analysis of neuroendocrine neoplasms

“…A significant challenge for the use of ctDNA in the NEN field is the relative lack of recurrent mutations in comparison with other tumors. Requirements for accurate ctDNA analysis include adequate tumor DNA being shed into the blood stream and a PCR primer based assay that detects the mutations of interest [34]. Unfortunately, these conditions are only present in a small subset of NET patients population [34].…”

“…Requirements for accurate ctDNA analysis include adequate tumor DNA being shed into the blood stream and a PCR primer based assay that detects the mutations of interest [34]. Unfortunately, these conditions are only present in a small subset of NET patients population [34]. In small bowel NET, tissue-based genomic sequencing revealed that the majority of recurrent mutations were in cyclin-dependent kinase inhibitor CDKN1B (8% of cases) [35].…”

PAM staining intensity of primary neuroendocrine neoplasms is a potential prognostic biomarker

“…While most (potential) prognostic NEN biomarkers are applicable to a subset of NENs, e.g. pancreatic or lung NENs, reduced PAM staining www.nature.com/scientificreports/ demonstrated utility across a spectrum of NENs 35 . Particularly notable findings of this study were: (A) PAM scoring was highly consistent among three independent reviews; (B) reduced PAM staining was associated with a stage-independent increased risk of death and shorter survival duration among patients who died; and (C) reduced PAM immunoreactivity may identify grade 1 or grade 2 NENs in patients with an increased risk of dying.…”

Systemic Treatment Selection for Patients with Advanced Pancreatic Neuroendocrine Tumours (PanNETs)

“…However, there is a lack of alternatives beyond the use of fasting gut hormones. Alternative possible biomarkers in the form of growth factors, such as VEGF and its receptors, placental growth factor (PlGF), Interleukin-8 (IL-8), PD-1/PD-L1 expression, T-cell immunoglobulin and mucin domain 3 (TIM3), X-linked transcriptional regulator (ATRX), death domain-associated protein 6 (DAXX) genes, circulating tumour cells, and circulating tumour DNA, have been studied without consensus on their utility [148][149][150][151][152]. The use of biomarkers can be employed beyond the selection of patients for specific therapies; understanding the biology of PanNETs, especially the mechanisms of acquired resistance (for example, to targeted therapy, although this applies equally to other treatments) is needed.…”