Circulating Neuroendocrine Tumor Biomarkers: Past, Present and Future

Abstract

Neuroendocrine tumors are a heterogeneous group of neoplasms originating from the diffuse endocrine system. Depending on primary location and hormonal status, they range in terms of clinical presentation, prognosis and treatment. Functional tumors often develop symptoms indicating an excess of hormones produced by the neoplasm (exempli gratia insulinoma, glucagonoma and VIPoma) and can be diagnosed using monoanalytes. For non-functional tumors (inactive or producing insignificant amounts of hormones), universal biomarkers have not been established. The matter remains an important unmet need in the field of neuroendocrine tumors. Substances researched over the years, such as chromogranin A and neuron-specific enolase, lack the desired sensitivity and specificity. In recent years, the potential use of Circulating Tumor Cells or multianalytes such as a circulating microRNA and NETest have been widely discussed. They offer superior diagnostic parameters in comparison to traditional biomarkers and depict disease status in a more comprehensive way. Despite a lot of promise, no international standards have yet been developed regarding their routine use and clinical application. In this literature review, we describe the analytes used over the years and cover novel biomarkers that could find a use in the future. We discuss their pros and cons while showcasing recent advances in the field of neuroendocrine tumor biomarkers.

Baseline tumor growth rate highlights the heterogeneity of well differentiated gastroenteropancreatic neuroendocrine tumors and predicts for increases in Ki67 index over time

“…The identification of active drugs in GEP‐NETs remains limited in part by the lack of validated molecular markers for risk stratification 34–36 . Strategies such as blood‐based biomarkers and assessment of radiomic imaging features also hold promise for assessing interpatient heterogeneity and have the appeal of using data from a single time point 37–41 . When feasible to acquire two pretreatment scans, documenting TGR 0 could enhance our ability to non‐invasively identify treatment‐naïve patients at greatest risk for future grade progression and change in Ki67 over time.…”

The Use of PDX1 DNA Methylation to Distinguish Two Subtypes of Pancreatic Neuroendocrine Neoplasms with Different Prognoses

“…In functional pNENs, secreted hormones-such as insulin, glucagon, vasoactive intestinal polypeptide, gastrin, and somatostatin-are also useful for predicting recurrence and treatment responses, besides their utility as diagnostic tools [6]. Unfortunately, a ubiquitously applicable serum biomarker is currently unavailable, which is mainly due to the heterogenous nature of pNENs [7]. Serum biomarkers mainly include secretory products, which lack sufficient diagnostic sensitivity, specificity, and prediction power for prognosis [6,7], but are, nevertheless, clinically important due to their ability to provide noninvasive and repeatable measurements.More recently, the genetic landscape of pNENs has been revealed due to advances in next-generation sequencing technology, and the knowledge regarding the molecular features of pNENs has been systematically advanced with multi-omics analyses, such as high-throughput transcriptomics, epigenomics, proteomics, metabolomics, and radiomics.…”

“…Unfortunately, a ubiquitously applicable serum biomarker is currently unavailable, which is mainly due to the heterogenous nature of pNENs [7]. Serum biomarkers mainly include secretory products, which lack sufficient diagnostic sensitivity, specificity, and prediction power for prognosis [6,7], but are, nevertheless, clinically important due to their ability to provide noninvasive and repeatable measurements.More recently, the genetic landscape of pNENs has been revealed due to advances in next-generation sequencing technology, and the knowledge regarding the molecular features of pNENs has been systematically advanced with multi-omics analyses, such as high-throughput transcriptomics, epigenomics, proteomics, metabolomics, and radiomics. The molecular subtyping of pNENs has established novel classifications based on common multigene mutations, the large-scale loss of heterozygosity, copy number variations (CNVs), and islet cell type-specific signatures.…”

“…In functional pNENs, secreted hormones-such as insulin, glucagon, vasoactive intestinal polypeptide, gastrin, and somatostatin-are also useful for predicting recurrence and treatment responses, besides their utility as diagnostic tools [6]. Unfortunately, a ubiquitously applicable serum biomarker is currently unavailable, which is mainly due to the heterogenous nature of pNENs [7]. Serum biomarkers mainly include secretory products, which lack sufficient diagnostic sensitivity, specificity, and prediction power for prognosis [6,7], but are, nevertheless, clinically important due to their ability to provide noninvasive and repeatable measurements.…”

“…Unfortunately, a ubiquitously applicable serum biomarker is currently unavailable, which is mainly due to the heterogenous nature of pNENs [7]. Serum biomarkers mainly include secretory products, which lack sufficient diagnostic sensitivity, specificity, and prediction power for prognosis [6,7], but are, nevertheless, clinically important due to their ability to provide noninvasive and repeatable measurements.…”