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Landscape of circulating diagnostic biomarkers in pancreatic malignancies

Pancreatic cancer remains the most lethal adult cancer in the US that is in large part due to the lack of effective early detection biomarkers. Although a variety of blood based technologies have been developed, each of these assays have different advantages and disadvantages. Here, we will review the landscape of blood based biomarkers in the context of pancreatic cancer early detection. Tumor biomarkers (CA19-9, CEA) are widely used, but often have limited specificity to cancer, and panel-based approaches combining multiple serum proteins may prove more promising in early detection of pancreatic cancer. Metabolic markers, including the substrates, intermediates, and by-products of aberrant pathways can also be quantified and used as biomarkers, particularly since pancreatic cancer almost universally exploits KRAS mutations leading aberration activation of the MEK/ERK/AKT pathways. More recent approaches have also attempted to use cell-free DNA released from tumor cells into the bloodstream to directly sequence and identify mutations and serve as a ‘liquid biopsy.’ Alternatively, approaches are being used to capture rare circulating epithelial cells that have entered into the bloodstream (circulating tumor cells, or CTCs) even in pre-neoplastic lesions. Extracellular vesicles (EVs) found in plasma are a new emerging source of tumor enriched cargo (DNA, RNA, proteins) providing a multi-prong approach towards early tumor detection. Although many of these approaches are promising, they need to be validated in large-scale human trials using appropriate controls. Altogether, the complementary performance characteristics of different biomarkers point to a combination of these technologies as the future of a pancreatic cancer early detection liquid biopsy.