Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19-9 blood markers

Abstract

Markers are needed to facilitate early detection of pancreatic ductal adenocarcinoma (PDAC), which is often diagnosed too late for effective therapy. Starting with a PDAC cell reprogramming model that recapitulated the progression of human PDAC, we identified secreted proteins and tested and validated a subset of them as potential markers of PDAC. We optimized an ELISA assay using plasma samples from patients with various stages of PDAC, from individuals with benign pancreatic disease, and from healthy controls. Clinical studies including a phase 1 discovery study (N=20 patients), a phase 2a validation study (N=189), and a second phase 2b validation study (N=537) revealed that concentrations of plasma thrombospondin-2 (THBS2) discriminated among all stages of PDAC consistently over the three studies with a Receiver Operating Characteristic (ROC) c-statistic of 0.76 in Phase 1, 0.842 in Phase 2a, and 0.875 in Phase 2b. The concentration of THBS2 in plasma performed as well at discriminating resectable stage I cancer as stage III/IV PDAC. THBS2 concentrations combined with those for CA19-9, a previously identified PDAC marker, yielded a c-statistic of 0.956 in the Phase 2a study and 0.970 in the Phase 2b study. THBS2 data improved the ability of CA19-9 to distinguish PDAC from pancreatitis. With a specificity of 98%, the combination of THBS2 and CA19-9 yielded a sensitivity of 87% for PDAC in the Phase 2b study. Given this, a THBS2 and CA19-9 panel assessed in human blood using a conventional ELISA assay may improve the detection of patients at high risk for PDAC.

The Translational Status of Cancer Liquid Biopsies

“…To address aforementioned study design issues, recommendations have been put in place for the phased design in biomarker discovery [305] aimed at better evaluation of classification accuracy in the intended clinical context. A novel candidate protein biomarker for pancreatic ductal adenocarcinoma (PDAC) has been put forth using the recommended study design [306,307]. Authors first carried out an experiment where they reprogrammed human PDAC cells into an induced pluripotent stem cell-like line (10-22 cell line) [308].…”

The circulating miRNAs as diagnostic and prognostic markers

“…Actually, there are no screening recommendations for pancreatic cancer and it is clear that primary prevention is of the utmost importance in diagnosis. The blood based-biomarkers carbohydrate antigen 19-9 (CA19-9), carcino-embryonic antigen [162] and/or genetic markers such as KRAS and p53 [163] are not recommended for screening and diagnosis, because of their poor sensitivity and specificity, while they are only used in patient follow-up. Because it is known that pancreatic cancer is characterized by common and frequent genetic mutations, such as KRAS (>90%), TP53 (>50%), SMAD4 (>60%) and CDKN2A (>80%) genes, as crucial regulators of gene expression, miRNAs represent a new promising class of eligible non-invasive biomarkers [164,165].…”

miRNA Profiling of Magnetic Nanopore–Isolated Extracellular Vesicles for the Diagnosis of Pancreatic Cancer

“…EVs have three key advantages for medical diagnostics relative to circulating molecules in the blood (e.g., proteins, cell-free DNA; refs. 13,14): (i) EVs package RNA that would otherwise be degraded in the bloodstream; (ii) the multiple RNA and proteins packaged within EVs can be used to perform multiparameter measurements that allow specific disease states to be classified; (iii) proteins on an EV's surface can be used to sort targeted EVs based on the cells of origin, allowing enhanced specificity in the measurement of EV cargo compared with molecular markers in the blood. EVs also have key advantages compared with circulating tumor cells (CTC).…”