Circulating Protein Biomarkers for Prognostic Use in Patients with Advanced Pancreatic Ductal Adenocarcinoma Undergoing Chemotherapy

SIMPLE SUMMARY: We investigated the connection between the levels of 92 circulating proteins and survival in patients with advanced pancreatic ductal adenocarcinoma. Serum samples from 363 patients with advanced pancreatic ductal adenocarcinoma were examined using the Olink Immuno-Oncology panel. Two protein signatures were found containing seven and four proteins, respectively. These two protein indices discriminated patients with very short overall survival (<90 days) from patients with long overall survival (>2 years), with AUC values of 0.97–0.99 in the discovery cohort, and 0.89–0.82 in the replication cohorts. Further analyses were conducted exploring early changes in protein levels, and protein expression in different treatment groups. ABSTRACT: Patients with advanced pancreatic ductal adenocarcinoma (PDAC) have a dismal prognosis. We aimed to find a prognostic protein signature for overall survival (OS) in patients with advanced PDAC, and to explore whether early changes in circulating-protein levels could predict survival. We investigated 92 proteins using the Olink Immuno-Oncology panel in serum samples from 363 patients with advanced PDAC. Protein panels for several survival cut-offs were developed independently by two bioinformaticians using LASSO and Ridge regression models. Two panels of proteins discriminated patients with OS < 90 days from those with OS > 2 years. Index I (CSF-1, IL-6, PDCD1, TNFRSF12A, TRAIL, TWEAK, and CA19-9) had AUCs of 0.99 (95% CI: 0.98–1) (discovery cohort) and 0.89 (0.74–1) (replication cohort). For Index II (CXCL13, IL-6, PDCD1, and TNFRSF12A), the corresponding AUCs were 0.97 (0.93–1) and 0.82 (0.68–0.96). Four proteins (ANGPT2, IL-6, IL-10, and TNFRSF12A) were associated with survival across all treatment groups. Longitudinal samples revealed several changes, including four proteins that were also part of the prognostic signatures (CSF-1, CXCL13, IL-6, TNFRSF12A). This study identified two circulating-protein indices with the potential to identify patients with advanced PDAC with very short OS and with long OS.