Background: Pancreatic ductal adenocarcinoma (PDAC) is the most lethal form of pancreatic cancer, being responsible for ~90% of all pancreatic cancers and having a 5-year survival rate of ~8.5%. The current clinical gold-standard for diagnosis of PDAC is the blood-based biomarker CA19-9. However, many studies have highlighted the limitations of CA19-9, specifically its relatively low sensitivity and specificity, and its inaccuracy in patients with certain underlying conditions. As such, there is an unmet need for robust diagnostic biomarkers for PDAC. Here, the diagnostic accuracy of all blood-based biomarkers examined in PDAC, reporting specifically on CA19-9, multi-marker panels containing CA19-9, novel single markers, and novel multi-marker panels for the diagnosis of PDAC. Methods: A systematic review of blood-based biomarkers for the diagnosis of PDAC was conducted in accordance with PRISMA standards. Individual search strategies using medical subject headings (MeSH) and ‘text words’ were developed for three academic databases: Medline, EMBASE and Web of Science. The 5,885 studies identified were subjected to two rounds of screening by two independent reviewers, with 250 studies being included in the meta-analysis. Data were extracted and assessed for bias using the QUADAS-2 Risk of Bias tool. Data were separated into two subgroups: those including CA19-9, and those without CA19-9 (novel). Patient cohorts examined were classified as “PDAC vs healthy”, “PDAC vs benign” and “PDAC vs mixed”. A multivariate three-level meta-analysis with subgroup moderators was run in R (v1.3.959) on all CA19-9 containing biomarker studies and subsequently on all novel biomarker studies, using reported AUC values as effect size. Results: Based on the three-level meta-analytic model, the pooled AUC value for CA19-9 alone (AUC=0.8473, 95% CI: 0.82-0.87) was significantly lower compared to the multi-marker panels containing CA19-9 (AUC=0.91, 95% CI:0.90-0.93) (p<0.0001). The estimated between-study variance in the model was I2Level 3= 63.55%, and the within-study variance was I2Level 2=36.45%. For the novel markers, the pooled AUC for single markers (AUC=0.79, 95% CI:0.75-0.83) was also significantly lower compared to novel multi-marker panels (AUC=0.87, 95% CI:0.85-0.89) (p<0.0001). Marker robustness was also influenced by the patient cohort examined, with CA19-9 markers performing best in all cohorts compared to novel markers; PDAC vs healthy (AUC=0.91, 95% CI:0.88-0.94), PDAC vs benign (AUC=0.85, 95% CI:0.84-0.87), and PDAC vs mixed (AUC=0.87, 95% CI:0.82-0.91) (p<0.0001). Conclusion: Overall, multi-marker panels show higher pooled AUC values than single markers, for both CA19-9 and novel datasets. Multi-marker panels containing CA19-9 demonstrate the most promising pooled AUC value, with CA19-9 alone performing inferiorly to novel multi-marker panels. These results indicate that CA19-9 may be best used as an addition to a panel of markers rather than alone, and that multi-marker panels ultimately generate the most robust results in a diagnostic capacity.

Citation Format: Laura E. Kane, Gregory S. Mellotte, Eimear Mylod, Rebecca O'Brien, Fiona O'Connell, Khanh Nguyen, Croí E. Buckley, Jennifer Arlow, David Mockler, Aidan D. Meade, Barbara M. Ryan, Stephen G. Maher. Diagnostic accuracy of blood-based multi-omic biomarkers for pancreatic adenocarcinoma: A systematic review and meta-analysis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-008.