From clinical insight to trial design: advancing circulating tumor DNA-informed care in pancreatic cancer.

Accurate, timely measurement of disease burden is a cornerstone of cancer care- particularly for pancreatic cancer, an aggressive malignancy often requiring strenuous treatment regimens with poor survival outcomes. However, current measures of pancreatic cancer, including imaging and biomarkers, are inadequate and often fail to keep up with real time changes in tumor biology and patient symptoms. The level of evidence in support of circulating tumor DNA (ctDNA) varies by disease, but remains largely empiric in pancreatic cancer. We analyze the use of ctDNA in five key settings along the pancreatic cancer continuum. We demonstrate a variety of potentially useful applications for ctDNA, including assessment of neoadjuvant therapy efficacy to better inform surgical management, early detection of recurrence during surveillance, and differentiation of tumor progression from pseudoprogression. To our knowledge, this is the first practice review with cases that present real-world examples of ctDNA-guided pancreatic cancer management while concurrently evaluating current standards and future directions across all major treatment settings. This integrated perspective highlights insights not available from single-setting cohorts, underscoring the substantial work still needed to define the precise role, standardization, and clinical implementation of ctDNA assays in both localized and advanced pancreatic cancer. A more deliberate and evidence-based integration of ctDNA with established imaging, biomarkers, and therapeutic strategies represents a critical objective in pancreatic cancer, for which we review representative trial designs intended to enable prospective validation and better define its impact on clinical outcomes.