Pancreatic cancer still has dismal survival rates and high rates of early recurrence despite improvements of multimodal treatment options and more and more aggressive surgical approaches in recent years. Thus, precise and personalized management strategies to improve patient outcomes are needed. Circulating tumor DNA (ctDNA), a component of cell-free DNA (cfDNA) in body fluids, harbors genetic and epigenetic signatures of tumors and can be detected noninvasively for example through simple blood collections or peritoneal fluid during staging laparoscopy (liquid biopsies). This biomarker provides real-time insights into systemic tumor burden, heterogeneity, and genetic profile and has been proven to be of significant prognostic relevance for several gastrointestinal malignancies. Furthermore, the testing of ctDNA has emerged as a pivotal prognostic biomarker to indicate patients with high biological risk for recurrence and worse overall survival. Especially in pancreatic cancer, it has been shown that preoperative ctDNA detectability in peripheral blood is associated with systemic tumor burden (even volumetric). This indicates potential micrometastatic or subclinical disseminated disease, suggesting a benefit from neoadjuvant chemotherapy to address the systemic component of the disease prior to surgery. Furthermore, dynamic changes in ctDNA during systemic treatment can predict therapeutic response and guide adjustments in treatment regimens. Postoperatively, ctDNA presence could assist in detecting minimal residual disease which also predicts early relapse, facilitating timely intervention (or immediate adjuvant chemotherapy as already shown in colorectal cancer, e.g., Dynamic trial). Therefore, perioperative ctDNA detection has the potential to refine the management of pancreatic cancer, enhancing decision-making processes and optimizing personalized treatment approaches in serving as an additional highly sensitive biomarker for guiding treatment decisions between upfront surgery and neoadjuvant chemotherapy in patients with resectable pancreatic cancer. The first ever personalized change of treatment decision from upfront surgery (by current gold standard staging) to neoadjuvant chemotherapy based on additional liquid biopsy results was documented in March 2024 (Linz, Austria).
