Molecular KRAS ctDNA Predicts Metastases and Survival in Pancreatic Cancer: A Prospective Cohort Study

Background: Patients with pancreatic ductal adenocarcinoma (PDAC) commonly have occult metastatic dissemination and current standard staging methods have significant limitations in identifying these patients. A clinically available assay allows for the identification of mutant KRAS (mKRAS) circulating tumor DNA (ctDNA) from patient plasma and peritoneal fluid that may identify these patients and impact treatment decision making. We investigated the patterns of diagnostic and prognostic capabilities of mKRAS ctDNA in patients with localized PDAC. Methods: Patients with non-metastatic PDAC were identified and underwent a full staging work-up during their first visit at our institution. Development of metastatic disease and long-term survival outcomes were assessed to compare between the mKRAS testing groups. Results: Between 2018 and 2022, 785 patients were evaluated. Among the 785 patients who underwent plasma mKRAS testing, 104 were mKRAS positive. Plasma mKRAS-positive patients were more likely to develop metastatic disease and had worse overall survival. In the 419 patients who underwent peritoneal mKRAS, 123 were mKRAS-positive and were more likely to harbor occult metastases or develop peritoneal rather than hematogenous metastases. For patients who underwent both baseline plasma and peritoneal mKRAS testing, any positive mKRAS test regardless of compartment was associated with worse outcomes. Conclusions: Detection of mKRAS ctDNA in plasma and peritoneal fluid of patients with localized PDAC is not only feasible but also identifies those at high risk of metastatic progression and worse survival outcomes. It allows for better prognostication and can significantly impact subsequent treatment decisions, particularly in patients where an aggressive surgical approach is being considered.