Minimal residual disease assessment through ctDNA facilitates tailored immunotherapy in MSI-high, NTRK1-fusion pancreatic adenocarcinoma.

Pancreatic cancer remains one of the most lethal malignancies, with limited integration of precision oncology into routine clinical care. We present a unique case of a RAS wild-type, MSI-H, TMB-H pancreatic ductal adenocarcinoma harboring a TPM3-NTRK1 fusion, monitored through 13 serial liquid biopsies over 3 years. Dynamic changes in NTRK1-fusion allele frequency, tumor mutational burden, and the emergence of an NTRK1 resistance mutation guided finely tuned, situation-adapted therapeutic adjustments: rapid disease control with targeted NTRK inhibition followed by durable remission under immune checkpoint blockade. This case highlights the power of comprehensive molecular profiling and high-frequency ctDNA monitoring to capture tumor evolution and minimal residual disease. Importantly, it further demonstrates how MRD-guided surveillance enables a precise balance between fast-acting targeted therapy and the sustained effects of immunotherapy, providing a blueprint for individualized, context-driven treatment strategies in rare molecular subtypes of pancreatic cancer.