From Genomic Insight to Clinical Impact: Dramatic Response in RET Fusion–positive Pancreatic Cancer

Background/Aim: Pancreatic cancer remains one of the deadliest solid malignancies despite advances in systemic treatment. Outcomes with current therapies remain modest, with a 5-year overall survival rate of no more than 20%. Although rare, oncogenic RET fusions represent a clinically actionable alteration and may predict substantial benefit from selective RET inhibition. Case Report: A 48-year-old woman with pancreatic ductal adenocarcinoma developed liver metastases after first-line modified FOLFIRINOX. Comprehensive genomic profiling of the initial biopsy identified an NCOA4–RET fusion involving NCOA4 exon 6 and RET exon 12. Selpercatinib was initiated through a compassionate-use program at 160 mg twice daily. After approximately three months, the patient achieved a reduction of more than 50% in the sum of target-lesion diameters according to RECIST version 1.1. The response was sustained for more than 12 months despite dose reduction for persistent grade 2 hypertransaminasemia. The most recent assessment showed continued regression, including complete disappearance of some liver metastases. The patient remains clinically well, with an ECOG performance status of 0 and ongoing treatment. Conclusion: This case demonstrates the potential for durable and clinically meaningful responses to RET-targeted therapy in RET fusion-positive pancreatic cancer. It also supports the use of comprehensive genomic profiling to identify rare but actionable molecular alterations in patients with advanced pancreatic cancer.