Durable response to selpercatinib in HOOK3-RET fusion positive, α-fetoprotein producing metastatic pancreatic ductal adenocarcinoma with intestinal-type differentiation.

Pancreatic cancer carries a poor prognosis, with few effective treatment options available. Various rearranged during transfection (RET) proto-oncogene fusions have been found in a small fraction of pancreatic cancers; however, the hook microtubule tethering protein 3 (HOOK3)-RET fusion has not yet been reported in the medical literature. The HOOK3-RET fusion was observed in a case of α-fetoprotein (AFP)-producing pancreatic ductal adenocarcinoma with widespread hepatic and lymph node metastasis in a 51-year-old South Asian male. The patient's serum carbohydrate antigen 19.9 was mildly elevated: 96.28 U/ml (normal, <37 U/ml), but the serum AFP level was very high (16,410.0 ng/ml; normal, <6.6 ng/ml). The patient did not respond to gemcitabine and cisplatin-based systemic chemotherapy. Next-generation sequencing of the patient's biopsy sample revealed a HOOK3-RET fusion. RET proto-oncogene fusions trigger a cascade of oncogenic signals, which promote the proliferation and survival of cancer cells. Selpercatinib, a selective inhibitor of receptor tyrosine kinase RET, blocks RET kinase activity by binding to its adenosine triphosphate-binding site, thus preventing the kinase from phosphorylating substrates and halting oncogenic signaling. The patient was treated with selpercatinib, which produced a durable response lasting over 15 months in this chemotherapy-refractory patient, highlighting the efficacy of selpercatinib in HOOK3-RET fusion-positive pancreatic cancer.