Acquired multiple secondary mutations upon PARPi resistance in a metastatic pancreatic cancer patient harboring a germline mutation.

PARP inhibitor (PARPi) therapies have been approved for treating multiple germline mutated (gm) advanced cancers including metastatic pancreatic cancer. Although significantly prolonged progression-free survival was observed in gm pancreatic cancer patients, there was no improved overall survival. The underlined resistant mechanism to PARPi therapy is worth pursuing. Here, we reported a patient with advanced pancreatic cancer harboring a germline deleterious V1804Kfs mutation as well as somatic mutations in , and . Stable disease was achieved with the combination therapy of cisplatin and PARPi olaparib, but the disease quickly progressed after 18 weeks of treatment. Next-generation sequencing (NGS)-based genomic profiling of the liver metastasis and liquid biopsy revealed four newly acquired indel mutations, including two reversion mutations that could potentially restore BRCA2 function in the PARPi-resistant tumor. Our case showed that although initial response to PARPi therapy can be achieved in advanced gm pancreatic cancer patient, the tumor rapidly evolved to acquire multiple secondary mutations to restore the integrity of DNA repair and confer drug resistance, which may contribute to the unimproved overall survival in pancreatic cancer patients.