Background: Whole exome sequencing in WD pNETs demonstrated an increased number of mutations in genes implicated in chromatin remodeling and in the PI3K/Akt/mTOR pathway. Next-generation sequencing (NGS) allows us to bring this technology to the clinic to better characterize WD pNETs and potentially offer tailored therapies. Methods: A NGS platform developed at Memorial Sloan Kettering Cancer Center (MSKCC) termed MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) was used. This platform screens for 341 cancer genes commonly altered across tumor types. Thus far, 14 patients with WD pNETs have consented to MSK-IMPACT. Results: To date, mostpatients harbor no clinically validated or actionable mutations. Two patients, however, harbor different and potentially actionable BRAF mutations. The first patient is a 39 year-old woman with a BRAF V600E mutation. She presented with somatostatin receptor-negative, aggressive disease involving the liver, lymph nodes, adnexa, and peritoneum. She was initially diagnosed elsewhere as having a signet ring cell adenocarcinoma, and responded to FOLFOX and bevacizumab. Pathology review at MSKCC, however, identified the tumor as metastatic WD pNET. Upon disease progression, a repeat biopsy confirmed metastatic WD pNET. She is currently on capecitabine and temozolomide with clinical improvement. The second patient is a 22 year-old woman with metastatic WD pNET with a BRAF K601E mutation. Her tumor also has an aggressive behavior; she has progressed on all conventional and nonconventional therapies. Given the finding of a BRAF K601E mutation, she received trametinib and dabrafenib, but developed disease progression after 3 months. Conclusions: Two potentially actionable BRAF mutations were identified from NGS of WD pNETs. BRAF mutations have not been previously reported in pNETs. It is unclear whether BRAF mutations are oncogenic drivers, and whether BRAF-targeted treatments would be beneficial. Both patients show an atypical, aggressive presentation and course. Further testing is warranted to determine the role and clinical significance of BRAF in pNETs. Evaluation using pNET tissue microarrays is ongoing and will be reported at the meeting.