Background: The rarity of NETs can limit clinical trial accrual to develop new therapies. Given fewer approved treatments, a better understanding of underlying biology is critical to development of and assignment of patients (pts) to clinical trials. Methods: Pts with NETs (excluding small/large cell lung cancer) of all grades at FCCC were enrolled onto a prospective IRB approved protocol that utilized an NGS platform to detect somatic mutations (SM) in 50 cancer-related genes (Cancer Code) on archived tissue from primary or metastatic sites. Genes tested included ABL1, AKT1, ALK, APC, ATM, BRAF, CDH1, CDKN2A, CSF1R, CTNNB1, EGFR, ERBB2, ERBB4, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, GNA11, GNAQ, GNAS, HNF1A, HRAS, IDH1, IDH2, JAK2, JAK3, KDR, KIT, KRAS, MET, MLH1, MPL, NOTCH1, NPM1, NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RB1, RET, SMAD4, SMARCB1, SMO,SRC, STK11, TP53 and VHL. Review of pathology specimens for grade and Ki -67 was also performed. Results: Thirty-nine pts (median age 59 y, males 46%) were enrolled from October 2013 to July 2014. Gene profiling results are available on thirty-five pts. Ki-67 score was reviewed for 31/35 tumors. 6 (20%) pts had high grade (HG) tumors (Ki-67 > 20%) and 25 (80%) had low/intermediate grade (LIG) tumors (Ki-67 ≤20%). Thirteen (37%) pts were found to have SMs and 22 (63%) did not, with 4 (12%) pts’ tumors having >1 SMs (2 HG and 2 LIG tumors). Incidence of SM was 41% (12/29) in Caucasians, 16% (1/6) in other races, 46% (6/13) in smokers and 30% (6/20) in non-smokers. Incidence of SM was 24% (6/25) in LIG NETs and 84% (5/6) in the HG NETs. Among HG tumors, 66% (4/6) harbored TP53 gene mutation and 33% (2/6) were BRAF mutation positive. Conclusions: Tumor-specific mutations are seen in a minority of low grade NETs but are common in high grade tumors. Interestingly, no mutations were identified in pts with unknown primary. Analysis of clinical outcomes based on treatment received is ongoing to assess for possible prognostic/therapeutic implications of these mutations.