Background: Metastatic appendiceal adenocarcinoma (AAC) is a heterogenous disease and the majority of patients present with diffuse metastases in the peritoneal cavity. Cytotoxic and targeted therapies are typically extrapolated from colorectal adenocarcinoma (CRC), however, it is not known whether this is effective or not. Herein we investigated the genetic profiles of these tumors in an effort to identify molecular characteristics and potentially actionable mutations, as well as the response to anti-EGFR therapy in RAS/BRAF wild type (wt) AAC. Methods: We identified patients (pts) with ACC treated at MSKCC who had tumor who had undergone molecular profiling, either by next generation sequencing using our MSK-IMPACT platform, or by MALDI-TOF mass spectroscopy genotyping (Sequenom). MSK-IMPACT tumors and matched normal samples were analyzed either on 410 gene panel. Sequenom (provided an 8 gene panel including KRAS, NRAS, BRAF, and PIK3CA). Via an IRB approved waiver, we collected tumor histology and evaluated pts who were RAS/RAF wt and had been treated with anti-EGFR therapy. Results: We identified a total 97 AAC pts, of whom 60 had Sequenom testing and 37 had IMPACT. Among pts analyzed with IMPACT, 24 had mucinous adenocarcinoma, 3 adenocarcinoma with signet ring, 7 adenocarcinoma ex goblet cell carcinoid, 3 invasive adenocarcinoma. In total 159 alterations were identified with a median 4.2 alterations/patient (range 0-10). Alterations were seen most commonly in KRAS (21/37), GNAS (12/37), TP53 (10/37), SOX9 (5/37), and SMAD4 (4/37). Potentially treatable alterations were present in 15% of patients and included BRAF V600E (1), MTOR (2), ERBB2 (1) and NTRK(2). Of the total 97 pts, 50 (52%) were RAS/BRAF wt. Of those,13 evaluable patients received anti-EGFR therapy with either panitumumab or cetuximab. There were no responders. Conclusions: Mutational sequencing in AAC indicates that 16% have mutations in genes such as BRAFV600E, MTOR, ERBB2 and NTRK with the potential to expand investigational options through increased access to trials of selectively targeted agents. Additionally, in RAS/BRAF wt pts, panitumumab/cetuximab does not appear to have therapeutic efficacy comparable to historic controls in RAS/RAF wt CRC.