Background: AGC represents the third leading cause of cancer related deaths. Chemotherapy for AGC is active but still of limited efficacy and targeted agents Trastuzumab and Ramucirumab have shown modest activity. Expanded molecular profile may provide critical information on druggable molecular aberrations and treatment options for these patients (pts). Methods: From 11/2010 to 11/2014, 101 pts with AGC underwent genetic/proteomic tumor profiling as part of the VHIO Phase I Trial Molecular Prescreening Program. Detection of mutations (mt) was performed with Multiplex-Single base extension followed by Mass-spect detection (Sequenom) or NGS (Amplicon-seq) (Illumina). Immunohistochemistry was used to assess HER2, PTEN and PDL1 expression. Amplification of HER2, PIK3CA, FGFR1, FGFR2, and METwere analyzed by in situ hybridization. Results: Median age of pts was 59-year, 66% men. Median prior treatment lines were 3 (1-6). Median overall survival was 18 months. As expected, HER2 was deregulated in 20%. PIK3CA mt and PTEN low expression were respectively found in 9% and 30%, with one pt harboring both molecular alterations. KRAS mt were found in 5%. PIK3CA, KRAS, FGFR4 and MSH6 mt coexisted in one pt. Amplification in FGFR2 (5%), MET (2%), and PIK3CA (1%) were also detected. One pt harbored amplification in 10 genes implicated in receptor tyrosine kinase- and cell cycle- pathways. PDL1 was positive in 6%; PIK3CA mt and PDL1 overexpression coexisted in 3%, ARID1A and SMAD4 also coexisted in another pt. Twenty-seven pts (27%) were treated with targeted therapies according to their molecular profile, with modest efficacy. Conclusions: Our molecular data is consistent with TCGA data. Pts. with AGC considered for genetic/proteomic tumor profile seem to derive benefit from this expanded characterization and treatment in phase I/II clinical trials with targeted agents.