Background: Relapsed/metastatic TNBC is an aggressive form of the disease that typically responds initially to chemotherapy, but eventually progresses in the majority of patients (pts). We hypothesized that a comprehensive NGS assay (FoundationOne) could identify novel therapy targets not routinely interrogated in TNBC pts. Methods: Hybridization capture of 3,769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to ≥ 50 ng of DNA extracted from 26 TNBC FFPE specimens and sequenced to high, uniform coverage. Genomic alterations (GA) including base substitutions, small indels, copy number alterations, and select gene fusions, were characterized and reported for each pt sample. Actionable GAs were defined as those identifying anti-cancer targeted therapies on the market or in registered clinical trials. Results: The 26 TNBC pts had a mean age of 49.6 yrs (range, 28-74). All 26 tumors were ER-/PR-/HER2- on routine slide-based testing. Samples used for NGS originated from breast (42%), lymph nodes and axilla (23%), chest wall and muscle (12%), skin (8%) and serous effusion (4%). All 26 cases harbored ≥1 GA, with a total of 113 GAs and a mean of 4.35 GAs per tumor. The most frequent currently unactionable GAs were TP53 (21, 81%) and MYC (8, 31%). Twenty two cases (85%) harbored ≥1 actionable GA; mean, 2.73 actionable GAs per tumor. The most common actionable GAs were PIK3CA (7, 27%), MCL1 (4,15%), PTEN (3,12%), BRCA1 (3,12%), and BRCA2 (2,8%). One pt (4%) had ALK amplification. Activating ERBB2 point mutations not detectable by IHC/FISH, potentially targetable with anti-HER2 therapies were identified in 2 pts; EGFR amplifications, potentially treatable with anti-EGFR TKI were identified in 2 pts (1 pt had both of these GAs). One pt with ERBB2mutation received neratinib monotherapy and one pt with EGFR amplification received capecitabine plus cetuximab; both had partial response lasting 8+ months. Conclusions: For TNBC, comprehensive genomic profiling can identify a significant number of actionable GAs not currently tested for in routine practice. Results point to the potential of MTOR, anti-HER2, and anti-EGFR targeted therapies for a significant subset of pts.