Background: The tropomysin receptor kinase A family includes the 3 NTRK1, NTRK2 and NTRK3 genes and plays major roles in neuronal development. The recent evidence of remarkable efficacy for kinase inhibitors (TKI) targeting NTRK across a wide variety of malignancies that harbor NTRK gene fusions has stimulated great interest in determining the type of cancers driven by these therapy defining NTRK genomic alterations. Methods: A consecutive series of 12,214 locally aggressive, relapsed and metastatic breast malignancies (mBM) were subjected to comprehensive genomic profiling (CGP) using DNA extracted from 40 µm of FFPE sections and adaptor ligation-based libraries to a mean coverage depth 719X for up to 315 cancer-related genes. The results were analyzed for all classes of genomic alterations (GA) including base substitutions, insertions and deletions, select fusions and rearrangements, and copy number changes. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA. Microsatellite instability (MSI) status was calculated by a customized algorithm. Results: 16 (0.13%) mBM (all female) harbored NTRK gene fusions. The median age was 51 years (range 34 to 70 years). There were 9 ductal carcinomas, 2 lobular carcinomas, 3 secretory carcinomas 1 metaplastic carcinoma and 1 angiosarcoma. Tumor stages at the time of sequencing were 12 Stage IV, 1 Stage III and 3 stage I (all 3 secretory carcinomas). In 9 cases, clinical receptor status was known: 3 (33%) were ER+/HER2- and 6 (66%) ER-/HER2- (all TNBC) with all 9 (100%) of cases HER2-. All 3 SCA were TNBC. 10 NTRK fusions involved NTRK1 featuring a variety of fusion partners (CGN, GATAD2B, LMNA, MDM4, PEAR1, and TPM3) and 6 involved NTRK3 (all ETV6 fusions). There were no NTRK2 fusions. NTRK fusion+ mBM featured a mean of 4.25 GA per sample. The most frequent non-fusion partner co-altered genes in this series of NTRK fusion+ mBM were: TP53 at 25%, IKBKE, PIK3C2B CCND1 at 19%, and AKT, PIK3CA, MYC, CDH1, CDKN2A, PTEN, FGF3, FGF4 and FGF19 all at 13%. The median TMB for NTRK fusion+ mBM was 0.9 mutations/Mb and no cases (0%) had a TMB > 10 mutations/Mb and no cases (0%) feared high microsatellite instability (MSI high). Clinical response assessment to NTRK TKI therapies in this series is ongoing. Conclusions: NTRK gene fusions although extremely uncommon in breast malignancies occur across a variety of tumor types, is universally HER2 negative, more frequent in TNBC than in ER+ tumors, is associated with a moderate frequency of additional genomic alterations and a complete absence of either high TMB or high MSI. This study confirms that a CGP assay, when applied to a large cohort of near universal clinically advanced disease can identify extremely rare alterations that can lead a small number of patients to highly effective precision therapies. Citation Format: Ross JS, Chung J, Elvin JE, Vergilio J-A, Ramkissoon S, Suh J, Severson E, Daniel S, Frampton GM, Fabrizio D, Hartmaier RJ, Albacker LA, Ali SM, Schrock AB, Miller VA, Stephens PJ, Gay LM. NTRK fusions in breast cancer: Clinical, pathologic and genomic findings [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-15.