Background: The genomic landscape of female breast cancer is rapidly evolving partially owing to advancements in next generation sequencing (NGS). Here we report the genomic characteristics of female breast cancer patients with locally recurrent inoperable and metastatic disease. Methods: IRB approval was obtained for a retrospective analysis of archived pathology on patients treated at Cancer Treatment Centers of America. Comprehensive genomic profiling of tumors was derived from Foundation One (F1) and Guardant 360 NGS. Clinical information was derived from retrospective chart review. Inclusions: adult females with breast cancer with stage IV metastatic disease or locally recurrent inoperable disease. Exclusions: Males, missing genomic and pathologic information. Results of clinical, pathologic, and genomic data were summarized. Results: 1788 patients met study criteria. Median age: 48 yrs., range 20-79 yrs. Race: Caucasian 1029/1788 (58%), African American 582/1788 (32%), Hispanic 77/1788 (4%), Asian 26/1788 (1%), other 73/1788 (4%). Receptor status: Hormone receptor ER(+) &/or PR(+) 950/1788 (53.1%); Triple negative 390/1788 (21.8%); HER2(+) 205/1788 (11.5%); missing/incomplete: 243/1788 (13.6%). Ki-67 status: High 548/705 (77.7%)/Low 57/705 (8.1%)/Intermediate (INT) 100/705 (14.2%). PD-L1 status: PD-L1(-) 346/544 (63.6%)/ PD-L1(+) 179/544 (32.9%)/PD-L1 (indeterminate or QNS) 19/544 (3.5%). NGS test total (1984 tests): F1 1023/1984 (52%), F1 CDx 703/1984 (35%), F1 Act 91/1984 (6%), F1 Liquid 82/1984 (6%), Guardant 360 85/1984 (4%). Biomarkers (1096 results): Microsatellite Instability (MSI) High 4/1096 (0.3%), MSI- Intermediate (INT) 2/1096 (0.1%), MS-stable 1017/1096 (93%), Cannot be determined (CBD) 73/1096 (7%). Tumor Mutation Burden (TMB) (842 results): TMB high 22/842 (3%), TMB INT 233/842 (28%), TMB low 513/842 (61%), CBD 74/842 (9%). Genomic abnormalities (% alterations per patient): TP53 999/1783 (56.03%), PIK3CA 610/1783 (34.21%), MYC 425/1783 (23.84%), CCND1 318/1783 (17.84%), FGF19 298/1783 (16.71%), FGF3 296/1783 (16.60%), FGF4 293/1783 (16.43%), ESR1 266/1783 (14.92%), FGFR1 276/1783 (15.48%), PTEN 239/1783 (13.40%), ZNF703 251/1783 (14.08%), ERBB2 218/1783 (12.23%), GATA3 178/1783 (9.98%), CDH1 165/1783 (9.25%), RAD21 157/1783 (8.81%). Pathway defects (expressed as total % of alterations): Alterations in FGF genes 10.64%, mTOR pathway 8.36%, HHR pathway 3.17%. Conclusions: Female breast cancer patients display a heterogeneous variety of complex genomic alterations. Mutations in FGF genes were most common. The single most common alteration was in TP53. Other common alterations include PIK3CA, MYC, CCND1, and ESR1.