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Background: The molecular characterization of primary breast cancers has led to signatures identifying risk of future metastasis and survival; however the underlying biology driving metastasis development is largely unknown. Methods: Utilizing a Rapid Autopsy Program, we have collected 61 metastatic breast cancer tumors from 7 individuals (4 triple negative, 2 HER2+, 1 ER+/HER2-) including primary tumors and 3-6 metastases/patient. We performed mRNA and DNA exome sequencing. We next used DawnRank, a novel network-based method that integrates DNA and RNA data to identify computationally determined "driver" genes (i.e. a DNA variant that significantly alters its gene expression-network) in each individual sample. Phylogenetic tree and clonal analysis were also performed, with the computationally determined drivers mapped onto these trees. Results: The breast cancer primaries were molecularly subtyped as 5 Basal-like, 1 HER2-Enriched, and 1 Luminal A; in all cases, the metastases clustered immediately adjacent to their primary tumor by hierarchical clustering analysis. Widespread DNA copy number alterations identified in the primary tumors were typically maintained throughout metastasis. On average, 1.9 ± 1.3% of DNA copy number altered genes, and 2.4 ± 0.95% of the somatic mutations per tumor were identified as "drivers" by DawnRank. There were an average of 199 ± 72 total drivers per tumor due to copy number alterations (amplifications or deletions) and 12 ± 23 drivers per tumor from somatic mutations. Phylogenetic tree analysis demonstrated that the majority of DNA copy number events occurred early in tumor development. Founding clones were defined as genetic events present in the primary and all matched metastases. Chr5q13 loss and TP53 mutation were the only consistent alterations in the founding clones of all 7 patients. Drivers on chr5q13 identified in this cohort include CCNB1, CDK7, and TAF9. Among the basal-like patients, all 5 patients' TP53 mutations were identified as a driver by DawnRank. 39% and 20% of drivers from copy number gains and losses, respectively, were identified in the primary tumor, while another 34% and 30% were not seen in the primary but were present in more than 1 metastasis within each patient. Metastasis-enriched copy number drivers not seen in any primary included FLT1, MAP2KR, and ARNT. 38% of the drivers resulting from somatic mutations were established in the primary and maintained in metastases. Of the remaining drivers from somatic mutation, only 18% were shared among metastases but not seen in the primary while 47% were not seen in any other tumor within a given patient (i.e. private to a single sample). TP53, PSEN1, CDC27, HDAC1, and BRCA1 were somatic mutation drivers established early in metastatic development, while CCNH was a consistent late driver. Conclusions: We present a novel computationally determined genetic "driver" analysis of matched breast cancer primaries and multi-organ metastases. In this cohort, our results suggest that most genetic drivers in a single tumor are based on copy number aberrations, are established early, and are maintained in metastases. In contrast to copy number, drivers from somatic mutations are acquired later, and most of the metastases continued to acquire new genetic driving features. Citation Format: Siegel MB, He X, Chen M, Hou JP, Garrett AL, Dye JB, Silva GO, Usary JE, Moylan VJ, Brady CM, Ma J, Thorne LB, Hoadley KA, Parker JS, Anders CK, Carey LA, Perou CM. Identification of early versus late drivers of breast tumors and metastasis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S4-01.