Background: The ability to perform multiple genomic tests on metastatic (met) bx may enable cancer research and precision medicine. Questions remain about feasibility of obtaining multiple met cores, usability of met bx for genomics, and utility of genomic profiling for identifying relevant targets. Methods: We developed a prospective bx protocol where multiple research bx are collected from mets and used for: pathology; ER/PR/HER2; OncoPanel, a CLIA 300 gene sequencing (seq) panel; whole exome seq (WES); transcriptome seq (RNA-seq); and single-cell RNA-seq (sc-RNA-seq). In some cases, tissue is used for cell line and xenograft generation. Archival primary bx is obtained when possible for parallel genomic studies. Patients (pts) are followed and serial bx obtained. Cell free DNA (cfDNA) is collected at time of biopsy and serially. Results: We obtained 51 met bx from 49 pts. 6 cores were taken per bx on avg (range 1-12). The number of bx with sufficient material for each test and success rates is shown in the Table. cfDNA was collected at 88 timepoints from 46 pts. In 2/51 bx, pathology found a tumor type other than breast cancer. Of the remaining 49, 12% changed ER or HER2 status. Of pts w OncoPanel data, 37.5% had ESR1 LBD mutations, 50% PIK3CA mutations, 16% ERBB2 mutations, and 3% FGFR1 amplifications. Overall, 75% had alterations in at least one of these genes, which are criteria for trials at our institution. Many pts had alterations in genes involved in resistance to therapies in preclinical studies (RB1, MYC, CCND1, NF1). Conclusions: A met bx program for cancer precision medicine is feasible, with ~90% of bx yielding sufficient tissue for pathology, receptors, CLIA targeted sequencing, WES, and RNAseq. Met bx have clinical implications, identifying a different cancer (4%), different targetable receptors (12%), and specific trials (>75%). For many genes, the mutational landscape differs significantly from primary breast cancer—highlighting the value of met bx.