Background: Genomic profiling of primary and recurrent metastatic breast cancer (rMBC) has revealed potential resistance mechanisms to therapy. In contrast, de novo stage IV breast cancer (DNIV) represents an opportunity to elucidate metastatic drivers in the absence of treatment selection. Methods: Targeted NGS (Oncopanel, OP) using multiplexed copy number variation (CNV) and mutation (mut) detection across the full coding regions of 300 genes and selected intronic regions of 35 genes was performed on either primary or metastatic samples collected in patients (pts) with DNIV or rMBC. Mut/CNV in primary and metastatic tumors were compared per subtype between DNIV and rMBC using Fisher´s exact test (significant p<0.05). FDR were computed (q<0.25). Results: Between 8/2013-9/2016, of 929 pts who underwent OP testing 212 presented with DNIV; 136 HR+/HER2- (64%); 35 HR+/HER2+ (17%); 25 TNBC (12%); 16 HR-/HER2+ (8%). In 168 (79%) pts, the primary was tested; 44 had a metastatic site tested. Comparison of primary HR+/HER2- tumors showed that DNIV pts were more likely to harbor mut in CDKN1B, SETD2 and PMS2 and less likely to have TP53 mut than rMBC (Table). Metastases in HR+/HER2- DNIV (n=29) had higher mut in CDH1, PTCH1 and CTNNB1 and fewer CCND1 amplification (amp) than rMBC (n=121), albeit these findings lost significance after FDR correction. DNIV primary TNBC (n=19) was significantly enriched for CIITA mut (26% vs. 0%; q=0.046) and MYB amp (21% vs. 0%, q=0.098) compared to rMBC (n=101). TP53 mut, amp in RAD21, MYC, MYB, PTK2 and EGFR, and deletions in CDKN2A/2B and MAP2K4 significantly predicted poorer overall survival in DNIV. Conclusions: DNIV primary and metastatic tumors have distinct genomic profiles compared to rMBC. Alterations in genes involved in epigenetic modulation (KMT2D, SETD2) and epithelial-mesenchymal transition (CDH1,PTCH1, CTNNB1) are more prevalent in HR+/HER2- DNIV. DNIV TNBC is enriched for CIITA mut, described to promote immune escape via reduced MHC class II expression. If validated, these findings may provide insight into mechanisms underlying metastatic potential.