Background: ER-PR+Her2- breast cancer is a rare subtype occurring at approximately 1% of all breast carcinomas. Most of these cancers behave in an aggressive fashion with limited benefit from anti estrogen therapy, similar to triple negative breast cancer (TNBC). Better characterization of these tumors is needed for predicting clinical behavior, response to endocrine therapy, and eligibility for clinical trials. Here we sought to evaluate the mutational profile of a well curated set of ER-PR+HER2- metastatic breast cancers and compare to other receptor phenotypes. Methods: 2049 consecutive breast cancers submitted to Foundation Medicine for comprehensive genomic profiling (CGP) were included. ER, PR and HER2 expression were abstracted from submitted pathology reports. Cases without complete ER, PR and HER2 information in pathology reports were excluded. CGP was performed as previously described (Frampton, 2013). Results: Patient ages were similar across subgroups. Generally, ER-PR+HER2- tumors were rare (n = 23, 1.1%) and most similar to TNBC in their genomic profiles. These tumors harbored high rates of TP53 and BRCA1 alterations and low rates of PIK3CA, ESR1, and CDH1 alterations. Genomic loss of heterozygosity (gLOH) was similar in the ER-PR+HER2- and ER+PR+HER2-subtypes (8.18% and 8.66% respectively), and lower than TNBC (17.19%). Notably, a high rate of RB1 alterations were identified in the ER-PR+HER2- patients (13%, 3/23), numerically higher than the other subtypes. EGFR, MET, PTEN, CDKN2A and KRAS alterations were also observed at a higher frequency in ER-PR+Her2- cancers (8.7, 4.2, 39.1, 13.0 and 13.0% respectively) relative to the other subtypes. IO drug biomarkers including MSI, TMB and PD-L1 IHC were similar among the groups. Conclusions: The mutational profile for ER-PR+Her2- metastatic breast cancer more closely resembles TNBC than ER+ breast cancer. These data suggest molecular profiling may be a useful adjunct to optimize treatment strategies for this rare subset of cancers. Based on molecular characteristics, we recommend including ER-PR+Her2- patients in clinical trials for TNBC. Finally, genes including RB1, CKDN2A, PTEN, EGFR and MET are mutated at higher frequency in ER-PR+Her2- cancers than other subsets, suggesting unique biology with potential therapeutic implications.