Background: That tumor heterogeneity exists and evolves over time is well appreciated but how often to biopsy patients’ metastatic BC is not well established. Methods: Immunohistochemical (IHC) and in situ hybridization (ISH) analysis of estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), and HER2 in 337 cases with > 1 asynchronous primary/metastatic BC molecular profiles and in 40 cases with > 1 synchronous molecular profiles was performed at a single institution. We evaluated differences in ER, PR and HER2 status in same or contralateral breast, and in primary vs. locally recurrent or metastatic BC’s. Results: We identified a change in ER or HER2 status in 8 (31%) synchronous BCs and in 55 (16%) primary/recurrent BCs, including in biopsies of distinct tumor foci within the same breast or metastatic organ site. Of the 8 synchronous bilateral primary BC’s, 4 (50%) had discordant ER results (ER, PR, and HER2 negative [TN] vs. ER+); 5 of 18 (28%) with two or more metastatic foci tested within the same organ had discordant ER results; 23% of BCs with biopsies of different organ sites had discordant ER results. Of the 55 paired primary/metastatic BCs, 15% of the discordant findings were in cases with biopsies from two different metastatic sites, 19% were in cases with one metastatic and one primary or local recurrent biopsy, and 23% were from 2 primary biopsies or from primary and locally recurrent disease. Discordance was bidirectional from either TN to ER+ or ER+ to TN, and independent of discordance in HER2. Conclusions: Standard systemic treatment of BC relies on reliable assessment by IHC analysis of ER, PR, and HER2. Within a patient, ER and HER2 status are not always concordant between lesions within the same breast, between bilateral BCs, and between distinct foci in a metastatic organ site. Patients are at risk of not being treated for the most clinically important foci of BC if the biopsy(s) obtained are not representative of the more aggressive areas of disease. Profiling should be performed on multiple BC samples both at diagnosis and at each time of recurrence/progression in the cancer continuum, to more accurately reflect the tumor profile at the time of treatment.