© 2020, The Author(s), under exclusive licence to United States & Canadian Academy of Pathology. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status provide clinical utility in guiding therapeutic decision-making in metastatic breast cancer (BC). Increasing data have shown substantial differences between the receptor profiles of primary BCs and their paired metastases. In this study, we provide a large single center cohort to assess the frequency of receptor conversion in metastatic BC. The overall discordant rates were 18.3%, 40.3%, and 13.7% for ER, PR, and HER2, respectively. The discordance was significantly higher for PR when compared with ER and HER2. The conversion occurred significantly as a switch from positive to negative receptor status when compared with that from negative to positive for all three receptors. Semiquantitative analyses revealed a significantly decreased expression of both ER (25%) and PR (57%) in the metastases. There was a higher rate of PR discordance in bone metastases when comparing to other common organs of relapse. Furthermore, in the subset of patients with a single primary and multiple distant metastases, the discordant rates among the distant sites were 27.5%, 39.4%, and 14.3% for ER, PR, and HER2, respectively. A positive ER status, be it in primary or metastatic BC, was associated with a prolonged metastasis-free survival when compared with ER-negative primary tumors without conversion. Furthermore, a positive ER status in metastatic BC regardless of primary was associated with a superior overall survival when compared with an ER-negative tumor without conversion. Thus, receptor conversion is a frequent event in the course of BC progression, and can also be seen between different metastatic sites. Moreover, some conversions are of prognostic significance. The findings may reflect tumor heterogeneity, sampling or treatment effect, but may also indicate alteration in tumor biology. Repeat biomarker testing is warranted in making appropriate treatment plans in the pursuit of precision medicine.