Discordances between hormone receptors and HER2 status in primary and metastatic breast cancer have been reported by several studies. In this context, systematic biopsies could be clinically relevant in breast cancer to confirm the biological characteristics of a suspicious lesion. In this article, illustrated by 2 case reports and based on a recent review on this topic, we discuss the clinical significance of receptor discordances and possible diagnosis of a secondary primary tumor. The role of these biopsies for the identification of new therapeutic targets is also envisaged as well as underlying mechanisms for receptors' modification like tumoral heterogeneity, clonal selection and technical artifacts.