Multiple ESR1 gene fusions have been recently identified in estrogen receptor alpha–positive (ERα⁺) metastatic breast cancer (depicted by the Circos plot). Active ERα fusion proteins enter the nucleus (depicted by the immunofluorescence) and drive estrogen-independent transcription of estrogen response and epithelial-to-mesenchymal transition genes (depicted by the heatmap), which form a diagnostic 24-gene signature (depicted by the ROC curve). This signature accurately diagnosed the presence of active ESR1 fusions and mutations expressed in ERα⁺ patient-derived xenografts and metastatic breast cancer patients. For details, see the article by Gou and colleagues on page 6259.