Since the discovery of ER as a predictive biomarker of response to ET,9 the use of hormone therapy has significantly reduced breast-cancer-related mortality.119 However, despite being administered in the adjuvant setting to eliminate MRD and prevent metastatic relapse (Fig. 4, part Ic), up to 30% of HR+ tumours eventually develop mechanisms of resistance to ET.120 In addition, accumulating evidence has suggested that ET largely induces cytostatic effects, blocking proliferation and forcing cells to enter a dormancy state, rather than killing DTCs121–124 (Fig. 4, part IId). This evidence concerns the gene ESR1 and neoplasm.