The metabolic differences described have been exploited by targeting the priming step of glycolysis (i.e., HK2) and glycolytic dependencies in different contexts thus suggesting that targeting glucose metabolism may be more effective in the sensitive setting in the ER+/HER2− subset while it can re-sensitize ER+/HER2+ PDR breast cancers to the initial therapy. This evidence concerns the gene ESR1 and breast cancer.