In contrast, in the absence of TP53 mutation, acquired ESR1 mutations may play a predominant role under the selective pressure of endocrine therapy, particularly aromatase inhibitors that block production of estrogen, giving rise to ESR1 mutation-enriched metastatic lesions in approximately 30% of ER + metastatic breast cancers (Fig. 6). Here, ESR1 is linked to breast carcinoma.