Mutations of the ESR1 gene have been increasingly recognized as an important mechanism of endocrine therapy resistance, with a prevalence that ranges from 11 to 39%. The majority of these mutations are located within the ligand-binding domain, especially codon 537 and 538, and result in an estrogen-independent constitutive activation of the ER and, therefore, resistance to estrogen deprivation therapy such as aromatase inhibition.