Changes of Y537 to cysteine (Y537C), asparagine (Y537N) or serine (Y537S) and D538 to glycine (D538G), represent the most common mutations identified in patients and functional studies in breast cancer cell lines have confirmed earlier findings of estrogen-independent activity and reduced sensitivity to selective estrogen receptor modulators (SERMs), such as tamoxifen, as well as selective estrogen receptor downregulators (SERDs) like fulvestrant [7–9, 13, 23, 24]. This evidence concerns the gene ESR1 and breast carcinoma.