After a failed development as a contraceptive, tamoxifen was reborn as a therapy for estrogen-driven breast cancer with an FDA approval in 1977.63,87 The efficacy of DES therapy in postmenopausal women with metastatic breast cancer was comparable to or higher than that of tamoxifen (response rates, 41% versus 33%),84 yet tamoxifen was more tolerable.83–85 E2 treatment results in growth arrest and apoptosis in estrogen-deprived cultured ER-positive breast cancer cells and may thus explain its therapeutic effect.86,88. This evidence concerns the gene ESR1 and breast cancer.