New stars in the sky of treatment for early breast cancer.

Since Sir George Beatson observed in 1896 that breast tumors in premenopausal women sometimes regressed after oophorectomy, 1 numerous investigations have established that estrogen stimulates the growth of breast-cancer cells. Three newer strategies reduce the growth-stimulating signals of estrogen: interfering with the binding of estrogen to its receptor, the primary mode of action of the antiestrogen agent tamoxifen in premenopausal and postmenopausal women; decreasing the estrogen levels in the blood and the tumor, the mechanism of action of aromatase inhibitors in postmenopausal women; and destroying the estrogen receptor, which is how the drug fulvestrant exerts its antitumor activity. During the course of the clinical development of these antiestrogen strategies, we have learned four major lessons. First, they work only in hormone-receptor–positive tumors, which account for two thirds of breast cancers. Second, cross-resistance can be circumvented in advanced disease (e.g., tamoxifen-resistant tumors are generally not resistant to aromatase inhibitors). Third, as adjuvant treatment, tamoxifen has had unprecedented success in reducing breast-cancer–related mortality worldwide. Finally, tamoxifen, and probably the other agents, can prevent breast cancer. 2