New hormonal approaches to the treatment of breast cancer.

From this data we can draw several conclusions. Although many new hormonal agents have been developed, there has not been significant improvement in tumor response to single agents over the past several decades. By applying knowledge of tumor ER and PR patient populations can be selected which will have a higher response rate to a given hormonal agent. The approach of combining chemotherapy and hormonal therapy does not appear to significantly alter the course of the disease. Sequential use of Tamoxifen, Premarin, and chemotherapy has been shown in cell lines and animal models to synchronize cells thus increasing the efficacy of chemotherapy. Clinical trials of this synchronization generally show higher response rates including significantly higher CR rates than chemotherapy alone. This approach appears promising and is undergoing further trials. LHRH agonists and tamoxifen are effective in premenopausal women with receptor positive tumors and may replace surgical ablative therapy. Aminoglutethimide is gaining wider acceptance as second-line therapy in postmenopausal ER-positive patients. The new agent 4-OHA may be as effective as AG but with fewer side effects. Toremifine a new antiestrogen and RU486 a new antiprogesterone are undergoing trials. While these new agents appear promising with fewer side effects or greater specificity of action, with the exception of sequential hormone priming/chemotherapy they represent 'the same old approach'. By this we mean manipulation of the hormonal environment of the cell in a continuous fashion acting via the estrogen receptor mechanism to achieve tumor regression. While certain new agents may be more tolerable, it is unlikely that a 'break through' will occur with this approach. The problem is the emergence of cells resistant to hormonal therapy. This occurs either through proliferation of a preexisting resistant clone or development under selective pressure of resistant tumors. Some but not all of these resistant clones have escaped by virtue of not having estrogen receptor present. Others have defects further along the action cascade of estrogen stimulation, such as a defective receptor which cannot bind effectively to the nuclear acceptor sites, or lacking certain other growth factors such as TGF-beta. Whatever the deficit, most patients eventually develop resistant tumors. It is in this direction, toward manipulating later points in the estrogen cascade which our attention should turn to achieve more effective hormonal therapy.