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Antiestrogens: Past, Present, and Future

Antiestrogens: Past, Present, and Future

Within the last 25 years, laboratory research on estrogen receptors and the development of the antiestrogen tamoxifen has dramatically refined and expanded the role of hormonal therapy in the treatment of breast cancer. An assessment of antiestrogens and their role in breast cancer therapy clinical practice was the focus of a roundtable symposium entitled "Antiestrogens: Past, Present, and Future," held in July 1996. The articles compiled in this supplement detail the discussions at the meeting of significant issues related to antiestrogen therapy, including patient selection, duration of treatment, secondary effects, and development of new antiestrogenic compounds.

The first article documents the development of our understanding of the mechanisms of hormonal therapy and traces the development of the antiestrogen tamoxifen citrate from the laboratory bench to its acceptance as primary and adjuvant treatment for breast cancer patients. Even with years of experience and an extensive clinical database for humans, several parameters related to the use of tamoxifen still need definition. Specifically, Nicholas Robert examines the clinical data pertaining to the administration of tamoxifen in combination with chemotherapy, receptor status, patient selection, and duration of tamoxifen therapy.

The estrogenic and antiestrogenic characteristics of tamoxifen contribute to a unique risks/benefits profile. Vasilios Assikis highlights the documented benefits of tamoxifen (decreased incidence of contralateral breast cancer and maintenance of bone mineral density and low lipid levels) and considers the potential risks that need to be considered in deciding treatment options.

Effects on the Endometrium

The possible association of tamoxifen with endometrial carcinoma has been publicized recently and warrants a careful interpretation of the data. Robert Morgan reviews the clinical studies reporting an association between tamoxifen and endometrial cancer, discussing the biases inherent in the studies and the potential for confounding variables. Endometrial effects are further explored by Richard Barakat, who examines expected changes in the endometrium associated with tamoxifen treatment and recommended routine gynecologic testing for patients taking tamoxifen.

The significance of studies of animals receiving tamoxifen and their relevance to human use is reviewed by James Swenberg, who discusses species differences in the metabolism of tamoxifen and in the formation of DNA adducts. He concludes that the known species-related differences make animal data less than useful in predicting events in humans, particularly in view of the broad clinical database on the use of tamoxifen in humans, which indicates the lack of related effects.

Secondary effects of tamoxifen contribute to both benefits and risks that can clearly impact a patient's quality of life, as indicated by Joseph Ragaz. In turn, quality of life may have an effect on prolonging overall and disease-free survival in patients with breast cancer because of effects on compliance. Dr. Ragaz evaluates the primary and secondary effects on survival by examining the impact of tamoxifen on contralateral breast cancer, cardiovascular events, uterine cancer, and thromboembolic episodes in order to provide a perspective on the absolute risks and benefits.

The Question of Compliance

The benefits and risks of tamoxifen treatment must be communicated directly and honestly to patients. When patients are informed, compliance with therapy improves and positively impacts their quality of life. The participants discussed tamoxifen treatment in relation to known side effects and their significance in counseling patients. John Glick discusses tamoxifen treatment from the perspective of the practicing oncologist, and Bonnie Reichman presents the concerns frequently expressed by patients.

Finally, Anthony Howell reports on other antiestrogenic compounds currently in development or in clinical trials.

The 7.5 million woman-years of laboratory and clinical experience with tamoxifen have contributed to its status as the "gold standard" hormonal treatment for women with breast cancer. The clinical database continues to expand as ongoing laboratory and clinical investigations are added that support the safety and efficacy of tamoxifen in breast cancer patients, both as primary therapy and adjuvant treatment. With our increased understanding of the benefits and risks of tamoxifen, physicians and patients can make well-informed decisions and feel comfortable with the use of this agent in the management of the disease.

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