Antiestrogens: Past, Present, and Future

Within the last 25 years, laboratory research on estrogen receptorsand the development of the antiestrogen tamoxifen has dramatically refinedand expanded the role of hormonal therapy in the treatment of breast cancer.An assessment of antiestrogens and their role in breast cancer therapyclinical practice was the focus of a roundtable symposium entitled "Antiestrogens:Past, Present, and Future," held in July 1996. The articles compiledin this supplement detail the discussions at the meeting of significantissues related to antiestrogen therapy, including patient selection, durationof treatment, secondary effects, and development of new antiestrogeniccompounds.

The first article documents the development of our understanding ofthe mechanisms of hormonal therapy and traces the development of the antiestrogentamoxifen citrate from the laboratory bench to its acceptance as primaryand adjuvant treatment for breast cancer patients. Even with years of experienceand an extensive clinical database for humans, several parameters relatedto the use of tamoxifen still need definition. Specifically, Nicholas Robertexamines the clinical data pertaining to the administration of tamoxifenin combination with chemotherapy, receptor status, patient selection, andduration of tamoxifen therapy.

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

Effects on the Endometrium

The possible association of tamoxifen with endometrial carcinoma hasbeen publicized recently and warrants a careful interpretation of the data.Robert Morgan reviews the clinical studies reporting an association betweentamoxifen and endometrial cancer, discussing the biases inherent in thestudies and the potential for confounding variables. Endometrial effectsare further explored by Richard Barakat, who examines expected changesin the endometrium associated with tamoxifen treatment and recommendedroutine gynecologic testing for patients taking tamoxifen.

The significance of studies of animals receiving tamoxifen and theirrelevance to human use is reviewed by James Swenberg, who discusses speciesdifferences in the metabolism of tamoxifen and in the formation of DNAadducts. He concludes that the known species-related differences make animaldata less than useful in predicting events in humans, particularly in viewof the broad clinical database on the use of tamoxifen in humans, whichindicates the lack of related effects.

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

The Question of Compliance

The benefits and risks of tamoxifen treatment must be communicated directlyand honestly to patients. When patients are informed, compliance with therapyimproves and positively impacts their quality of life. The participantsdiscussed tamoxifen treatment in relation to known side effects and theirsignificance in counseling patients. John Glick discusses tamoxifen treatmentfrom the perspective of the practicing oncologist, and Bonnie Reichmanpresents the concerns frequently expressed by patients.

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

The 7.5 million woman-years of laboratory and clinical experience withtamoxifen have contributed to its status as the "gold standard"hormonal treatment for women with breast cancer. The clinical databasecontinues to expand as ongoing laboratory and clinical investigations areadded that support the safety and efficacy of tamoxifen in breast cancerpatients, both as primary therapy and adjuvant treatment. With our increasedunderstanding of the benefits and risks of tamoxifen, physicians and patientscan make well-informed decisions and feel comfortable with the use of thisagent in the management of the disease.