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
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.