V. Craig Jordan, OBE, PhD, DSc

Victor Vogel’s excellent review of the clinical basis for preventing breast cancer in high-risk women demonstrates the significant advances that have been made through the clinical trials mechanism. However, it is the progress in deciphering the link between hormones and the development and growth of breast cancer that is the true success story in this setting.

The Study of Tamoxifen and Raloxifene (STAR) compared and contrasted the efficacy and side effects of tamoxifen, the established agent, with raloxifene (Evista)—a medicine that is currently used for the prevention of osteoporosis in high-risk postmenopausal women, but also reduces the incidence of breast cancer.

Twenty years ago, antiestrogen therapy with tamoxifen played only a secondary role in breast cancer care. All hopes to cure metastatic breast cancer were still pinned on either the discovery of new cytotoxic drugs or a dose-dense combination of available cytotoxic drugs with bone marrow transplantation. A similar strategy with combination chemotherapy was employed as an adjuvant for primary breast cancer. Simply stated, the goal was to kill the cancer with nonspecific cytotoxic drugs while keeping the patient alive with supportive care. However, medical research does not travel in straight lines, and an alternative approach emerged to solve the problem of controlling tumor growth with minimal side effects: targeted therapy. The approach of using long-term antihormone therapy to control early-stage breast cancer growth would revolutionize cancer care by targeting the tumor estrogen receptor (ER). The success of the strategy would contribute to a decrease in the national mortality figures for breast cancer. More importantly, translational research that targeted the tumor ER with a range of new antiestrogenic drugs would presage the current fashion of blocking survival pathways for the tumor by developing novel targeted treatments. But a surprise was in store when the pharmacology of "antiestrogens" was studied in detail: The nonsteroidal "antiestrogens" are selective ER modulators—ie, they are antiestrogens in the breast, estrogens in the bone—and they lower circulating cholesterol levels. This knowledge would establish a practical approach to breast cancer chemoprevention for women at high risk (tamoxifen) and low risk (raloxifene).

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.

Tamoxifen is currently the endocrine treatment of choice for all stages of breast cancer and is the gold standard for antiestrogen treatment. Over the last 25 years, the drug has revolutionized breast cancer therapy. The extension of the use of this agent has occurred because of open dialogue between the laboratory and the clinic, in which laboratory findings led to extension of clinical use. Tamoxifen was originally discovered as part of a contraceptive research program at ICI Pharmaceuticals (now Zeneca). On the basis of the estrogen dependence of many breast cancers, tamoxifen, a potent antiestrogen, was predicted to have anticancer activity. Laboratory and animal studies demonstrated efficacy in breast cancer and an ability to block binding of estradiol to the estrogen receptor of human breast cancer. Preclinical studies showed the benefit of long-term vs short-term tamoxifen treatment, a finding duplicated in the clinic. [ONCOLOGY 11(Suppl 1):7-13, 1997]

Tamoxifen is the most widely prescribed endocrine therapy for breast cancer, with more than 7.5 million woman-years of clinical experience. Tamoxifen has both antiestrogenic and estrogenic activity. The antiestrogenic activity

An expert panel of nine international cancer researchers and practicing oncologists met in Boston to discuss the past, present, and future uses of antiestrogens in the treatment of breast cancer. The first article in this series, based on the symposium presentations, focused on the optimal duration of tamoxifen use (October 1996). This month, the panel explores the noncancer benefits of tamoxifen, as well as the potential risk of endometrial cancer. The symposium was sponsored by Zeneca Pharmaceuticals.