[Endocrine therapy for breast cancer: past and present].

The endocrine therapy for breast cancer could be traced back to the excision of the metastatic breast cancer by oophorectomy in a premenopausal women performed by Beatson in 1896. After the development of more than 100 years, endocrine therapy plays an important role in adjuvant therapy, the rescuing treatment of its recurrence due to metastasis, and the new adjuvant endocrine therapy for breast cancer. Through analyzing the changes in the 4 aspects of endocrine treatment of breast cancer, i.e., the original simple excision of the endocrine organs, tamoxifen, drug-induced ovarian castration and the 3th generation aromatase inhibitor, the characteristics of different ages of endocrine therapy can be summarized, which would provide the reference for the new developmental trend of this therapy.

Four decades of discovery in breast cancer research and treatment--an interview with V. Craig Jordan. Interview by Marc Poirot.

V. Craig Jordan is a pioneer in the molecular pharmacology and therapeutics of breast cancer. As a teenager, he wanted to develop drugs to treat cancer, but at the time in the 1960s, this was unfashionable. Nevertheless, he saw an opportunity and through his mentors, trained himself to re-invent a failed "morning-after pill" to become tamoxifen, the gold standard for the treatment and prevention of breast cancer. It is estimated that at least a million women worldwide are alive today because of the clinical application of Jordan's laboratory research. Throughout his career, he has always looked at "the good, the bad and the ugly" of tamoxifen. He was the first to raise concerns about the possibility of tamoxifen increasing endometrial cancer. He described selective estrogen receptor modulation (SERM) and he was the first to describe both the bone protective effects and the breast chemopreventive effects of raloxifene. Raloxifene did not increase endometrial cancer and is now used to prevent breast cancer and osteoporosis.The scientific strategy he introduced of using long term therapy for treatment and prevention caused him to study acquired drug resistance to SERMs. He made the paradoxical discovery that physiological estrogen can be used to treat and to prevent breast cancer once exhaustive anti-hormone resistance develops. His philosophy for his four decades of discovery has been to use the conversation between the laboratory and the clinic to improve women's health.

Tamoxifen: catalyst for the change to targeted therapy.

In the early 1970s, a failed post-coital contraceptive, ICI 46,474, was reinvented as tamoxifen, the first targeted therapy for breast cancer. A cluster of papers published in the European Journal of Cancer described the idea of targeting tamoxifen to patients with oestrogen receptor positive tumours, and proposed the strategic value of using long-term tamoxifen therapy in an adjuvant setting with a consideration of the antitumour properties of the hydroxylated metabolites of tamoxifen. At the time, these laboratory results were slow to be embraced by the clinical community. Today, it is estimated that hundreds of thousands of breast cancer patients are alive today because of targeted long-term adjuvant tamoxifen therapy. Additionally, the first laboratory studies for the use of tamoxifen as a chemopreventive were published. Eventually, the worth of tamoxifen was tested as a chemopreventive and the drug is now known to have an excellent risk benefit ratio in high risk pre-menopausal women. Overall, the rigorous investigation of the pharmacology of tamoxifen facilitated tamoxifen's ubiquitous use for the targeted treatment of breast cancer, chemoprevention and pioneered the exploration of selective oestrogen receptor modulators (SERMs). This new concept subsequently heralded the development of raloxifene, a failed breast cancer drug, for the prevention of osteoporosis and breast cancer without the troublesome side-effect of endometrial cancer noted in post-menopausal women who take tamoxifen. Currently, the pharmaceutical industry is exploiting the SERM concept for all members of the nuclear receptor superfamily so that medicines can now be developed for diseases once thought impossible.

Tamoxifen (ICI46,474) as a targeted therapy to treat and prevent breast cancer.

Antihormonal therapy targeted to the oestrogen receptor (OER) is recognized as a significant advance in the treatment and prevention of breast cancer. However, the research method used to achieve the current successes seen in the clinic was not linear but was based on the changing fashions in research and the application of appropriate testing models. The discovery and investigation of nonsteroidal antioestrogens by the pharmaceutical industry during the 1960s was initially an exciting prospect for clinical development. The drugs were superb antifertility agents in laboratory animals, so the prospect of marketing a 'morning after' pill was a high priority. Unfortunately, the reproductive endocrinology of the rat was found to be completely different from that of the human. Antioestrogens, in fact, improved fertility by inducing ovulation in subfertile women so much of the drug development was discontinued. The successful reinvention of ICI46,474 from its origins as a failed contraceptive to a pioneering breast cancer treatment targeted to the OER presaged the development of the current menu of medicines targeted to a range of different survival mechanisms in cancer cells.

Tamoxifen: a most unlikely pioneering medicine.

For more than 25 years, tamoxifen has been the gold standard for the endocrine treatment of all stages of oestrogen-receptor-positive breast cancer, and the World Health Organization lists tamoxifen as an essential drug for the treatment of breast cancer. It is estimated that more than 400,000 women are alive today as a result of tamoxifen therapy, and millions more have benefited from palliation and extended disease-free survival. Interestingly, tamoxifen also became the first cancer chemopreventive approved by the Food and Drug Administration (FDA) for the reduction of breast-cancer incidence in both pre- and post-menopausal women at high risk. However, 40 years ago, it was hard to imagine that a non-toxic targeted treatment for breast cancer could be developed at all.

Tamoxifen: a personal retrospective.

Tamoxifen, originally described as an anti-oestrogen and antifertility agent in the rat, is now a pioneering medicine for the treatment and prevention of breast cancer. Its success is the result of an effective collaboration between laboratory research and clinical trial processes. However, this drug is more than just an anti-oestrogen to treat breast cancer. Laboratory and clinical research defined the concept of selective oestrogen receptor modulation in the 1980s. Non-steroidal anti-oestrogens show oestrogen-like activity in bones and lower cholesterol, but block oestrogen action in the breast and uterus. This realisation led to the development of chemical cousins, known as selective oestrogen receptor modulators. One of these compounds, raloxifene, is used for the prevention of osteoporosis, but is currently being tested as a preventive for breast cancer.

Tamoxifen treatment for breast cancer: concept to gold standard.

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.

The development of tamoxifen for breast cancer therapy: a tribute to the late Arthur L. Walpole.

Tamoxifen, a nonsteroidal antiestrogen, is now the endocrine treatment most widely used in breast cancer, both in the adjuvant and advanced disease settings. Here we will trace the development of tamoxifen for advanced breast cancer in postmenopausal patients, consider the biological basis for the recent successful use of tamoxifen for long-term adjuvant therapy, and discuss the use of tamoxifen in premenopausal patients with advanced disease. In part, this will be a historical review offered as a tribute to the late Dr. Arthur L. Walpole, who must receive the chief credit for the discovery of tamoxifen and its subsequent application as an anticancer agent.