Remembering Charles B. Huggins' Nobel Prize for Hormonal Treatment of Prostatic Cancer at its 50th Anniversary.

Charles B. Huggins received the Nobel Prize in 1966. Based on archival sources from the Nobel archive we have found that nominators emphasised the practical therapeutic applications of his discoveries that were showing 25 yr after his key publications.

[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.

Adjuvant endocrine therapy for premenopausal women with early breast cancer.

Adjuvant endocrine therapy is a pivotal component of treatment for premenopausal women with early-stage hormone receptor-positive breast cancer. Currently, the standard endocrine therapy for premenopausal women is tamoxifen; a role for ovarian suppression or ablation has also been identified. Uncertainty remains about the optimal use of endocrine therapy in this setting. The role of ovarian suppression with tamoxifen or aromatase inhibitor, the optimal duration of adjuvant endocrine therapy and the utility of biomarkers and pharmacogenetic studies to select therapy are questions worthy of further investigation.

Twenty years of systemic therapy for breast cancer.

The past 2 decades of systemic therapy for breast cancer have been a period of monumental change, in terms of both theory and technology. Adjuvant therapy developed from two strands of research--one in systemic chemotherapy and one in hormonal therapy--both of which were aided by the application of higher statistical methodology to clinical trials. The agent with the single greatest public health impact in oncology has been tamoxifen, but problems with tamoxifen therapy led to the development of the aromatase inhibitors, and further research led to the use of hormonal therapy in a chemopreventive capacity. The evolution of systemic chemotherapy for breast cancer has been an interplay between theory-driven approaches and new agents. By the late 1980s, accumulating data revealed that overexpression of HER2 (erbB2) played an important role in a substantial portion of breast cancers, which prompted the development of trastuzumab (Herceptin), an agent targeting HER2-positive disease. Determining HER2 status proved essential to assessing patient eligibility for trastuzumab therapy. Decoding of the human genome and application of bioinformatics further revolutionized the possibilities in breast cancer treatment.

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.

Hormonal therapy: historical perspective to future directions.

Prostate cancer is second only to lung and bronchial cancer as the leading cause of cancer death in men. Local treatment, surgery, and radiation remain the mainstay of treatment for early-stage disease. However, in locally advanced and advanced disease, there has been considerable evolution in the hormonal therapies. Suppression of testosterone production, the primary goal of hormonal therapy, may be accomplished with the use of estrogens, antiandrogens, and agonists and antagonists of luteinizing hormone-releasing hormone (LHRH). This article provides an overview of the primary hormonal therapies currently used in prostate cancer. Estrogen therapy was initially the predominant medical form of hormone manipulation and an alternative to orchiectomy. However, serious thrombogenic side effects were associated with its use, which decreased after the introduction of LHRH agonists in the 1980s. Many of the side effects occurring with oral estrogen therapy may be modulated by parenteral administration, and thus estrogen use is being revisited. LHRH agonists effectively reduce testosterone levels to castration levels (<50 ng/mL) within 2 to 4 weeks, although their use is associated with tumor flare. Antiandrogen monotherapy may offer quality-of-life benefits over treatment with androgen deprivation. The additive benefit of combined androgen blockade is yet to be determined. Recent evidence suggests that hormonal therapy may offer a survival benefit when initiated in earlier stages of prostate cancer. Future investigations will be directed to determining the most efficacious regimens.

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.

From taxol to Taxol: the changing identities and ownership of an anti-cancer drug.

This paper analyzes the emergence and evolution of taxol, the world's bestselling anti-cancer drug. Over the years taxol has changed its identity, its status as property, and its association with different places (from the old-growth forests of Washington State to the government agencies of Washington, D.C., to laboratories in France). Taxol is not only a profitable pharmaceutical commodity and a substance injected into women with breast and/or ovarian cancer; it is also a natural product found in the bark of Taxus brevifolia (the Pacific yew, which is native to the North American Pacific Northwest) and a chemical substance that was discovered and brought to the point of commercial production in the public sector. We explore its role in several controversies: the destruction of old-growth forests, public participation in policy making, and the privatization of intellectual property and its effect on the price of drugs.

A history of prostate cancer treatment.

The increased incidence of prostate cancer has led to remarkable changes in diagnosis and treatment over the past century. What were the first ways in which prostate cancer was treated, and how did these evolve into the variety of therapeutic strategies from which patients have to choose today?