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).
The fascinating story of the discovery and development of tamoxifen as a treatment for breast cancer described by Dr. Jordan has opened up a most remarkable area of human biology, which has implications far beyond the prevention and treatment of one disease. In many respects, it is a piece of biology at the very forefront of our understanding of how the body functions in health and disease.
The whole story exemplifies the very best outcomes from successful interactions of laboratory and clinical scientific research to arrive at important scientific results, which not only improve our understanding of the underlying biology, but also produce results with substantial clinical significance and worthwhile therapeutic outcomes. It is the story of a close, successful two-way interaction between laboratory and clinical scientists.
Early Development of Tamoxifen as a Cancer Treatment
We have frequently seen drugs that were unsuccessfully developed for one purpose but, by a chance observation of a side effect, subsequently developed for another purpose. For tamoxifen, however, this sideways step was the result of lateral thought at a time when the endocrine treatment of metastatic breast cancer involved such toxic treatments as adrenalectomy, androgens, and high-dose steroids.
Following laboratory data from Jordan's lab and an early clinical report by Cole et al in 1971, the initial small phase II clinical trial of tamoxifen for the treatment of advanced breast cancer was published by Ward in 1973, reporting a 40% response with "trivial side effects." This led to the clinical development of a very well tolerated drug for the treatment of metastatic breast cancer in pre- and postmenopausal women. As Jordan describes, by the mid-1970s it became the standard of care for first-line treatment of patients with estrogen receptor (ER)-positive advanced breast cancer.
Tamoxifen as a Targeted Therapy for Breast Cancer
Dr. Jordan's identification of tamoxifen as the first targeted therapy for breast cancer is interesting. In many ways, it is as he describes, although because of the ubiquitous nature of ER in normal tissues, this would not make tamoxifen any more targeted than many chemotherapy agents that now have well defined targets in cancer cells. The uniqueness of tamoxifen is that it appears to have a differential effect on the target, acting as an antagonist in cancer cells, whereas in most but not all normal tissues it acts as an agonist. This effect is dose-dependent, with higher doses of estrogen being antiproliferative in cancer cells. Classical targeted therapy is usually directed against something uniquely overexpressed in cancer and not normal cells. However, the ER target in breast cancer is of special clinical use because, although it does not define who will respond to endocrine treatment, its absence clearly defines who will not respond.
Much ongoing research is attempting to clarify why only a portion of ER-positive cancers respond. Also of considerable interest is how ER recognizes tamoxifen as an agonist or an antagonist in different tissues. As a result of this research, a most intricate and remarkable mechanism has been identified, dependent on the interaction of many different proteins. How estrogen triggers this mechanism, involving so many different genes and a multitude of different effects in so many different tissues, gives us an insight into the orchestrated control of so much activity in the body. This incredible piece of biology has been studied so extensively because of its importance in many endocrine and malignant diseases and the interaction of drugs like tamoxifen with this system. Jordan's work has been at the center of this important clinical-laboratory interface.
Tamoxifen as Adjuvant Therapy for Breast Cancer
Clinically, the next step was to evaluate tamoxifen as adjuvant therapy following surgery for primary breast cancer. At the time, the basis for choosing any agent for a trial as adjuvant therapy was the need for established preclinical activity and clear evidence of an objective response in advanced disease. As Dr. Jordan notes, by 1980 both of these criteria were met for tamoxifen and trials of adjuvant tamoxifen therapy were started in Europe and the United States.[3-6] Both showed a reduction in the risk of relapse. Subsequently, the 1984 Oxford overview analysis of tamoxifen adjuvant trials confirmed a significant survival advantage following adjuvant tamoxifen therapy.
Tamoxifen for Prevention of Breast Cancer
Professor Powles is a consultant for Eli Lilly and Pfizer.
1. Cole MP, Jones CT, Todd ID: A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI46474. Br J Cancer 25:270-275, 1971.
2. Ward HW: Anti-oestrogen therapy for breast cancer: A trial of tamoxifen at low dose levels. Br Med J 1:13-14, 1973.
3. Baum M, Brinkley DM: Dossett JA, et al: Controlled trial of tamoxifen as adjuvant agent in management of early breast cancer. Lancet 1:257-261, 1983.
4. Scottish Cancer Trials Officer: Adjuvant tamoxifen in the management of operable breast cancer. The Scottish Trial. Lancet 2:171-175, 1987.
5. CRC Adjuvant Breast Trial Working Party: Cyclophosphamide and tamoxifen as adjuvant therapies in the management of breast cancer. Br J Cancer 57:604-607, 1988.
6. Fisher B, Brown A, Wolmark N, et al: Prolonging tamoxifen therapy for primary breast cancer. Findings from the National Surgical Adjuvant Breast and Bowel Project clinical trial. Ann Intern Med 106:649-654, 1987.
7. Early Breast Cancer Trialists’ Collaborative Group: Effects of adjuvant tamoxifen and cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomized trials among 28,896 women. N Engl J Med 319:1681-1692, 1988.
8. Powles TJ, Hardy JR, Ashley SE, et al: A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer. Br J Cancer 60:126-131, 1989.
9. Cuzick J, Powles T, Veronesi U, et al: Overview of the main outcomes in breast-cancer prevention trials. Lancet 361:296-300, 2003.