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).
Mina and Sledge presented a valuable overview of the changes that have occurred during the past few decades in the treatment of breast cancer. I am pleased to be invited to offer my personal observations on the changes that have occurred in the endocrine treatment of breast cancer over this period. These changes are considerable, and I will approach my task as an observer from the bottom looking up. I say this because, as a new PhD graduate in pharmacology who had studied "antiestrogens" as an academic exercise from 1969 to 1972, I was told I could now do anything I wanted. I chose to contribute to the reinvention of an orphan drug, ICI 46,474, into tamoxifen.
Each generation creates and defends its own fashion in cancer research, and this concept is well illustrated by the early resistance to change in the approach to treating breast cancer. Virtually no one was interested in "another endocrine therapy," as combination cyto-toxic chemotherapy was predicted to cure cancer.
In contrast, it is now clear that the approach to health care has changed in the past 20 years, not once but twice, as a result of advances in endocrine therapy. In the first case, Mina and Sledge identify tamoxifen as the first targeted treatment for breast cancer. This is a reasonable assessment, as the translation work on tumor targeting ultimately was shown to be successful. Perhaps equally important was the fact that tamoxifen has a beneficial therapeutic ratio that facilitated its use as a long-term adjuvant therapy. The application of the laboratory strategy of long-term antihormonal therapy targeted to the estrogen receptor (ER)[3,4] saved lives, which in turn has contributed significantly to the national reductions in mortality.[5,6]
Secondly, the knowledge gained with tamoxifen propelled the drug forward for testing as the first chemopreventive for any cancer, created a new drug group—the selective ER modulators (SERMs)—and resurrected keoxifene, a failed breast cancer drug,to be the first SERM for the treatment and prevention of osteoporosis, but with the ability to reduce the risk of breast and endometrial cancer.
The story of the discovery of tamoxifen as a "morning after pill" in the 1960s to then being reinvented as a targeted breast cancer therapy in the 1970s has been recounted recently.[3,4]Nevertheless, the tale is important to retell, as it illustrates how changing fashions in research can influence progress. The development of the oral contraceptive by Pincus and colleagues at the Worcester Foundation during the 1950s changed society forever. Despite enthusiasm to create new ways to manipulate reproduction, the fashion of research in reproductive biology declined steadily throughout the 1960s with a decreased investment in the development of new contraceptive methods. But, in its place, the "War on Cancer" was declared in 1971.
The tale of tamoxifen also illustrates the length of time that must be taken to evaluate successful treatment strategies to effect changes in health care. Nevertheless, momentum to change the approach to the treatment of breast cancer, and, indeed, of any cancer, accelerated with tamoxifen. The drug became a ubiquitous tool to test targeting in breast cancer. More importantly, tamoxifen set the stage for the current optimism that important advances in cancer research are within our grasp and the sincere belief that clever people will solve problems and develop practical ways to kill cancer cells selectively with minimal side effects for the patient.
Although it is not possible to recapture the exact mood of the clinical community during the early 1980s, it is fair to say that chemotherapy was king. It is possible, however, to illustrate the unimportance of antihormonal therapy by reference to the work of opinion leaders at the time.
From the Bottom Looking Up
In the early 1980s, you could refer to two bibles if you wanted to know about a particular treatment or medicine. Goodman and Gilman's The Pharmacological Basis of Therapeutics (7th edition),published in 1985, is where you would go first to look up the importance of tamoxifen in medicine. The book has less than a page on the anticancer uses of tamoxifen and a short discussion of antiestrogen action relevant to the induction of ovulation. What you will find is reference to a couple of review articles that were written to consolidate all the small and scattered reports about the pharmacology, clinical studies, and future potential of antiestrogens.[9,10]
The second book—the Pharmacologic Principles of Cancer Treatment—was edited by Bruce Chabner and published in 1982. In this 443-page book, the structure of tamoxifen is shown on page 148 and descriptive information about antiestrogen therapy appears on pages 164 and 165. The absence of anything futher about the agent was not an omission. There was not much optimism about the use of tamoxifen at that time. Although a preliminary study of the efficacy of ICI 46,474 (tamoxifen) first appeared in 1971, the response rates were the same as for other endocrine therapies. The clinical development of tamoxifen to treat advanced breast cancer did not set the world on fire! Importantly, however, there were fewer side effects compared to other treatments. Tamoxifen was approved for the treatment of advanced breast cancer in the United States in December 1977, but how could the drug be used to its best advantage in the clinic?
Focus on Chemotherapy
In the early 1980s, most eyes were focused on the merits of combination chemotherapy and its value as a curative adjuvant therapy. Reference to the proceedings of a 4-day meeting reported in Adjuvant Therapy of Cancer IV, edited by Stephen Jones and Syd Salmon (1984), illustrates the quest by cooperative groups worldwide to use chemotherapy to cure cancer. Almost half of the 64 papers presented focus on the adjuvant therapy of breast cancer, with only 8 of the 26 breast cancer papers mentioning the evaluation of 1 or 2 years of tamoxifen treatment in their protocols. Away from the application of adjuvant therapy to enhance survival, the quest for cancer cure was focused on dose-dense chemotherapy and the empirical application of bone marrow transplantation. This was admirably reviewed by I. Craig Henderson in Breast Diseases.
That said, why did the process of moving from concept to changes in health care take such a long time for a novel targeted therapy with few side effects?
Dr. Jordan is supported by SPORE in Breast Cancer CA89018, R01 GM061756, The Avon Foundation, and the Weg Fund of the Fox Chase Cancer Center.
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36. 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.
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38. Jordan VC: Antiestrogenic and antitumor properties of tamoxifen in laboratory animals. Cancer Treat Rep 60:1409-1419, 1976.
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55. Hardell L: Tamoxifen as risk factor for carcinoma of corpus uterus. Lancet, 2:563, 1988.
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66. Jordan VC: Chemosuppression of breast cancer with tamoxifen: Laboratory evidence and future clinical investigations. Cancer Invest 6:589-595, 1988.
67. Lerner LJ, Jordan VC: The development of antiestrogens for the treatment of breast cancer: Eighth Cain Memorial Award Lecture. Cancer Res 50:4177-4189, 1990.
68. Black LJ, Jones CD, Falcone JF: Antagonism of estrogen action with a new benzothiophene derived antiestrogen. Life Sci 32:1031-1036, 1983.
69. Jordan VC, Gosden B: Inhibition of the uterotropic activity of estrogens and antiestrogens by the short acting antiestrogen LY117018. Endocrinology 113:463-468, 1983.
70. Gottardis MM, Ricchio ME, Satyaswaroop PG, et al: Effect of steroidal and nonsteroidal antiestrogens on the growth of a tamoxifen-stimulated human endometrial carcinoma (EnCa101) in athymic mice. Cancer Res 50:3189-3192, 1990.
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99. Hard GC, Iatropoulos MJ, Jordan K, et al: Major difference in the hepatocarcinogenicity and DNA adduct forming ability between toremifene and tamoxifen in female Crl:CD(BR) rats. Cancer Res 53:4534-4541, 1993.
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101. Jordan VC: Selective estrogen receptor modulation: Concept and consequences in cancer. Cancer Cell 5:207-213, 2004.
102. Yao K, Lee ES, Bentrem DJ, et al: Antitumor action of physiological estradiol on tamoxifen-stimulated breast tumors grown in athymic mice. Clin Cancer Res 6:2028-2036, 2000.
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