The Search for Antiestrogens

“A clinical trial is just a mechanism by which to evaluate what you have done in the laboratory.”

-Bernard Fisher, March 2008

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.

It is fair to say that our knowledge of the link between ovarian hormones and breast cancer growth goes back to 1896, when George Beatson described the regression of breast cancer in a premenopausal woman following an oophorectomy.[1] This was not random surgery, but a clinical study based on observations in animals. As a young doctor, Beatson had spent summer holidays in Scotland and knew that lactation could be modified in cattle following ovariectomy. He subsequently pursued investigations in rabbits to establish ovarian–mammary gland interactions.

Circuitous Route to Discovery

In the early 1920s, estrogen had been identified in the ovaries, and by 1936, based upon his studies in mice, Lacassagne had suggested “that a therapeutic antagonist to the congestion of oestrone in the breast should be found to prevent breast cancer.”[2] However, where to start? Research does not travel in straight lines, and discovery in one discipline can often be adapted to solve problems in another. The target for estrogen action-the estrogen receptor-was discovered by Jensen in the estrogen target tissues of the rat.[3] In the 1950s and 1960s, however, the research on hormone action was focused on understanding reproduction and contraception and not breast cancer research. The pharmaceutical industry was determined to find contraceptives.

One compound, ICI 46474 was found to be extremely effective for this purpose in rats but did the exact opposite in women.[4] The drug was “an orphan” looking for applications, and was subsequently reinvented as tamoxifen, the first targeted breast cancer therapy and the first agent used as an antiestrogen to reduce the incidence of breast cancer in high-risk women.[5]

Enter Raloxifene

Raloxifene (Evista) also had an “orphan” origin. The compound was originally called keoxifene, which was considered a failed breast cancer drug. However, the description of selective estrogen-receptor modulation of the so-called nonsteroidal antiestrogens[6] suggested that compounds in this group could be used not only to prevent osteoporosis, but to prevent breast cancer at the same time. Selective estrogen-receptor modulators, or SERMs, could switch on some target sites in a woman’s body as estrogens and switch off others as antiestrogens. Keoxifene was renamed raloxifene and, through the clinical trials mechanism, became the second agent in the clinician’s armamentarium for reducing breast cancer incidence in high-risk women.[7,8]

Raloxifene is the chemopreventive of choice for postmenopausal women, to prevent both breast cancer and osteoporosis, but unlike tamoxifen, this agent is not associated with an increased risk of endometrial cancer. In fact, overall, the side-effect profile of raloxifene is more favorable than that of tamoxifen.[9]

On the other hand, tamoxifen is the only game in town for reducing the risk of breast cancer in premenopausal women, but in this population, there is no elevated risk for either blood clots or endometrial cancer. Additionally, the pharmacogenomics of tamoxifen can now be used to identify women who should not be taking tamoxifen.[10]

Closing Reflections

Victor Vogel dedicates his article to the late Marty Abeloff, and I would like to close with my own personal thoughts about this thoughtful and gentle man. I first met him during the early 1980s, but I got to know him well in an unusual setting in Baltimore. Marty and I were expert witnesses for a Federal lawsuit brought by Zeneca against generic drug manufacturers who chose to challenge tamoxifen’s patents. This all occurred in 1995, and Zeneca was resoundingly successful in defending the patents. I discovered Marty was among the first oncologists to use tamoxifen in the United States, and he was impressed by the sometimes dramatic responses with few side effects. Marty was a giant in medical oncology, and he will be sorely missed.

-V. Craig Jordan, OBE, PhD, DSc

References:

References

1. Beatson GT: On treatment of inoperable cases of carcinoma of the mamma: Suggestions for a new method of treatment with illustrative cases. Lancet 2:162-165, 1896.

2. Lacassagne A: Hormonal pathogenesis of adenocarcinoma of the breast. Am J Cancer 27:217-225, 1936.

3. Jensen EV, Jacobson HI: Basic guides to the mechanism of estrogen action. Recent Progr Hormone Res 18:387-414, 1962.

4. Jordan VC: Tamoxifen: A most unlikely pioneering medicine. Nat Rev Drug Discov 2:205-213, 2003.

5. Jordan VC: Tamoxifen: Catalyst for the change to targeted therapy. Eur J Cancer 44:30-38, 2008.

6. Jordan VC: Selective estrogen receptor modulation: A personal perspective. Cancer Res 61:5683-5687, 2001.

7. Cummings SR, Eckert S, Krueger KA, et al: The effect of raloxifene on risk of breast cancer in postmenopausal women: Results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA 281:2189-2197, 1999.

8. Jordan VC: Chemoprevention of breast cancer with selective oestrogen-receptor modulators. Nat Rev Cancer 7:46-53, 2007.

9. Vogel VG, Costantino JP, Wickerham DL, et al: The Study of Tamoxifen and Raloxifene (STAR): Report of the National Surgical Adjuvant Breast and Bowel Project P-2 trial. JAMA 295:2727-2741, 2006.

10. Goetz MP, Rae JM, Suman VJ, et al: Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23:9312-9318, 2005.