Commentary (Powles): Improvements in Tumor Targeting, Survivorship, and Chemoprevention Pioneered by Tamoxifen

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,[1] the initial small phase II clinical trial of tamoxifen for the treatment of advanced breast cancer was published by Ward in 1973,[2] 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.[7]

Tamoxifen for Prevention of Breast Cancer

Finally, researchers considered the most controversial extension of tamoxifen use-the possibility that the drug could prevent breast cancer. This step signified a different dimension of clinical testing because it involved giving a drug to many thousands of healthy women in order to prevent a relatively small number of cancers, many of which would be curable anyway. Furthermore, it was essential that the drug was safe for use in healthy women.

Following the Oxford meta-analysis in 1984, we felt that it was likely that tamoxifen-which at the time had been given to over 6 million women-was safe and that its efficacy as adjuvant therapy was evident. Jordan's preclinical data demonstrating prevention of tumors in rodents were convincing. The early clinical data showing that the agent reduced contralateral breast cancer when used as adjuvant therapy completed the requirements for starting a feasibility randomized placebo-controlled trial in healthy pre- and postmenopausal women. The primary objectives of this feasibility trial were to show that recruitment, compliance, and safety were possible in healthy women. There was much opposition to this trial, but in 1986 it was started at the Royal Marsden; 2,500 women were recruited, and we were able to show that it was possible to do such trials.[8]

Three other trials were subsequently initiated, and nearly 25,000 healthy women were randomized. A meta-analysis of these trials showed that tamoxifen reduced the incidence of breast cancer by about 40%.[9] Nevertheless, considerable intertrial variation in the magnitude of the effect was observed, probably due to the different risk criteria for entry into the respective studies. Moreover, new toxicity problems with the drug were identified-in particular, endometrial polyps and cancer and an increase in the risk of thromboembolism.

Overall, these results gave a clear indication that breast cancer was preventable. However, a better risk-benefit ratio was generally considered to be necessary for antiestrogens to be accepted for breast cancer risk reduction, particularly in Europe.

Post-Tamoxifen Prevention Strategies

Prevention outcomes could be improved in two ways. The first method would be to use more effective and/or less toxic agents such as the new selective estrogen receptor modulators (SERMs), which offer additional benefit by preventing osteoporotic fractures. More than 70,000 women are currently enrolled in prevention trials of the SERMs raloxifene (Evista), lasofoxifene, and arzoxifene. The preliminary results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) P2 trial comparing raloxifene with tamoxifen were recently reported, showing similar efficacy but less toxicity for raloxifene compared to tamoxifen. In contrast, aromatase inhibitors have been shown to be more effective than tamoxifen as adjuvant therapy, with a larger risk reduction for contralateral new breast cancers. These agents are therefore likely to be more effective but have more toxicity than raloxifene.

The second method of improving efficacy is to identify an algorithm of risk factors (such as mammographic breast density) that predict for estrogen-promoted breast cancers. This could identify a group of women at high risk of breast cancer for whom antiestrogenic interventions would be more effective.

The results so far indicate that many if not most breast cancers could be prevented using antiestrogen therapy. In the foreseeable future, we should be able to identify a significant proportion of women at high risk of breast cancer, which can be prevented by using these agents.

Conclusion

As Jordan says in his article, the development of tamoxifen has been a most remarkable story of laboratory and clinical scientific interactions, which have produced one of the most outstanding clinical advances in oncologic therapeutics. It is also a lesson to all investigators, who need to be focused and persistent if we are to have any hope of cracking the clinical oncologic challenges of the future.

-Trevor Powles, CBE, PhD, FRCP

Disclosures:

Professor Powles is a consultant for Eli Lilly and Pfizer.

References:

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.