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).
Historically, antiestrogen therapy in the form of oophorectomy was among the first treatments that took advantage of the differential influences of growth and proliferation that exist between cancer cells and most normal tissue. The clinical observations of the 19th century have been translated into one of the most effective cancer treatment strategies in history. First identified as a potential "morning after pill," tamoxifen is now the most widely utilized anticancer medication prescribed worldwide.
Rather than simply presenting important milestones in the development of endocrine therapy, Dr. Craig Jordan elegantly reviews the history of the development of endocrine therapy from a clinical, laboratory, and societal perspective. His contributions to the field are well documented and reflected in his article. The author highlights many of the obstacles faced in the development of endocrine therapy. In addition, he correlates discoveries and observations made in the laboratory that were also reflected in the clinical use of endocrine therapy.
The saying "timing is everything" surely applies to the development and use of tamoxifen. This medication was discovered to be an active treatment of advanced breast cancer before its target, the estrogen receptor, was truly known. Hand in hand with the identification and cloning of the estrogen receptor came the understanding of tamoxifen's mechanism of action and the agent's increased use.
Evolution of Drug Trials
Tamoxifen's clinical development was also instrumental in molding the way clinical studies were conducted. The original randomized clinical studies evaluating the use of tamoxifen in the late 1970s demonstrated a disease-free survival benefit when used as adjuvant therapy.[2,3] Most studies did not have sufficient power to consistently demonstrate an improvement in survival, and it was not until the Early Breast Cancer Trialists’ Collaborative Group meta-analysis was conducted that the benefit became clear: Adjuvant tamoxifen reduced the risk of recurrence and death for women with breast cancer. The evaluation of tamoxifen in underpowered studies highlighted the need for large randomized clinical trials to demonstrate benefits in outcome, so that promising therapies are not shelved due to limitations in study design.
Dr. Jordan's review also highlights how the use of the right preclinical model can assist in the development of a lifesaving drug. Tamoxifen was shown to prevent the development and progression of breast cancer in animal models. However, the clinical observation that tamoxifen reduces the risk of new breast cancers in patients treated with tamoxifen was just as relevant in moving this agent into the prevention setting as were the preclinical models. Clinical observations regarding the use of tamoxifen continue to guide laboratory-based research and vice versa.
For example, tamoxifen is associated with several unfavorable side effects, in part due to its estrogen-agonist action. Development of newer selective estrogen receptor modulators will potentially allow an enhanced therapeutic index with decreased toxicity. In addition, despite high levels of estrogen receptor expression, some cancers are inherently resistant to tamoxifen or develop resistance to tamoxifen after prolonged exposure to the agent. Ongoing research focuses on identifying mechanisms of endocrine resistance. This investigation will hopefully lead to targeted drug development that will restore or establish sensitivity to antiestrogen agents.
The hypothesis that an "estrogen-free" environment would lead to control of breast cancer was driven not only by the clinical experience with oophorectomy and older aromatase inhibitors but also by the clinical benefits and estrogen-agonist toxicities of tamoxifen. The ultimate goal of this therapeutic approach was the ability to reduce estrogen levels in breast tissue and breast cancer without having any agonist effects on the uterus or liver.
The development of the third-generation aromatase inhibitors has benefited from the experience gained during the investigation of tamoxifen's activity. Large randomized studies were done to demonstrate the improvement in outcome associated with estrogen deprivation. The adjuvant studies evaluating anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) were all designed with a generous sample size, and these studies have demonstrated a small but definite absolute benefit in reducing the risk of breast cancer-related events associated with the use of an aromatase inhibitor compared to tamoxifen.[7,8]
In keeping with lessons learned from the development of tamoxifen, those who criticize the adjuvant aromatase inhibitor studies for not yet showing an overall survival advantage over tamoxifen should remember how long it took for some of the well-designed adjuvant tamoxifen studies to demonstrate an overall survival advantage. In the same vein, the lessons learned regarding tamoxifen's toxicity after prolonged administration should also keep investigators and clinicians vigilant regarding potential (and as yet unknown) long-term side effects of aromatase inhibitors.
The evolution of endocrine therapy in the treatment of breast cancer during the past 20 years has changed not only our care of patients with breast cancer but also our approach to the development, investigation, and use of many newer anticancer therapies. The identification of a target that differentiates malignant tissue from most normal tissue, the development of a preclinical model to validate new agents, and the investigation of agents in large randomized clinical trials have all been influenced by the development of tamoxifen.
Our task as clinicians and investigators is to learn from our past experiences. We should recognize that our drug development strategy should be adapted to fit changes in science and technology, to reduce the chances that an effective therapy is abandoned because it doesn’t fit the current model. The observations made in the lab and the clinic continue to complement and influence each other. Thanks to Dr. Jordan and many other dedicated scientists and clinicians, the treatment of hormone-sensitive breast cancer continues to evolve and inspire.
-Marjorie C. Green, MD
-Gabriel N. Hortobagyi, MD, FACP
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Clarke MJ: Ovarian ablation in breast cancer, 1896-1998: Milestones along hierarchy of evidence from case report to Cochrane review. BMJ 317:1246-1248, 1998.
2. Controlled trial of tamoxifen as adjuvant tamoxifen in management of early breast cancer: Interim analysis at 4 years of Nolvadex Adjuvant Trial Organisation. Lancet 1:257-261, 1983.
3. Scottish Cancer Trials Office: Adjuvant tamoxifen in the management of operable breast cancer: The Scottish Trial. Lancet 2:171-175, 1987.
4. Early Breast Cancer Trialists’ Collaborative Group: Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomized trials among 28,896 women. N Engl J Med 319:1681-692, 1988.
5. Armamento-Villareal R, Sheikh S, Nawaz A, et al: A new selective estrogen receptor modulator, CHF 4277.01, preserves bone mass and microarchitecture in ovariectomized rats. J Bone Miner Res 20: 2178-2188, 2005.
6. Gururaj AE, Rayala SK, Vadlamudi RK, et al: Novel mechanisms of resistance to endocrine therapy: Genomic and nongenomic considerations. Clin Cancer Res 12:1001s-1007s, 2006.
7. Howell A, Cuzick J, Baum M, et al, for the ATAC Trialists’ Group: Results of the ATAC trial after completion of 5 years adjuvant treatment for breast cancer. Lancet 365:60-62, 2005.
8. Thurlimann B, Keshaviah A, Coates AS, et al: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747-2757, 2005.