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.
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3. Scottish Cancer Trials Office: Adjuvant tamoxifen in the management of operable breast cancer: The Scottish Trial. Lancet 2:171-175, 1987.
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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.
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