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Originally published as JCO Early Release 10.1200/JCO.2008.17.5190 on June 2 2008 © 2008 American Society of Clinical Oncology.
The 38th David A. Karnofsky Lecture: The Paradoxical Actions of Estrogen in Breast Cancer—Survival or Death?
From the Fox Chase Cancer Center, Philadelphia, PA Corresponding author: V. Craig Jordan, OBE, PhD, DSc, Medical Sciences, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111; e-mail: v.craig.jordan{at}fccc.edu
During the first David A. Karnofsky Award lecture entitled "Thoughts on Chemical Therapy" in 1970, Sir Alexander Haddow commented about the dramatic regressions observed with estrogen in some breast cancers in postmenopausal women, but regrettably the mechanism was unknown. He was concerned that a cancer-specific target would remain elusive, without tests to predict response to therapy. At that time, I was conducting research for my PhD on an obscure group of estrogen derivatives called nonsteroidal antiestrogens. Antiestrogens had failed to fulfill their promise as postcoital contraceptives and were unlikely to be developed further by the pharmaceutical industry. In 1972, that perspective started to change and ICI 46,474 was subsequently reinvented as the first targeted therapy for breast cancer. The scientific strategy of targeting the estrogen receptor (ER) in the tumor, treating patients with long-term adjuvant therapy, examining active metabolites, and considering chemoprevention all translated through clinical trials to clinical practice during the next 35 years. Hundreds of thousands of women now have enhanced survivorship after their diagnosis of ER-positive breast cancer. However, it was the recognition of selective ER modulation (SERM) that created a new dimension in therapeutics. Nonsteroidal antiestrogens selectively turn on or turn off estrogen target tissues throughout the body. Patient care was immediately affected by the recognition in the laboratory that tamoxifen would potentially increase the growth of endometrial cancer during long-term adjuvant therapy. At that time, a failed breast cancer drug, keoxifene, was found to maintain bone density of rats (estrogenic action) while simultaneously preventing mammary carcinogenesis (antiestrogenic action). Perhaps a SERM used to prevent osteoporosis could simultaneously prevent breast cancer? Keoxifene was renamed raloxifene and became the first SERM for the treatment and prevention of osteoporosis as well as the prevention of breast cancer, but without an increase in endometrial cancer. There the story might have ended had the study of antihormone resistance not revealed a vulnerability of cancer cells that could be exploited in the clinic. The evolution of antihormone resistance over years of therapy reconfigures the survival mechanism of the breast cancer cell, so estrogen no longer is a survival signal but a death signal. Remarkably, remaining tumor tissue is again responsive to continuing antihormone therapy. This new discovery is currently being evaluated in clinical trials but it also solves the mystery mechanism of chemical therapy with estrogen noted by Haddow in the first Karnofsky lecture.
By looking back, we can see the way forward. In 1970, Sir Alexander Haddow, FRS presented the first David A. Karnofsky Memorial Lecture entitled "Thoughts on Chemical Therapy."1 Paul Ehrlich, MD, was the individual who revolutionized therapeutics when he first created a "chemotherapy" (chemical therapy) through rational synthesis, followed by predictive testing in laboratory models, and then clinical trials to demonstrate the cure of syphilis with Salvarsan.2 He next turned to the treatment of cancer, but after more than a decade, he declared the year before he died in 1915: "I have wasted fifteen years of my life in experimental cancer research."3 In his Karnofsky lecture, Haddow echoed Ehrlich's sentiment with the statements "the fact that the cancer cell is but a modification of the normal somatic cell holds out little prospect of a chemotherapia specifica in Ehrlich's sense" and "the need exists for some method of prior screening to indicate the optimal choice (of chemotherapy) in particular cases... . efforts thus far have been disappointing."1 Haddow did, nevertheless, mention his results with the first chemical therapy for the treatment of any cancer—high-dose estrogen therapy. Haddow's work in 19444 showed that 25% of patients with advanced breast cancer treated with high doses of estrogen had clear responses. In 1944, the steroid estradiol was not available for therapeutics. Instead, synthetic estrogens called triphenylethylenes (made by Imperial Chemical Industries [ICI], now AstraZeneca) were used because they were cheap, effective, and long acting. Haddow noted "the extraordinary extent of tumor regression observed in perhaps 1% of postmenopausal cases has always been regarded as of major theoretical importance and it is a matter of some disappointment that so much of the underlying mechanisms continue to elude us."1 It should be stressed that Haddow's studies were a paradox, as a link between ovarian estrogen and breast cancer growth had already been established.5-7 What was the mysterious anticancer mechanism of high doses of synthetic estrogens? On the other side of the Atlantic in England, armed with a Medical Research Council Scholarship, I was struggling with a PhD thesis (1969 to 1972) entitled "Structure activity relationships of some substituted triphenylethylenes" at the University of Leeds. These estrogenic compounds had evolved into contraceptives or morning after pills, but had failed because they did the exact opposite in women—they induced ovulation.8 No one was recommending a career studying triphenylethylenes in 1972; in fact, only after repeated failures did the Leeds University Medical School secure an examiner for my thesis. He was Arthur Walpole, PhD, who many years before had been interested in cancer therapy9 but, in 1972, was Head of the Fertility Control program at ICI. He had discovered a triphenylethylene derivative, ICI 46,474, a contraceptive in rats which failed in that indication in women. ICI 46,474 was a drug looking for an application. as an antiestrogen,10 so it could possibly be useful as palliative therapy for advanced breast cancer. However, no laboratory studies then supported this indication. From the age of 16, I was completely enthralled with organic chemistry, but I wanted to apply chemical therapy to treat cancer. This was a very unfashionable career choice in the 1970s (Table 1) and there were no career opportunities for me at that time. Only a 2-year appointment at the Worcester Foundation for Experimental Biology in Massachusetts to work with Mike Harper (the other patent holder of ICI 46, 474) would change everything. Harper had left the Foundation when I arrived in September 1972, and I was told that I could do anything I wanted for 2 years. I chose to call Arthur Walpole about converting ICI 46,474 into a breast cancer drug but targeted to estrogen receptor (ER)–positive disease in patients.11 What I did not know at the time was that the administration at ICI had terminated the clinical development program but Walpole had threatened to resign unless the orphan project went forward.11,12 My call, and our friendship, secured funding to conduct the first systematic laboratory study of the potential applications of ICI 46,474 as a targeted anticancer agent.12 No studies in this area other than antifertility studies were conducted by ICI staff. The subsequent continuing investment by ICI Pharmaceuticals Division in my laboratory at the University of Leeds (Pharmacology Department, 1974 to 1979) would shape the clinical application of tamoxifen as a long-term adjuvant therapy13,14 targeted to the ER15 and as the first agent approved to reduce the incidence of any cancer in high risk pre- and postmenopausal women.16-19
A number of laboratory principles were defined in the 1970s during the evaluation of tamoxifen's antitumor pharmacology. These principles would ultimately have implications for the successful application of tamoxifen as an adjuvant therapy and as a chemopreventive agent in women at high risk for breast cancer. At that time, the principles as a whole were not embraced by the clinical community primarily because nearly all hopes were pinned on combination cytotoxic chemotherapy to cure both metastatic breast cancer and node-positive breast cancer.20 A palliative "hormone" (as tamoxifen was then classified) was unlikely to provide benefit. The key to success was the application of the antiestrogen to patients with a potentially responsive tumor (ER positive), with micrometastatic disease (stage I/II) but for the appropriate duration of adjuvant treatment. In the 1960s, there was sufficient evidence to conclude that some breast cancers grew in response to estrogenic hormones.21 The discovery of the ER22 and the development of the ER assay21 to predict which patients would not respond to endocrine ablative surgery became an important practical advance. The idea was simple. Patients whose tumors had no ERs would not respond to estrogen withdrawal because estrogen was not required for tumor growth. An unnecessary ablative operation (oophorectomy, adrenalectomy, or hypophysectomy) would be avoided.23 At that time, the clinical application of nonsteroidal antiestrogen (triphenylethylene derivatives) as breast cancer therapies were disappointing with numerous toxic adverse effects,11 except for ICI 46,474.24,25 Lois Trench was the first drug monitor for ICI 46,474 in the United States, and in general, she played a pivotal role in the development of tamoxifen. Specifically, she arranged for ER-positive breast tumors to be dispatched to my laboratory at the Worcester Foundation. I also went to Elwood Jensen's laboratory at the Ben May Laboratory for Cancer Research (University of Chicago) to learn sucrose density gradient analysis to measure ERs in breast tumors and to learn how to create hormone-dependent tumors in rats by the oral administration of the mammary carcinogen dimethylbenzanthracene (DMBA).26 Armed with these techniques, I returned to the Worcester Foundation and, with resources from ICI Americas, my laboratory demonstrated that tamoxifen blocked estrogen binding to the human tumor ER15 and that two sustained release injections of tamoxifen would almost completely prevent rat mammary carcinogenesis.16,17 Lois Trench arranged for me to introduce tamoxifen first to the Eastern Cooperative Oncology Group in 1974,27,28 and I was subsequently asked to introduce the pharmacology of tamoxifen to the National Surgical Adjuvant Breast and Bowel Project in 1976.29 This started an association with both organizations that developed the idea of long-term adjuvant tamoxifen therapy30-32 and more recently, breast cancer risk reduction with the selective ER modulators (SERMs) tamoxifen and raloxifene.33
The idea that tamoxifen should be applied as a long-term adjuvant therapy for patients with ER-positive primary breast cancer was first publicly presented in the United Kingdom at Cambridge University in September, 197734 and subsequently at the second Adjuvant Therapy of Cancer Meeting in Tucson, AZ, in 1979.35 The specific conclusion, based on the DMBA model system, was that long-term tamoxifen was the most effective suppressant of occult mammary tumor growth and short-term therapy was unlikely to be effective in clinical trial. At that time, in the mid-1970s, there were sincere concerns that only short-term therapy with tamoxifen should be tested because the drug was effective only in 30% of unselected patients and the average duration of the response was only about 1 year. Longer therapy was "guaranteed" to encourage the rapid development of drug resistance in the occult micrometastases. Michael Baum, who led the NATO group, (Nolvadex Adjuvant Trial Organization, but called NATO to enhance the likelihood that US clinicians would read the papers in the erroneous belief that it was a US clinical trials organization) was the first to report that 2 years of tamoxifen enhanced survival of unselected patients with breast cancer.36 However, it was the report from the Scottish Trials Office37 (by coincidence, on my birthday, July 25, 1987) that definitively showed a remarkable survival advantage for unselected women who received 5 years of adjuvant tamoxifen compared with a control group who only received tamoxifen on disease recurrence. Longer was better than shorter therapy, as none of the 1-year adjuvant trials showed a survival benefit; only the overview analysis of randomized clinical trials showed a clear pattern of success for the laboratory concept, especially in premenopausal women with ER-positive breast cancer.14,38 Interest in developing a strategy to address the chemoprevention of breast cancer grew and evolved during the early years of the 1980s.39 However, based on the laboratory data with the DMBA-induced rat mammary carcinoma model16,17 and the subsequent finding that tamoxifen inhibited the development of contralateral primary breast cancer,40 Trevor Powles, at the Royal Marsden Hospital in England, initiated the first pilot study in high-risk women41 to ascertain volunteer compliance and to eventually address issues of cardiovascular and gynecological safety and the effects of tamoxifen on bone density.42-44 In contrast, studies conducted at the Wisconsin Comprehensive Cancer Center followed the translational research path from the laboratory to the clinic (see SERM: Laboratory Observations to Clinical Practice). Overall, the published safety data (with the exception of tamoxifen-induced rat liver cancer45-48) translated from the laboratory10,49-51 to patients41,48,52-54 and provided an appropriate basis to advance chemoprevention trials. Although the Fisher et al study18,19 was definitive and the most comprehensive, several smaller studies supported the general conclusions that tamoxifen reduced the risk of breast cancer, not only during treatment55 but for perhaps a decade thereafter when drug-related adverse effects are minimal.19,56,57 What has been learned through the experience of adjuvant tamoxifen treatment is that compliance is essential to receive the full benefit of long-term therapy, and that longer therapy is better than shorter therapy.14,38 Early studies demonstrated that metabolic tolerance to long-term adjuvant tamoxifen treatment does not occur even after a decade of treatment.30,58 In other words, tamoxifen does not get metabolized to estrogen-like metabolites or become rapidly excreted. However, there are wide interpatient variations in circulating levels of both tamoxifen and metabolites, which this has been a mystery until recently. Hot flashes, or other menopausal symptoms, are the main reason for stopping therapy prematurely, but as it turns out, menopausal symptoms are associated with a good prognosis and with an improved control of disease recurrence.59,60 The metabolites of tamoxifen are antiestrogenic (Fig 1) and the conversation of tamoxifen to 4-hydroxytamoxifen is an advantage—but not a requirement—for antiestrogenic activity.61,62 4-hydroxytamoxifen continues to be an important laboratory tool for the laboratory study of antiestrogen action63,64 and has been used to study the crystal structure of the ER with estrogens and antiestrogens.65 However, a related metabolite endoxifen or 4-hydroxy-N-desmethyl tamoxifen66 is the major antiestrogenic metabolite of tamoxifen in patients and is produced by the enzyme CYP2D6 (Fig 1).67 Variants of the enzyme can either increase or decrease tamoxifen metabolism in patients producing more or less endoxifen. It is believed that elevated endoxifen can cause hot flashes which may suggest that the application of a selective serotonin reuptake inhibitor (SSRI) to alleviate these symptoms would be a reasonable course of action to maintain patient compliance. However, certain SSRIs, such as fluoxetine and paroxetine, block CYP2D6 and are contraindicated for patients taking adjuvant tamoxifen (Fig 1).68-70 Venlafaxine is the SSRI of choice because it has a low affinity for CYP2D6. The general principle is to ensure appropriately high levels of endoxifen are produced to provide the best chance for therapeutic success with tamoxifen (Fig 1).
The received wisdom in the 1980s was that estrogen could prevent both osteoporosis and coronary heart disease (the latter was subsequently proven to be incorrect in the Women's Health Initiative nearly two decades later).71 The proposed clinical evaluation of tamoxifen, a so-called antiestrogen, as a chemopreventive in healthy pre- and postmenopausal women, raised the concern that an antiestrogen would prevent the development of breast cancer, but increase the risk of crushing osteoporosis and death from coronary heart disease. In my laboratory at the Wisconsin Comprehensive Cancer Center (Madison, WI), we initiated a program to evaluate the pharmacology of tamoxifen so we could predict the extent of toxic adverse effects in subsequent clinical trials. At that time, we were positioning the overall program at Wisconsin to conduct a chemoprevention study. We discovered that tamoxifen exhibited target site-specific actions as an estrogen in the mouse uterus72 and human endometrial cancer,50 as an antiestrogen in rat mammary carcinogenesis13,17,73 and in human breast cancer cells,72 but was an estrogen-like drug able to preserve bone density in ovariectomized rats.49 Our findings that the target-specific action of tamoxifen-induced endometrial cancer growth50 had immediate clinical consequences that were to improve health care.74,75 The public discussions that followed caused clinical trials organizations to evaluate their emerging data. An elevated incidence of endometrial cancer in postmenopausal patients was noted in those women who received tamoxifen.51,76 Initially, the description of this adverse effect caused unprecedented concern that there would be a high incidence of poor-grade endometrial cancer,77 but the results of Fisher et al's chemoprevention study18 clearly demonstrated that there was no elevation in endometrial cancer in premenopausal women, but a four- to five-fold increase in endometrial cancer with good grade (early detection) in postmenopausal women. The involvement of gynecologists in the treatment plan for breast cancer provided the necessary safeguards for patients. Overall, it is now established that the benefits of long-term adjuvant tamoxifen treatment far outweigh the risks of endometrial cancer,14,38 but it was clear even in 1989 that an alternative approach to chemoprevention was necessary.78,79 The idea was simple: "We have obtained valuable clinical information about this group of drugs that can be applied in other disease states. Research does not travel straight lines and observations in one field of science often become major discoveries in another. Important clues have been garnered about the effects of tamoxifen on bone and lipids so it is possible that derivatives could find targeted applications to retard osteoporosis or atherosclerosis. The ubiquitous application of novel compounds to prevent diseases associated with the progressive changes after menopause may, as a side effect, significantly retard the development of breast cancer. The target population would be postmenopausal women in general, thereby avoiding the requirement to select a high-risk group to prevent breast cancer."79 This strategic prediction was not made in isolation. We had already completed laboratory studies with a chemical cousin of tamoxifen, called keoxifene, to show it prevented rat mammary carcinogenesis73 and almost completely blocked tamoxifen-stimulated endometrial cancer growth80 but prevented bone loss in ovariectomized rats.49,81 However, at that time in 1990, nobody cared.
The compound known as LY156758 or keoxifene82 started life as an antiestrogen and all initial efforts in testing were focused on an application as a breast cancer drug. It was to be a competitor for tamoxifen. However, keoxifene failed in that application83 because the drug group has poor bioavailability84 and crossresistance with tamoxifen.85 As with tamoxifen, keoxifene was a drug looking for an application. Scientists at Eli Lilly eventually confirmed86 the earlier results that keoxifene preserved bone density49 and like tamoxifen10 also lowered circulating cholesterol (tamoxifen already had a patent as a hypocholesteremic agent11). The trial Multiple Outcomes of Raloxifene Evaluation (MORE) addressed the hypothesis that raloxifene could reduce the incidence of fractures in high-risk osteoporotic postmenopausal women. The results showed raloxifene did reduce spinal fractures by approximately 50% during the 3-year treatment period.87 Raloxifene was the first SERM approved to treat and prevent women at risk for osteoporosis. The second preplanned evaluation was breast and endometrial safety. I was the chair of the Oncology Advisory Committee established to monitor breast cancer incidence. We found a significant 70% decrease after 3 years of raloxifene88 in the incidence of breast cancers and after 4 years89 of raloxifene treatment for osteoporosis. A subsequent evaluation of a placebo-controlled trial called Raloxifene Use for the Heart (RUTH), designed to evaluate the cardio protective actions of the SERM,90 also noted a significant decrease in invasive breast cancer incidence and more importantly, both MORE88 and RUTH90 showed no elevation in endometrial cancers. However, the RUTH trial showed no improvement or benefit for patients at risk for dying from cardiac disease if they took raloxifene.90 As a public health intervention, the original proposal78,79 that a SERM used to prevent osteoporosis in women at risk for osteoporosis could simultaneously reduce the incidence of breast cancer appears to be valid. With the current shift in the prescribing of hormone replacement therapy in the wake of the Women's Health Initiative71 in the United States and the Million Women's Study91 in the United Kingdom, a decrease in the incidence of ER-positive breast cancer has been noted by Ravdin.92 With the availability of raloxifene as long-term therapy to treat and prevent osteoporosis, it is clear that there will potentially be a reduction in breast cancer incidence in the general population. This anticipated decrease in breast cancer incidence with long-term raloxifene use is evidenced by the data published by Martino et al.93 These data were recently used to estimate decreases in breast cancer incidence in large populations of women not identified as at risk for breast cancer.94 The good safety and efficacy profile for raloxifene made it the agent of choice to compare head-to-head against tamoxifen in the Study of Tamoxifen and Raloxifene (STAR) to reduce breast cancer incidence in postmenopausal women deemed at high risk. Norman Wolmark invited me to be the scientific chair on the STAR trial advisory board just in case there were any toxicological or pharmacologic surprises. None occurred. Overall, the results33 were another important step forward in chemoprevention; tamoxifen and raloxifene reduced the incidence of breast cancer equally, but the safety profile of raloxifene is superior. Based on the clinical trials,19,33,55,93,95 it is now possible to summarize progress in chemoprevention (Table 219,33,39,88,96), because agents can now be applied selectively to patient populations. However, each agent has been reinvented and then transitioned from the laboratory through clinical trials to an advance in health care, a process that extended over 30 years. It is perhaps important to state that the prudent use of tamoxifen or raloxifene to reduce the risk of breast cancer in the appropriate groups of high risk women is an important advance in therapeutics. Regrettably, there is reluctance to use these approved agents within the high-risk population, but often this is because of misinformation about the risks as physicians are now in a position to pick the right agent for the right patient.
The acceptance of the concept of long-term antihormone therapy to target, treat, and prevent breast cancer20 raised the specter of drug resistance to SERMs. Twenty years ago, my team took a long-term view by creating a whole range of breast and endometrial cancer models resistant to tamoxifen and raloxifene.97-101 Our goal was to anticipate the clinical development of drug resistance and to understand mechanisms so that second-line therapies could be deployed rationally. The models were developed naturally by first establishing estrogen stimulated tumor growth in athymic mice followed by long-term SERM treatment to identify SERM-resistant tumors. All our models were retransplanted into subsequent generations of mice so that the impact of long-term SERM therapy could be evaluated in hormone-responsive breast and endometrial cancer. What is unique about SERM resistance is that both breast and endometrial tumors grow in response to either SERMs or estrogen. No estrogen (mimicking aromatase inhibitor treatment) or the use of a pure antiestrogen (ICI 164,384102 or fulvestrant103,104) prevent SERM resistant tumor growth. This is why aromatase inhibitors or fulvestrant are effective second-line therapies after tamoxifen failure.105,106 However, the early models of SERM resistance did not reflect the majority of clinical experience. The natural laboratory models developed during a year of therapy97,107 and therefore reflected drug resistance in patients with metastatic breast cancer who are only treated successfully for 1 year. In other laboratories, ER-positive models were developed that were engineered by stable transfection of the HER2/neu gene.108,109 These tumors are resistant to tamoxifen but reflect a small subset of clinical disease, including ER/HER2/neu–positive breast cancer. We took the strategic decision to determine what would occur if breast tumors were retransplanted into successive generations of tamoxifen stimulated mice for 5 years or more (ie, to replicate the actual clinical conditions employed during long-term adjuvant therapy). Remarkably, drug resistance evolves (Fig 299,110) and the survival signaling pathway in tamoxifen resistant tumors becomes reorganized so that instead of estrogen being a survival signal, physiologic estrogen now inhibits tumor growth. This discovery99,111 provided an invaluable insight into the evolution of drug resistance to SERMs and prompted the reclassification of the process through phase I (SERM/estrogen stimulated growth) and phase II (SERM stimulated growth estrogen inhibited growth). This new knowledge now provides an opportunity to treat patients with low-dose estrogen after exhaustive antihormone therapy.
The apoptotic action of physiological estrogen to cause dramatic tumor regression of long-term tamoxifen-resistant ER-positive breast cancers grown in athymic mice99,111 was subsequently extended to long-term raloxifene resistance112 and ER-positive breast cancer cells maintained in an estrogen-deprived environment for prolonged periods.110,113-116 Most importantly, the apoptotic results observed with estrogen-deprived cells were noted both in vitro and in vivo by inoculation into athymic mice.110 Mechanistic studies, using our unique laboratory models, demonstrate that the antihormone resistant cells have reconfigured the ER signal transduction pathway so despite the fact that the ER still regulates the appropriate estrogen-regulated genes (including pS2 and myc)117 there is a profound effect of estrogen to activate the fas (death) receptor system115,118 or to alternatively have a direct effect on mitochondrial function via the bcl2 system.111,119 Thus, an understanding of the paradoxical actions of estrogen has emerged that depend on the state of estrogen deprivation of the breast cancer cell. In an estrogen rich environment, the estradiol-ER complex is a survival system promoting tumor growth. In contrast, in an estrogen-deprived environment (treatment with tamoxifen or an aromatase inhibitor) estrogen action is replaced by internal survival signaling based on the selection of cells with enhanced growth factor receptors. The growth factor receptors120 initiate cascades that phosphorylate either unoccupied ER or ER liganded by SERMs. This model would also explain the earlier observations why high-dose estrogen therapy was only effective as a treatment for breast cancer in women many years after the menopause.1 Natural estrogen deprivation had occurred. The process is accelerated and enhanced, however, in patients treated long-term with SERMs or aromatase inhibitors so that only low doses of estrogen are necessary to cause experimental tumors to regress. The question now becomes, can this new laboratory knowledge be translated to patient care? Several clinical trial groups are currently addressing this issue. In our own case, we are recruiting patients with metastatic breast cancer who have succeeded and experienced treatment failure with at least two successive endocrine therapies (Fig 3) and we are determining the efficacy of a 12-week purge of high-dose estradiol (30 mg daily) therapy. The goal is to confirm and extend the previously study published by Lonning and colleagues121 and then to determine the minimum dose of estradiol necessary to induce the anticipated 30% response rate.121 Based on our previous laboratory studies,99 we propose to retreat responding patients with anastrozole to determine efficacy.
Overall, our clinical program is part of a multi-institutional Center of Excellence grant BCO50277 entitled "A New Therapeutic Paradigm for Breast Cancer Exploiting Low-Dose Estrogen-Induced Apoptosis" that will map the survival and death pathways of our models and integrate clinical material to determine the validity of the laboratory-derived molecular mechanisms and, ultimately, to address the issue of why the majority of tumors do not respond to estrogen alone. Knowledge of the new apoptotic biology of estrogen could be enhanced in the future in much the same way as the modest responses initially observed were enhanced to benefit patients with tamoxifen and raloxifene. The philosophy is to deploy the right treatment at the right time and for the right patient.
In closing, it is perhaps pertinent to re-examine Haddow's comments delivered during the first David A. Karnofsky lecture in 1970. He saw little evidence that specific chemical therapies could be developed and there was really no predictive test to identify tumors that could respond to a chemical therapy. The idea of a targeted drug was to be advanced soon thereafter during the 1970s20 when the ER assay evolved from being a predictive test for endocrine ablation to become the target for a failed contraceptive to be reinvented as tamoxifen and to be used for long durations in the treatment and prevention of breast cancer.11 However, translational research does not travel in straight lines: one needs luck so the unanticipated can be integrated into the treatment plan and perhaps, if one is lucky, new innovations in therapy can be developed. SERM was unanticipated and much luck led to progress in treatment. Issues over the increased risk of endometrial cancer caused by tamoxifen treatment coupled with the recognition that the drug group called the nonsteroidal antiestrogens122 could enhance bone density in animals49,123 and man54 opened the door for the development of raloxifene81 as the first SERM for the treatment and prevention of osteoporosis as well as the reduction of risk for breast cancer,33,88 but with no increase in endometrial cancer risk. Chemoprevention has now extended from an idea16,17,124 to a clinical reality (Table 2). The enormous impact that tamoxifen has had on the treatment of breast cancer for 25 years (1978 to 2003) naturally encouraged efforts to improve treatment responses and reduce the adverse effects noted with tamoxifen.125 This goal has been achieved with the introduction of a range of aromatase inhibitors for the treatment of breast cancer in postmenopausal women.125,126 The principles of treatment remain the same: targeting the ER and then employing long-term therapy now for perhaps up to 15 years to exploit the trend observed in MA-17 (tamoxifen followed by an aromatase inhibitor).127 Tamoxifen surprisingly did not go away, but remains the treatment of choice for premenopausal women with breast cancer, the appropriate agent for risk reduction in premenopausal women, a major drug of interest for the study of pharmacogenomics, and the major life-saving antihormone in countries throughout the world that do not have the sophisticated and wealthy health care system we have in the United States. Furthermore, the laboratory principle from the 1970s that "longer is better" for adjuvant therapy13,128 continues to be evaluated in the Adjuvant Tamoxifen Long Against Short (ATLAS) trial that compares 10 years of tamoxifen with 5 years of tamoxifen. If 10 years of tamoxifen treatment is superior to 5 years, then the public health impact will be profound as this cheap and easily accessible drug can continue to provide benefit in lives saved. The current approaches and advances in the antihormone therapy of breast cancer are summarized in Figure 4.
Finally, the paradox of estrogen action in dictating the survival or death of breast cancer cells has become transparent, closing a circle of knowledge left hanging in the wake of Haddow's Karnofsky presentation in 1970.1 The dramatic results he observed with high-dose estrogen therapy in a small fraction of women1 was a powerful testament to the potential of chemical therapy. Unfortunately, there was no knowledge about the mechanisms to further exploit the concept. Fashions in therapy began to move toward blocking estrogen action and shifted from the more toxic high doses of estrogen to the less toxic but equally efficacious tamoxifen.129 Now we find ourselves returning to the beginning of "chemical therapy" because unusual and unanticipated laboratory observations were placed on the web of knowledge. This knowledge has remained dormant until it could now be called to the center of the web when the fashion in research again changes. The discovery of apoptosis as a natural process to destroy aberrant cells130 would probably have never be linked in the same sentence with "hormone" therapy. However, it is now clear that antihormone drug resistance can reprogram some hormone responsive cancer cells to be supersensitive to the apoptotic actions of physiological estrogen.99,111 These tantalizing laboratory observations now provide another opportunity for chemical therapy to aid patients. The knowledge is already finding its way into clinical trials, so that in the future it may be possible that the antihormone resistant disease from select patients can be destroyed by an "estrogen purge" and then patients could again be maintained for a longer period on an antihormone therapy. We have perhaps researched the zenith of our abilities to manipulate the ER with our current armamentarium. So, is this then the end of our story? Certainly not. There is much still to be accomplished. The SERM concept has now been extended to include all members of the steroid receptor superfamily20,131 so that in the future diseases may be selectively treated that until now had been thought to be untreatable. New specific medicines are now being developed to achieve this goal.131,132 But, where could the estrogen-induced apoptosis story take us? It may be that the modest results observed in select sensitive patients with ER-positive metastatic breast cancer could be amplified by the prudent use of selective survival inhibitors. If the cancer cell is prevented from surviving, then perhaps the mild estrogen apoptotic trigger will kill more tumor cells. Indeed, if we can work out how the ER complex naturally seeks out its intracellular trigger, then perhaps that trigger could be the next target for chemical therapy for a range of cancers beyond breast cancer.
The author(s) indicated no potential conflicts of interest.
I thank the generations of "tamoxifen teams" who converted ideas into lives saved during the past 35 years.
published online ahead of print at www.jco.org on June 2, 2008. Supported by the Department of Defense Breast Program under Award No. BC050277, Center for Excellence SPORE in Breast Cancer CA 89018 R01 GM067156, Fox Chase Cancer Center Core Grant No. NIH P30 CA006927, the Avon Foundation, the Genuardi's Fund, and the Weg Fund of the Fox-Chase Cancer Center. Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. Author's disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
