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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda 4 Other Therapeutic Uses of Antiprogestins ENDOMETRIOSIS Endometriosis is a non-malignant, albeit progressive, disease attributable to the presence of endometrial glands and stroma (supporting connective tissue) in ectopic locations (outside the endometrium of the uterus) most commonly within the pelvic cavity. Although multiple pathophysiologic mechanisms underlying the genesis of endometriosis have been proposed, the precise etiology of the disease remains unknown. Hard numbers on the actual prevalence of endometriosis are not available, and because diagnosis is frequently difficult and not regularly reported, the estimates of prevalence constitute approximations at best. Some afflicted patients are diagnosed incidentally during laparoscopy or exploratory laparotomy for a variety of other indications. Some investigators have reported that endometriosis may be detected in 5 to 15 percent of abdominal laparotomies performed on reproductive-age females. That incidence may increase to 30 to 40 percent in the infertile population. The most typical symptomatic complaints associated with endometriosis include chronic pelvic pain, dysmenorrhea (painful menses), dyspareunia (painful intercourse), and infertility. However, not all patients with endometriosis are symptomatic. Moreover, correlation between the severity of this disease and the manifestation of symptomatology is far from absolute. Pelvic examination may reveal evidence of active endometriosis, provided the disease has extended to the lower pelvis, most importantly to the uterosacral ligaments. Alternatively, the presence of
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda large ovarian cysts, also known as endometriomas, may be detected. Sonographic assessment of the latter may enhance the clinician's diagnostic suspicion. In the final analysis, however, the diagnosis of endometriosis requires surgery and is a histologic diagnosis complemented by direct observation of the typical lesion through laparoscopy or laparotomy. Unanswered questions about the precise etiology of endometriosis notwithstanding, there is little doubt about the hormonal responsiveness of ectopic endometrial tissue. In general, estrogen deprivation, progestin excess, and androgen excess appear to have a favorable, albeit reversible, impact on the disease. Although regression of the lesions in many, but not all, patients can be documented when such regimens are used, the effect is always palliative, not curative. By using these findings therapeutic strategies over the last 30 years have made use of the progestational effect of high-dose combination oral contraceptives to produce pseudopregnancy, the apparent antiendometrial effect of testosterone, the progestational-androgenic effect of danazol, and the hypoestrogenic impact of gonadotropin-releasing hormone (GnRH) agonists to produce pseudomenopause. Surgical therapy has always constituted a component of the treatment regimen, particularly when endometriosis is associated with infertility. Here, too, only palliation can be anticipated. Moreover, significant concerns currently exist as to the very utility of this approach in light of the iatrogenic insult acquired in the process. Clearly then, long-term prevention may well be the best strategy for individuals with known early disease. Utility of Mifepristone (RU 486) for Treatment of Endometriosis The first suggestion about the utility of mifepristone to treat endometriosis can be traced to an article by van Uem et al. (1989), who observed that the administration of mifepristone to female monkeys treated with human menopausal gonadotropin and human chorionic gonadotropin resulted in the genesis of an atrophic to weakly proliferative endometrium on menstrual cycle day 25, despite serum estradiol concentrations in excess of 300 pg/ml. These effects were observed whether mifepristone was begun on cycle day 3 or 7. Thus, when administered daily in early or midfollicular phase at a dose of 10 mg/kg, mifepristone elicited a persistent retardation of early proliferative endometrium. Apparently it antagonized the mitogenic effects of estrogens. This observation prompted the investigators to suggest that mifepristone might exhibit noncompetitive antiestrogenic activity. To elaborate on this action of mifepristone, Wolf and associates (1989) examined its action in estradiol-treated monkeys. Use of mifepristone
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda alone at a dose of 1 mg/kg was associated with the induction of a secretory endometrium, but higher doses (5 mg/kg) inhibited both proliferation and secretory activity. Thus, in the absence of progesterone, the actions of mifepristone were biphasic in nature. This mifepristone action appears to be associated with an increase in the estrogen-receptor content of the relevant endometrium, a dose-dependent phenomenon (Neulen et al., 1990). However, the latter observation may be affected to some degree by the choice of the denominator—that is, protein versus cellular DNA content. More recently, the effects of mifepristone were examined using rats in which endometriosis had been experimentally induced (Tjaden et al., 1993). Animals were treated daily with mifepristone (10 mg/kg body weight subcutaneously) for two, four, six, or eight weeks. No regression of endometriosis was observed. The precise reasons for this apparent species/model specificity remain unknown. Stimulated by the preceding observations, Kettel and associates (1991) reported the first relevant (though preliminary) human study on the endocrine response to long-term administration of mifepristone to patients with endometriosis. Six women who had normal menstrual cycles and who had endometriosis were recruited for the study, and received mifepristone at a dose of 100 mg/day for three months. Importantly, this regimen produced uniform amenorrhea. The mean circulating levels of luteinizing hormone (LH) and the LH pulse amplitude (but not frequency) were increased. An antiglucocorticoid effect was apparent as assessed by an increase in the circulating levels of cortisol and adrenocorticotropic hormone (ACTH). Pelvic pain was reportedly lessened in all subjects, but there was no significant change in the extent of the disease as evaluated by follow-up laparoscopy. Unpublished observations reported by Yen at the Institute of Medicine workshop addressed the administration of mifepristone for a period of six months. Nine women with symptomatic endometriosis, who had no improvement with other forms of medical therapy, were recruited and treated with 50 mg/day mifepristone. Again, amenorrhea was uniformly induced. Likewise, all subjects reported a significant decrease in pelvic pain and dysmenorrhea. American Fertility Society (AFS) scores, a measure of the extent of disease, improved significantly in eight of nine subjects. Bone mineral density measurements of the lumbar spine and femur revealed no adverse effect. An initial increase in the circulating levels of LH and testosterone was noted in the first month of treatment. The levels of estradiol remained in midfollicular phase range. No antiglucocorticoid effect was noted. Side effects included transient, mild increases in liver transaminase (20 percent of patients), which returned to normal after one month. A follow-up study using a lower dose of 5 mg/day of mifepristone administered for six
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda months is ongoing. Early results in this study appear promising. It is possible, then, that doses of mifepristone as low as 5 mg/day may prove effective in treating the symptoms and extent of disease in endometriosis. Summary The very limited body of data currently available to assess the use of mifepristone for the treatment of endometriosis is nevertheless encouraging enough to warrant additional investigation. The main promise offered by mifepristone therapy for treating endometriosis is preservation of follicular phase levels of estradiol. This would protect women from the consequences of very low estrogen (hypoestrogen), a side effect of other effective forms of therapy (e.g., GnRH agonists). These side effects include transient decrements in bone density and hot flashes. It is important to note, however, that although GnRH may well induce a hypoestrogenic state, such an effect may be indispensable to therapeutic efficacy. With regard to other side effects, it is quite conceivable that the dose of mifepristone could be reduced to a level at which its antiglucocorticoid side effects would be negligible. Other antiprogestins with a higher level of specificity for the progesterone receptor (lower antiglucocorticoid activity) could also be tested. It appears that much of the therapeutic benefit derived from antiprogestins in general or from mifepristone in particular may have to do with an ''antiestrogenic" effect exerted directly at the level of the endometrium. By extrapolation, similar effects would be exerted at the level of the ectopic endometrial implants. Although the precise cellular mechanism involved remains unknown, empirical observations in the monkey appear to bear out this effect of mifepristone. For the most part, the women in the available studies reported pain relief and, at least in one study, a real decrease in the overall extent of disease as assessed by the AFS scores. Clearly, additional studies would be required to further evaluate these initial promising observations. UTERINE LEIOMYOMAS (FIBROIDS) Uterine leiomyomas, also known as fibroids, are benign tumors of smooth muscle cell origin and varying amounts of fibrous tissue (thus the term "fibroid"). Leiomyomas, which may be single or multiple and highly variable in size, are the most common pelvic tumor recognized, occurring with the highest frequency during the fifth decade of a woman's life. Although the precise cellular mechanism underlying the pathogenesis of leiomyomas remains unknown, there is little question about the hormonal dependence of this condition. Indeed, it would appear that estrogen deficiency and perhaps pro-
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda gestin excess exert a beneficial, though temporary, effect on leiomyoma growth. The symptoms related to leiomyomas are primarily a result of pressure from an enlarging pelvic mass. Dysmenorrhea and abnormal menstrual bleeding are also relatively common symptoms. The diagnosis of uterine leiomyoma can be made by pelvic examination and confirmed by sonographic or magnetic resonance imaging. Treatment, medical as well as surgical, is contingent upon the age of the individual, the severity of the symptoms, and the attendant medical complications. High-dose progestin therapy as well as GnRH agonists have been shown to decrease overall uterine volume by as much as 50 percent, usually in the course of a three-month treatment period. Clearly, however, the effect of medical therapy is temporary, and no therapy has thus far been used on a long-term basis. In the face of persistent symptoms, surgical therapy is usually applied in advanced disease following the failure of medical therapy and, ideally, when no pregnancies are desired. Utility of Mifepristone for Treatment of Uterine Leiomyomas The only published study using antiprogestins to treat uterine leiomyomas was conducted by Murphy et al. (1993). The investigators examined the effects of daily administration of mifepristone at a dose of 50 mg for three months on 10 patients with uterine leiomyomas and regular menstrual cycles. Invariably, amenorrhea was induced. The volume of the leiomyomas decreased by 49 percent after 12 weeks of therapy. The circulating levels of LH (but not follicle-stimulating hormone) virtually doubled during the first three weeks of treatment, in association with a significant increase in the circulating levels of androstenedione and testosterone. However, these hormonal alterations were limited to the first month of therapy and returned to normal thereafter. Similarly, a significant increase was noted in the circulating levels of dehydroepiandrosterone sulfate and cortisol at 12 weeks, which suggests an antiglucocorticoid effect. Importantly, however, the circulating levels of estradiol and estrone were unchanged relative to early follicular phase values. Myomectomy or hysterectomy was performed in 6 of 10 patients at the end of treatment. Reportedly, progesterone-receptor (but not estrogen-receptor) immunoreactivity was significantly reduced in both leiomyomas and myometrium after therapy, compared to untreated controls. Side effects included mild atypical hot flashes and a transient elevation in serum transaminase accompanied by joint pain. These were experienced at the end of treatment in one patient who had prompt resolution of the side effects after discontinuing the drug. Bone mineral density at the level of the spine and hips remained unaffected after three months of therapy. In a follow-up dose-response study discussed at the workshop, Yen
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda (Appendix B8) reported on the use of 25- and 5-mg daily doses of mifepristone. Specifically, 17 patients were given 25 mg daily; seven patients were given 5 mg daily for a total of three months. Again, all patients became amenorrheic. Two patients given a 25-mg dose had mild elevations of liver transaminase, which resolved within one month of discontinuing the medication. After three months of treatment, Yen found a 68.4 percent decrease in leiomyoma volume in patients given 25 mg/day. The corresponding decrease for the 5-mg/day dose was 29.2 percent. No antiglucocorticoid effect was noted at the 25- and 5-mg/day dose levels. The 25-mg/day dose resulted in a substantial reduction of uterine blood flow as assessed by Doppler sonography; but long-term efficacy has yet to be established. Recommendation No. 13. The committee recommends further studies to determine the minimal effective dose of mifepristone and other antiprogestins for the treatment of endometriosis and uterine leiomyomas. Measures of outcome should not be limited to pain relief alone, but should also address the likelihood of improving fertility. Once such studies are completed, randomized clinical trials should be undertaken to compare the safety and efficacy of mifepristone and other antiprogestins with current therapies for the treatment of endometriosis and uterine leiomyomas. Recommendation No. 14. The committee recommends additional research to elucidate the antiestrogenic property of mifepristone and other antiprogestins. Research models should include endometrial cultures, explants, and in vivo systems. It is also important to clarify the molecular events involved and, in all such investigations, to characterize whenever possible the steroid-receptor status of the endometriotic and fibroid tissues under study. BREAST CANCER Interest in the study of antiprogestins in breast cancer is understandable, given the well-known prognostic importance of the progesterone receptor in this disease and the activity of a variety of diverse endocrine manipulations for its treatment (Hamm and Allegra, 1991). Approximately 30 percent of unselected patients and 50 to 80 percent of estrogenand progesterone-receptor-positive, metastatic breast cancer patients will have some degree of benefit from a variety of endocrine interventions. Although these patients may improve temporarily in response to these treatments, they are not cured.
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda Paradoxically, both estrogen and progesterone in low doses stimulate breast cancer growth, whereas high dosages of either are growth inhibitory and are used clinically in the treatment of breast cancer. In addition, the antiestrogen tamoxifen is generally the mainstay of first-line therapy for advanced estrogen-receptor-positive tumors because of its efficacy, safety, and convenience (Hamm and Allegra, 1991). In this context, it is not surprising that another endocrine manipulation with antiprogestins appears to have activity in breast cancer. Although research on the potential cancer applications of antiprogestin therapy has lagged behind endocrine and reproductive research, a number of issues that merit further study were identified at the committee's workshop, and some of these issues are discussed below. However, given the many complexities of the progesterone receptor and of the effects of binding with agonists and antagonists in different tissues described at the workshop, there are undoubtedly many reasonable research questions to be addressed, and the issues raised in the following discussion are meant to be illustrative rather than exhaustive. Mechanism of Action The mechanism by which antiprogestins exert their growth-inhibitory effects is complex and not fully understood. Even among the antiprogestins there are structural and functional variations suggesting that there may be important differences among this class of compounds in their mechanisms of action. Weigel (Appendix B2) points out that the three-dimensional structures of the two clinically available antiprogestins, mifepristone and onapristone, are quite different and that they appear to inhibit progesterone-receptor function by different mechanisms. Horwitz (Appendix B9) describes the tissue-specific differences in progesterone effects and the implications of these differences for breast cancer treatment. In contrast to its actions in the uterus, progesterone at low dosage approximating physiologic ranges is growth stimulatory in the normal breast; most mitoses occur in the late luteal phase of the menstrual cycle coincident with the rise in progesterone. Blockade of this mitogenic effect was described as a potential strategy for breast cancer prevention. On a molecular basis, there are a number of differences among progesterone receptors when bound to various antiprogestins (some antiprogestin-receptor complexes bind to DNA, and others do not). These differences govern agonist versus antagonist activities. For example, as Horwitz described at the IOM workshop (see also Horwitz, 1992), several progesterone antagonists are "transcriptionally silent" when occupying smaller type A progesterone receptors (PR-A) but stimulate strong transcription when occupying the larger type B receptors (PR-B) (Weigel, Appendix B2). The tissue distribution
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda of these naturally occurring progesterone receptors has not been fully elucidated but has obvious biologic and toxicity implications, and this represents an important area for future research. The complex effects of PR-A and PR-B are further complicated by the fact that some PR-B effects may not appear to require DNA binding. In other studies of these receptors it appears that PR-A dominates PR-B; equimolar amounts of A abolish the agonist activity of B. The agonist activity of an antiprogestin bound to the PR-B represents a potential mechanism of clinical resistance to antiprogestin. The fact that PR-B agonist activity may be mediated by binding, not to DNA but to other regulatory proteins that might be distributed differently than the progesterone receptors, may also help explain tissue-specific differences in response to progesterone and antiprogestins. Intriguing data by Michna et al. (1992) and Henderson at the IOM workshop have suggested a novel mechanism of action for the antiprogestins onapristone (ZK 98 299) and Schering's ZK 112 993. Specifically, morphologic and cell-cycle distribution data suggest that they induce terminal differentiation and produce cell death through apoptosis (programmed cell death)1 rather than necrosis. Data on down-regulation of tenascin, an extracellular matrix glycoprotein of tumor stroma, in rat mammary tumors provide additional support for the induction of terminal differentiation as an underlying mechanism of growth inhibition by onapristone. Interestingly, although ovariectomy and antiestrogen therapy were associated with growth inhibition in this model, neither was associated with decreased expression of tenascin (Volleyer et al., 1992). These observations may be important in attempting to define a unique clinical role for antiprogestins in the endocrine armamentarium and certainly deserve additional study. Data from other studies that demonstrate enhanced antitumor activity with combination endocrine therapy may also have important implications for the future clinical development of antiprogestins (Baker et al., 1989). Improved antitumor activity was observed in rat mammary tumor models with combination endocrine therapies incorporating antiprogestins and antiestrogens or HL-releasing hormone (LHRH) agonists. Significant down-regulation of estrogen- and progesterone-receptor content was noted. Data on endocrine combinations are also presented by Horwitz (Appendix B9) in a rat dimethylbenzanthracene (DBA) (carcinogen-induced) breast cancer model with established tumors. These data demonstrated that the combination of an 1 In the normal course of events cells of the body die and are replaced by new cells; the programming and mode of this metabolic "suicide" have been given the name apoptosis to distinguish them from the type of death called necrosis. This latter implies that some harmful agent, foreign to the cell's own metabolic programs, has caused the cell to die.
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda antiestrogen (tamoxifen) and antiprogestin produced tumor regressions comparable to ovariectomy, whereas either agent alone only produced tumor stasis. In the DMBA model, tamoxifen down-regulated the estrogen receptor; however, it also exerted agonist activities and thereby up-regulated the progesterone receptor. Mifepristone down-regulated both the estrogen receptor and the progesterone receptor. In other DMBA experiments with established tumors, progesterone was able to overcome the growth inhibition produced by tamoxifen. This finding suggests that tamoxifen could not inhibit the progestin-mediated growth-stimulatory effects. Addition of mifepristone with progesterone effectively reestablished tamoxifen growth inhibition. These results provide a rationale for future study of combination endocrine therapy. Such study would be further enhanced by the availability of compounds with pure antiprogestin properties and, therefore, presumably more specificity and less toxicity. Clinical Issues To date, the clinical activity of antiprogestins in breast cancer patients is sparse and clinically unimpressive. Data on 33 patients treated with mifepristone have been published. No other clinical trials have been completed, although onapristone recently entered its first clinical trial in cancer patients in Europe, and larger trials of mifepristone are ongoing in Europe and Canada. In the largest experience (Horwitz, Appendix B9, and references in Maudelonde et al., 1987, and Romieu et al., 1987, therein), 22 postmenopausal or oophorectomized patients with advanced breast cancer were treated with mifepristone (200 mg daily). All patients' tumors had progressed while they were on tamoxifen, and all had received at least one other prior therapy including chemotherapy, radiation, or another endocrine treatment. Conventional response criteria were not used in this trial, so it is difficult to determine whether any of the patients had an objective partial response.2 Twelve patients were judged to have had partial regression or stabilization of disease. In only four patients was the effect persistent for three months. An analgesic effect on bone pain was also noted. Estrogen- and progesterone-receptor status were not available for many of these patients. In a second study, 11 postmenopausal patients received mifepristone doses of 200 to 400 mg daily as second-line treatment following tamoxifen (Michna et al., 1989; Bakker et al., 1990; Horwitz, Appendix B9). 2 Typical criteria for partial response require a 50 percent reduction in the sum of the products of the perpendicular diameters of the measured lesion.
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda One partial response in a patient with lymph node metastases was observed, but the response lasted for only five months. Disease did not progress in six patients for periods of three to eight months. The appearance of toxicities was delayed; these included weight loss in ten patients, fatigue, anorexia, nausea, malaise, somnolence, and one grand mal seizure. A rise in serum creatinine and an increase in eosinophil counts were also observed. Of interest is the fact that 3 of the 11 patients responded to third-line treatment with the progestin megestrol acetate. This included the one patient who had also responded to mifepristone. A number of endocrine levels were evaluated in this study. Increases were noted in estradiol, ACTH, cortisol, and androstenedione, but sex hormone-binding globulin levels decreased with treatment. The authors attributed increases in estradiol in these postmenopausal women to increased adrenal stimulation secondary to antiglucocorticoid effects of mifepristone and subsequent peripheral conversion of adrenal androgens to estrogens in these postmenopausal women. This increase in estrogens, which could be potentially deleterious to the treatment of breast cancer, hypothetically could be overcome by combining the antiprogestin with an antiestrogen or aromatase inhibitor. Preclinical data supporting the utility of such an approach are mentioned above (Kian et al., 1989; Bakker et al., 1990). Adjuvant Therapy and Chemoprevention Potential uses for antiprogestins in adjuvant therapy (postoperative therapy undertaken when no detectable tumor is present to reduce the risk of recurrence) or chemoprevention (treatment of well women to lower the risk of initial development of cancer) arose at the committee's workshop during the discussion of Horwitz's presentation, undoubtedly stimulated in part by the experience with the use of the antiestrogen, tamoxifen, for these indications. However, given the current status of the clinical development of antiprogestins, specifically mifepristone, such applications to chemoprevention are purely speculative at present. Although a number of interesting theoretical applications have been identified, clinical experience with these compounds is too limited at present. In addition, the potential for agonist as well as antagonist activity (discussed in several papers in Appendix B) and the preclinical observation of tumor stimulation (Bowden et al., 1989) suggest that cautious observation will be required prior to clinical trials in early breast cancer or prevention. Substantial clinical activity and acceptable toxicity in advanced disease patients would be required before one could seriously consider using antiprogestins as an adjuvant treatment for breast cancer and certainly prior to their introduction for the chemoprevention of breast cancer. In addition, antiprogestin therapy would need
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda to distinguish itself from other available endocrine therapies, most notably tamoxifen, for this latter indication. Long-term toxicity experience will also be an important issue in assessing the therapeutic potential of antiprogestins in the treatment of curable early breast cancer and/or chemoprevention. Resistance Eventually all advanced breast cancers become hormone independent and increasingly resistant to any subsequent therapy. It is this development of resistance that limits the potential utility of antiprogestins and other endocrine therapies for the treatment of advanced disease. Further understanding of the mechanisms of resistance will be essential for future attempts to improve the efficacy of endocrine treatment. Dose Issues The issue of optimal dose remains unsettled. In some studies the antiproliferative effects of antiprogestins on breast cancer cells in vitro have been shown to be dependent on dose and progesterone-receptor content (Bardon et al., 1985). The use of a biologic end point (induction of menses with onapristone) to define an adequate dose makes certain assumptions regarding the relative sensitivities of tumor and endometrium to antiprogestins. It also assumes that the antihormonal mechanism underlies the antiproliferative actions of antiprogestins and that optimal doses for antiproliferative effects, differentiation, and other important actions such as growth factor induction will be similar. In that regard, it is interesting to note that tamoxifen, the best studied of the antihormonal agents used in breast cancer, is active in some patients with estrogen-receptor-negative tumors, suggesting that nonhormonal antitumor effects may be important. Tamoxifen exhibits other potential antitumor mechanisms, including induction of a number of polypeptide hormones, and inhibition of activation of protein kinase C and calmodulin (O'Brian et al., 1985; Horgan et al., 1986; Musgrove et al., 1989; Sunderland and Osborne, 1991). However, increased doses have not proved beneficial in tamoxifen therapy (Stewart et al., 1982; Rose et al., 1992). Nonetheless, given the uncertainties regarding the mechanism of action of antiprogestins, further exploration of dose, toxicity, and activity relationships seems reasonable. Conclusions The committee reached the following conclusions about the current state of the science for the use of antiprogestins to treat breast cancer:
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda The antiprogestins have potential as growth-inhibitory compounds against breast cancers. Whether this antitumor activity will be unique among the many other available endocrine therapies for breast cancer remains to be seen. There are at present too few clinical data to assess adequately the clinical potential of antiprogestins in the treatment of metastatic breast cancer, much less to assess their potential applications for adjuvant therapy or chemoprevention. The exact mechanism by which antiprogestins exert their antitumor effect is unclear at present. However, data suggest that more than one mechanism exists because the receptor-antiprogestin complexes of at least two of the clinically available antiprogestins appear to interact with DNA differently (the mifepristone-receptor complex binds DNA, but the onapristone-receptor complex does not). Although animal models can provide hypotheses, the biologic complexity and heterogeneity of breast cancer and the limitations of these models will require that many questions be addressed in human clinical trials. Even if the clinical experience with antiprogestins demonstrates substantial activity with an acceptable toxicity profile, it will still be important to define a unique mechanism or role for the use of antiprogestins as compared to other available endocrine therapies. Further elucidation of the antiproliferative mechanism of action, especially the differentiating effects, and of potential synergistic combination hormonal therapies will be useful in this regard. Recommendation No. 15. The committee recommends research to clarify the activity of antiprogestins in women with advanced (metastatic) breast cancer. Trials should be conducted by using more homogeneous groups of patients. Potential sources of heterogeneity should be reduced by including patients with only minimal prior therapy for their breast cancer and by performing pharmacokinetic evaluations to ensure consistent drug exposure and to facilitate concentration-response correlations. In these studies, tumor progesterone-receptor and estrogen-receptor status should be measured routinely. Recommendation No. 16. Clinical trials of antiprogestins for treatment of breast cancer should include ancillary investigations to clarify mechanisms underlying the activity of antiprogestins. Examples of such studies include histologic evaluation of tumor tissue before and after treatment
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda assessment of cell-cycle distribution before and after therapy by use of flow cytometry assays of transforming growth factor (TGFß) induction and other potential indicators of cell differentiation characterization of the progesterone receptor, including quantitation not only of total receptor content but also of A and B receptors and receptor mutants (Western blot technology currently exists for this analysis); and assays for the expression of other growth factors such as TGFa, epidermal growth factor (EGF), and insulin-like growth factor (IGF), which may be modulated by antiprogestins. Recommendation No. 17. The committee recommends that studies establish the maximum tolerated dose of antiprogestins for treatment of breast cancer. Further exploration of potential toxicity at various doses should be undertaken in additional Phase 1 clinical trials. Recommendation No. 18. The committee recommends additional preclinical exploration of the molecular mechanisms of action of antiprogestins for treatment of breast cancer. Such studies should include further characterization of progesterone receptors, including the natural A and B forms, as well as possible genetic mutants, and their distribution in normal and malignant tissue; this will be important for the rational use of antiprogestins in future clinical trials investigation of the use of antiprogestins as differentiating agents that produce programmed cell death (apoptosis)—a possible novel mechanism of action; and exploration of the mechanism of tumor resistance to antiprogestins and other effects of long-term administration. MENINGIOMAS Meningiomas are tumors arising from the membranes surrounding the brain. Meningiomas are common tumors, generally nonmalignant and slow-growing, which can, however, threaten brain function or even life if they are not surgically removed. More frequent in women, meningioma growth is accelerated during pregnancy. Several papers in Appendix B allude to a rationale for the treatment of meningiomas with antiprogestins. The vast majority of meningiomas express progesterone
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda receptors, although there is some controversy as to whether the progesterone receptor is functional in meningioma. Recent data from 33 meningiomas evaluated for progesterone-receptor mRNA by Northern blot analysis (Carroll et al., 1993) revealed that 64 percent of specimens were positive (indicating positive receptor status). Of note was a statistically significant difference in expression between women and men. For women, 81 percent of specimens—and for men, 19 percent of specimens—were positive. Additional evidence of functional receptors has been reported by using immunohistochemistry to identify progesterone-receptor protein product. Six of eleven samples demonstrated intense nuclear staining at this location, which was compatible with a functional receptor (Carroll et al., 1993). The results of an initial clinical trial using an antiprogestin in patients with recurrent meningiomas following surgery and radiotherapy have been published and updated (Grunberg et al., 1991a,b). Twenty-four patients with recurrent or unresectable meningiomas have been treated with mifepristone (200 mg daily) for considerable periods—some for more than two years. Thirteen patients were treated for more than 12 months; 20 patients were treated for more than 6 months. (At the IOM workshop, Grunberg described results extending the published data for 28 patients treated for a median of 27 months. Maximum duration of therapy is 62 months. Twenty patients have been treated for periods of one year or longer. All five of the premenopausal women in this study had cessation of menses for the duration of therapy, and two who ceased therapy (one after eight months and one after two years) had a return of normal menses.) Response criteria in the 1991 reports were less stringent than those conventionally employed in cancer clinical trials. However, six patients had some improvement manifest by a minor decrease in tumor measurement by computed tomography or magnetic resonance imaging, or some improvement in visual field examination associated with amelioration of visual symptoms or headache. Progesterone-receptor status could not be obtained on most patients. Toxicities associated with daily chronic administration appeared tolerable and included fatigue, hot flashes, breast enlargement and tenderness, thinning of hair, and rash. Amenorrhea occurred in the three premenopausal patients; however, menses resumed in two patients following cessation of therapy. Conclusions The committee reached the following conclusions about the current state of the science for the use of antiprogestins to treat meningioma: Mifepristone appears to have some activity in recurrent or unresectable meningiomas, though the clinical importance of this observa-
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda tion in patients having a disease with a highly variable natural history remains to be defined. The lack of good alternative treatments for this group of patients and the mechanistic rationale make this an attractive treatment for further study. Daily chronic administration of mifepristone appears tolerable in this group of patients. Recommendation No. 19. A randomized Phase 3 trial will be required to define the role of antiprogestins in the management of patients with unresectable meningioma. Such a trial is ongoing in the Southwest Oncology Group. The committee recommends that these data be reviewed carefully to define directions for further research on this disease. REFERENCES Bakker, G.H., Setyono-Han, B., et al. Endocrine and antitumor effects of combined treatment with an antiprogestin and antiestrogen or luteinizing hormone-releasing hormone agonist in female rats bearing mammary tumors. Endocrinology 125:1593–1598, 1989. Bakker, G.H., Setyono-Han, B., Portengen, H., et al. Treatment of breast cancer with different antiprogestins: Preclinical and clinical studies. Journal of Steroid Biochemistry and Molecular Biology 37:789–794, 1990. Bardon, S., Vignon, F., Chalbos, D., et al. RU 486, a progestin and glucocorticoid antagonist, inhibits the growth of breast cancer cells via the progesterone receptor. Journal of Clinical Endocrinology and Metabolism 60:692–697, 1985. Bowden, R.T., Hissom, J.R., and Moore, M.R. Growth stimulation of human T47D human breast cancer cells by the antiprogestin RU 486. Endocrinology 124:2642–2644, 1989. Carroll, R.S., Glowacka, D., Dashner, K., et al. Progesterone receptor expression in meningiomas. Cancer Research 53:1312–1316, 1993. Grunberg, S.M., Weiss, M.H., Spitz, I.M., et al. Treatment of meningioma with the oral antiprogestational agent mifepristone. Proceedings of the American Society of Clinical Oncology 10:126, 1991a. Grunberg, S.M., Weiss, M.H., Spitz, I.M., et al. Treatment of unresectable meningiomas with the antiprogesterone agent mifepristone. Journal of Neurosurgery 74:861–866, 1991b. Hamm, J.T. and Allegra, J.C. New hormonal approaches to the treatment of breast cancer. Critical Reviews in Oncology/Hematology 11:29–41, 1991. Horgan, K., Cooke, E., Hallett, M.B., et al. Inhibition of protein kinase C mediated signal transduction by tamoxifen. Importance for antitumor activity. Biochemical Pharmacology 35:4463–4465, 1986. Horwitz, K.B. The molecular biology of RU 486. Is there a role for antiprogestins in breast cancer? Endocrine Reviews 13:146–163, 1992. Kettel, L.M., Murhpy, A.A., Mortola, J.F., et al. Endocrine responses to long-term administration of the antiprogesterone RU 486 in patients with pelvic endometriosis. Fertility and Sterility 56:402–407, 1991. Kian, J.G.M., DeJong, F.H., Bakker, G.H., et al. Antiprogestins, a new form of endocrine therapy for human breast cancer. Cancer Research 49:2851–2856, 1989. Maudelonde, T., Romieu, G., Ulmann, A., et al. First clinical trial on the use of the
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