[CANCER RESEARCH 49, 2851-2856, June 1, 1989] Antiprogestins, a New Form of Endocrine Therapy for Human Breast Cancer1
Jan G. M. Klijn,2Frank H. de Jong, Ger H. Bakker, Steven W. J. Lamberts, Cees J. Rodenburg, and Jana Alexieva-Figusch Department of Medical Oncology (Division of Endocrine Oncology) [J. G. M. K., G. H. B., C. J. K., J. A-F.J, Dr. Daniel den Hoed Cancer Center, and Department of Endocrinology ¡F.H. d. J., S. W. ]. L.J, Erasmus University, Rotterdam, The Netherlands
ABSTRACT especially pronounced effects on the endometrium, decidua, ovaries, and hypothalamo-pituitary-adrenal axis. With regard The antitumor, endocrine, hematological, biochemical, and side effects of chronic second-line treatment with the antiprogestin mifepristone (RU to clinical practice, the drug has currently been used as a contraceptive agent or abortifacient as a result of its antipro 486) were investigated in 11 postmenopausal patients with metastatic breast cancer. We observed one objective response, 6 instances of short- gestational properties (2, 22-24). Based on its antiglucocorti term stable disease, and 4 instances of progressive disease. Mean plasma coid properties, this drug has been used or has been proposed concentrations of adrenocorticotropic hormone (/' < 0.05), cortisol (/' < for treatment of conditions related to excess corticosteroid 0.001), androstenedione (/' < 0.01), and estradici (P < 0.002) increased production such as Cushing's syndrome (19, 25-27) and for significantly during treatment accompanied by a slight decrease of sex treatment of lymphomas (24) and glaucoma (28); because of its hormone binding globulin levels, while basal and stimulated gonadotropi effects on the immune system, the drug has been suggested to levels did not change significantly. The increased basal cortisol levels be potentially relevant to treating AIDS patients (24). could not be further stimulated by synacthen, nor suppressed by 1 mg of Its antiprogestational and antiglucocorticoid properties dexamethasone. Plasma estradiol concentrations were significantly cor related with both androstenedione (/' < 0.05) and cortisol levels (/' < might prompt the use of mifepristone in the treatment of cancer. Growth-inhibitory effects have been demonstrated in breast 0.01). The percentage of eosinophilic white blood cells (P < 0.02) and mean plasma creatinine concentration (/' < 0.05) increased significantly. cancer cells in vitro (11, 29-33) and also in mammary tumors Side effects frequently occurred during long-term treatment and appeared in rats (33, 34), in rat (35, 36) and human pituitary tumor cells to be caused mainly by the antiglucocorticoid properties of the drug. It is (19), in adrenal tumor cells (27), in hepatoma cells (21), and in concluded that antiprogestins form a new treatment modality in the human meningioma cells (37). However, at present, clinical endocrine treatment of human breast cancer. New antiprogestins with data on long-term antiprogestational treatment of human can less antiglucocorticoid side effects might be especially of value as an cer are scarce as for other clinical applications. Since we showed adjunct to antiestrogenic treatment in view of our finding that combined growth-inhibitory effects of antiprogestational treatment both antiestrogenic and antiprogestational treatment caused additive growth- in vitro on human breast cancer cells and in vivo in rats with inhibitory effects in rat mammary tumors. DMBA-induced mammary tumors (33, 34), we now studied the antitumor and side effects of treatment with mifepristone in INTRODUCTION patients with metastatic breast cancer. In addition we investi gated hematological, biochemical, and endocrine parameters. Recently, the first antiprogestational agent was synthesized Furthermore, we have looked for the antitumor efficacy of and tested (1, 2). This steroid [17/3-hydroxy-ll/3-(4-dimeth- combined antiestrogenic and antiprogestational treatment in ylaminophenyl)-17a-(prop-1 -ynyl)estra-4,9-dien-3-one], initial rats with DMBA-induced mammary tumors in view of the ly indicated by its code name RU 38486, is currently named potential clinical value of such combination in the treatment of mifepristone. This compound was shown to have a high affinity for the PgR,3 resulting in mainly antiprogestational effects (1- breast cancer. 11). Only a very few progestomimetic activities have been demonstrated or suggested (9-11). In addition, apart from being PATIENTS, MATERIALS, AND METHODS a PgR antagonist, mifepristone has glucocorticoid receptor- blocking activity without agonistic effects, as concluded from This study was started after approval by a local Human Investigations both in vitro and in vivo experiments (2, 12-21). The affinity Committee and by the Netherlands Cancer Foundation (Protocol KWF- CKVO 86-09). Eleven postmenopausal patients (mean age, 63 yr; range, for the PgR is 5 times higher than that of progesterone, while 46 to 75 yr) gave informed consent. They were treated daily during 3 the affinity for the GR is 2 to 3 times higher than that of to 34 wk with 200 to 400 mg of mifepristone (RU 486; Roussel-Uclaf, dexamethasone (2, 12). Also, a weak affinity for the AR, but France) p.o. in 2 dosages as a second-line single treatment after first- not for the ER or mineralocorticosteroid receptors, has been line treatment with tamoxifen irrespective of the response to tamoxifen. reported (2, 12). In 4 patients, the receptor status of the primary tumor was unknown, Many biological effects of mifepristone have been described, 3 patients had an [ER+, PgR+] tumor, and 4 patients an [ER+, PgR-] both with respect to the effects resulting from binding of the tumor (Table 1). drug to the PgR as well as of binding to the GR. The drug has Hematological (hemoglobin, white blood cell count and cell differ entiation, platelets), biochemical (Na+, K+, glucose, liver, and renal Received 10/31/88; revised 1/30/89; accepted 3/1/89. function tests), and one or more endocrine parameters (LH, FSH, The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in estradiol, SHBG, prolactin, ACTH, cortisol, androstenedione, LHRH accordance with 18 U.S.C. Section 1734 solely to indicate this fact. test, TRH test, synacthen test, dexamethasone-screening test) were 1This study was supported by The Netherlands Cancer Foundation (KWF- investigated in 10 patients before and after 4, 8, 12, and 16 wk of CKVO 86-09) and Roussel B. V. (Hoevelaken). 2To whom requests for reprints should be addressed, at Division of Endocrine treatment. Basal plasma hormone concentrations were also measured Oncology (Biochemistry and Endocrinology), Dr. Daniel den Hoed Cancer Cen after 2 wk of treatment. A p.o. glucose (100 g) tolerance test was carried ter, P. O. Box 5201, 3008 AE Rotterdam, The Netherlands. out in 5 patients before and after 3 mo of treatment with mifepristone. 3The abbreviations used are: PgR, progesterone receptor; GR, glucocorticoid The LHRH test (LH and FSH measured 30 min after 100 n%of LHRH receptor; AR, androgen receptor; ER, estradiol receptor; DMBA, dimethyl- i.v.) and TRH test (prolactin measured 30 min after 400 Mgof TRH benz(a)anthracene; LH, luteinizing hormone; FSH, follicle-stimulating hormone; PRL, prolactin; SHBG, sex hormone binding globulin; ACTH, adrenocorticotro i.v.) were performed after 4, 8, and 12 wk; the synacthen test (cortisol pic hormone; LHRH, luteinizing hormone releasing hormone; TRH, thyrotropic measured 30 min after 250 ¿igofACTH i.m.) and the dexamethasone- releasing hormone. screening test (cortisol at 8:00 a.m. after 1 mg of dexamethasone p.o. 2851
Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1989 American Association for Cancer Research. ANTIPROGESTIN THERAPY FOR HUMAN BREAST CANCER Table 1 Response to second-line treatment with mifepristone related to tumor receptor status and response to first- and third-line endocrine therapy to to toTAM" RU486(secondline)NC(8)NCmegestrolacetate(third (fmol/mgPatient ER (fmol/mgprotein)00030206248Site (firstline)PR protein)I ofmetastasisSkin, line)*PR 2523 InnSkin, (44fPR (21)NC boneBoneLung, (64)NC(6)NC (4+)PDNC(6)NC(4)NC(3.5)PDCR(1 2504 905 pericardLungSkin, (22)CR(18)NC(4)PR 371678 4*)NC(17*)PR InnSkin, (3+)PDNC(4)PDPDPR boneInn, (14)PDPDResponse 3009 boneBone, 4021011 skin.liverSkin,pleura,
boneInn, 32PgR boneResponse (5)Response (3*) °TAM, tamoxifen; Inn, lymph node; PR, partial response; NC, no change; PD, progressive disease; CR, complete response. '' Response to third-line therapy was only evaluated when megestrol acetate was used. c Numbers in parentheses, duration of response (mo). at 11:00 p.m. the evening before) after 12 wk of treatment. LH, FSH, Two patients (Nos. 2 and 6) had to stop treatment with and PRL were measured by radioimmunoassays as described before mifepristone because of side effects (in the absence of tumor (38). Cortisol, estradici, and androstenedione were measured by kits progression). One of these patients was hospitalized because of (radioimmunoassay) provided by DPC (Los Angeles, CA), while SHBG a grand mal seizure and subcoma under suspicion of cerebral was measured by kits (immunoradiometric assay) provided by Farmos/ métastases.Treatment with dexamethasone was instituted, and Oulu, Finland). Tumor ER and PgR contents were assessed according to procedures of the European Organization for Research and Treat mifepristone treatment was stopped. However, on the computed ment of Cancer (39). tomography scan of the cerebrum, métastaseswere not found, Skin and lymph node métastaseswere measured every 4 wk. X-rays and the patient improved remarkably after 3 days and was of specific bone and lung lesions were performed each 4 wk during the dismissed from the hospital without complaints. These obser first 3 mo of treatment and thereafter every 3 mo. Bone scans were vations suggest that this complication was initiated by mifepri performed before and a half year after start of treatment. Measurement stone. In view of the long half-life of mifepristone of about 20 of response occurred according to International Union against Cancer h, the improvement might be related to both excretion of criteria. mifepristone and treatment with high-dose dexamethasone that For statistical methods, we used Student's paired t test and the overcame the antiglucocorticoid activity of the gradually de nonparametric method of Wilcoxon. creasing plasma levels of mifepristone. For testing the antitumor efficacy of combined antiestrogenic and antiprogestational treatment, rats with DM HA induced mammary tu Endocrine Effects. In addition to plasma ACTH (Table 2), mors were treated with tamoxifen (400 Mgper kg daily) and mifepristone plasma cortisol concentrations showed a highly significant in (10 mg per kg daily) as single treatment and in combination. For crease during treatment (Fig. 1; Table 2), indicating stimulation methods, we refer to Ref. 33 and legends of Fig. 4. of the pituitary-adrenal axis. In contrast to a normal increase of plasma cortisol concentrations by stimulation with synacthen before treatment (Table 3) from 384 ±37 to 836 ±54 nmol/ RESULTS liter (mean increase ±SEM of 128 ±21%, n = 7), there was no significant change (only 30 ±13% increase; Table 2) of the Clinical Results increased basal cortisol levels by synacthen during mifepristone Antitumor Effects. One of 11 patients showed a partial re treatment (from 869 ±122 to 1049 ±77 nmol/liter; n = 6). sponse of her lymph node métastases(58% decrease of tumor Moreover, the increased basal cortisol concentrations could not size) lasting 5 mo; 6 patients showed stable disease of 3- to 8- be suppressed by 1 mg of dexamethasone during treatment, in mo duration; and 4, progressive disease from start of treatment. contrast to the normal suppression before mifepristone treat The relationship between the tumor receptor status and the ment (Table 3). response to endocrine treatment modalities is indicated in Table Surprisingly, plasma androstenedione (Table 2) and espe 1. Also the response to third-line endocrine treatment (180 mg cially plasma est radio! levels (Fig. 1; Table 2) increased signif of megestrol acetate daily) is indicated. icantly during treatment. We found no significant effects on Side Effects. Eight patients experienced anorexia and a gen basal and stimulated gonadotropin concentrations, while erally slight degree of nausea. Tiredness (6 times), not feeling plasma SHBG concentrations slightly decreased (Table 2). well and dizziness (4 times), and somnolence (4 times) were Plasma estradiol concentrations were positively correlated with also relatively frequent complaints. Side effects generally did plasma androstenedione (P < 0.05; Table 2) and cortisol con not occur in the first week of treatment, but sometimes after centrations (P< 0.01; Fig. 2). weeks or months of treatment, suggesting that certain plasma Basal PRL levels did not change during mifepristone treat levels of mifepristone have to be reached before side effects ment, while TRH-stimulated plasma prolactin concentrations occur. The first 10 patients showed a decrease in body weight tended to increase, i.e., from 31.2 ±9.9 to 45.3 ±3.4 ^g/'iter (mean, 3 kg; range, 0.9 to 7.5 kg), while Patient 11 had an (not significant, n = 6; Table 2), possibly in relation to the initial body weight increase of 5 kg which was followed by a increase in plasma estradiol levels. decrease of 2 kg without other side effects. We did not observe Effects on Hematological Parameters. During treatment with significant effects on blood pressure. However, one patient mifepristone, we observed a significant increase (P < 0.02) of using antihypertensive drugs before treatment no longer re the percentage of eosinophilic white blood cells from 1.0 ± quired antihypertensive treatment after the start of treatment 0.35 to 1.65 ±0.33% (mean ±SEM, n = 10). There was no with mifepristone. significant effect on hemoglobin levels, total WBC, or percent- 2852
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Table 2 Summary of results of treatment with mifepristone in ten patients with metastatic breast cancer Before treatment During treatment P value HematologicalparametersHemoglobin (mmol/liter)WBC(10'/litcr)Lymphocytes ±0.24°5.55 ±0.295.55 ±0.4723 ±0.3224 (%)Eosinophils ±2.61.0 ±2.81.65 (%)Biochemical ±0.33141.7 ±0.33142.2 <0.02NSNSP
parametersNa* (mmol/liter)K* ±0.704.17 ±1.043.82 (mmol/liter)Creatinine ±0.1487 ±0.18103 (/imol/liter)Glucose ±4.15.04 ±5.55.16 <0.05NSNSP (mmol/liter)Peak ±0.228.28 +0.159.30 test)Endocrineglucose (p.o. glucose tolerance ±0.9231 ±0.8580
parametersACTH (ng/ml)Cortisol ±14353 ±161041 <0.05P< (nmol/liter)Androstenedione ±453.2 ±819.9 0.001P<0.0\P (nmol/liter)Estradici ±0.623 ±1.8113 (pmol/liter)SHBG ±7105 ±2380 <0.0020.10 (nmol/liter)BasalLH ±1335.8 ±934.8 >P>0.05NSNSNSNSNSNSP
(units/liter)ALH ±10.251.8 ±11.246.1 test)BasalFSH(LHRH ±15.140.1 ±23.437.0
(units/liter)AFSH ±9.811.6 ±9.214.8 test)Basal(LHRH ±2.65.8 ±4.64.9 PRL(jig/liter)Stimulated ±0.931.2 ±0.745.3 test)SynacthenPRL (TRH ±9.9228 ±3.4130 basal)Dexamethasonetest (% of ±2159 ±131146± <0.01/><0.01/>
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Cortisol spicuous in both studies was the relatively short duration of response. Although on one hand this might be explained by the fact that mifepristone was not used as a first-line treatment, O 1200 - another explanation might be the striking increase of plasma estradici levels as first observed in the present study. Although 1000 - mifepristone can inhibit the estradiol-stimulated growth of
900 - breast cancer cells in vitro (32, 33), the rise of plasma estradici eoo - may be a disadvantage of this type of treatment. Moreover, apart from this rise of plasma estradici and decrease of SHBG TOO- also, the increase of plasma androstenedione concentrations 600 - might have an unfavorable effect on the growth of breast cancers 500 - (43, 44).
400 - Previously we reported mifepristone-induced stimulation of the pituitary-ovarian function as evidenced by increases of 300 - plasma LH, estradici, and progesterone concentrations in cy 200 - cling rats with DMBA-induced mammary tumors (33). Short- 100 - term treatment of premenopausal women with mifepristone can -1— —I— —I— —I— —I- have diverse effects on menstrual and hormonal patterns de 24 8 pending on the phase of the menstrual cycle during which the Weeks of treatment drug was administered (4, 6-8). The previously unknown rise E2 of plasma estradici concentrations in postmenopausal patients is probably not a result of stimulation of the pituitary-ovarian 8 8 function, but rather of stimulation of the pituitary-adrenal axis O 140 - E leading to an increase of the secretion of adrenal androgen, a '»- which can be used as a substrate for peripheral aromatase 120 . activity. Binding of mifepristone to hypothalamic and pituitary
110 - GR causes a strong increase of ACTH and consequently of
100 - cortisol secretion due to its antiglucocorticoid properties. Ad renal activity is apparently maximal during treatment with 200 90 - to 400 mg of mifepristone per day; the high plasma cortisol eo- levels could not be stimulated or suppressed by exogenous 70 - ACTH or dexamethasone, respectively. The increase of plasma
60 - androstenedione, the positive correlation between plasma estra
90 - dici and both cortisol and androstenedione levels, and the observation that the peak value of estradici in plasma was 40 . reached later (Fig. 1) than that of cortisol support the hypoth X- esis that the rise of plasma estradici is mainly derived from 20 - peripheral conversion of adrenal androgens. Mifepristone itself io- appeared to have no direct effect on aromatase activity (5). The effects of the increase of peripheral estrogens during mifepristone therapy might be counteracted by the simultane ous administration of an antiestrogen, such as tamoxifen. In Weeks of treatment Fig. 1. Effects of treatment with the antiprogestin mifepristone on basal deed, results of our experimental studies indicate that the plasma cortisol and C-stradini(F:) concentrations. Points, mean; bars, SEM. combination antiprogestational and antiestrogenic treatment with mifepristone and tamoxifen was much more effective (at nistn of antitumor action is unclear. The number of patients least additive) than single treatment with each drug alone. with known tumor receptor status in both studies is small. Additive effects of tamoxifen and RU 486 were also observed From these patients together, 6 of 7 with a PgR-positive tumor in vitro (31). Therefore, in patients with breast cancer, combi (all also ER positive) showed partial response (3 times) or nation treatment with an antiestrogen and an antiprogestin minimal response/stable disease (3 times). None of 8 patients aiming at simultaneous blockade of both ER and PR might be with PgR-negative tumors (5 ER positive) improved, while 3 very attractive. In this way, during treatment with antiproges- (all with ER-positive tumors) showed only stable disease. These tins, tamoxifen can block the potential stimulatory effects of results might suggest that the drug acts via the PgR as shown estradiol on the tumor cells and prevent possible by-passing in in vitro studies (30). Interestingly, mifepristone induced mechanisms of action on tumor growth via the ER when only remissions in advanced breast cancers that were resistant to PgR is blocked by the antiprogestin. other first-line endocrine therapies (Patient 11; Ref. 41). Con Apart from the endocrine data, the increased percentage of
Table 3 Plasma conisol concentrations (nmol/liter) before and after stimulation with 250 ¡igofsynacthen and before and after suppression with 1 mg of dexamethasone prior to and during treatment with mifepristone
synacthen384 synacthen836 dexamethasone353 dexamethasone59 Before mifepristone treatment ±37" (7)* ±54 (7) ±45 (8) ±9 (8) During(6)' mifepristone treatmentBefore 869 ±122 (6)After 1049 ±77 (6)Before 1041 ±81 (27)After 1146 ±355 Mean ±SEM. * Numbers in parentheses, number. 2854
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Fig. 2. Correlation between plasma cortisol and estradici concentrations (r = 0.52, /' < 0.01) in 32 blood samples taken from 10 pa tients before and during treatment with mite- pristone. E2, estradici.
o 100
mmol/l eosinophilic white blood cells in our patients supports the 10 presence of antiglucocorticoid effects of treatment with mife pristone. Also, the clinical side effects are generally the opposite 9 - of those observed in patients treated with high-dose progestins causing Cushingoid-like side effects. In addition, endocrine 8 _ findings during chronic mifepristone treatment were roughly 7 _ similar with those found in patients with familial cortisol re sistance (45). It was striking that all side effects of mifepristone 6 - treatment disappeared when this treatment was followed by treatment with high doses of progestins, i.e., 180 mg of meges- trol acetate per day. 4 _ The significant increase of plasma creatinine concentrations during mifepristone treatment might be explained by a decrease in plasma volume and/or renal blood flow. In dogs, Wade et al. I I 60 120 180 240 (46) demonstrated increased aldosterone and renin levels during high-dose treatment with mifepristone. These authors reported Minutes a 4% increase in body weight explained by water retention, Fig. 3. Glucose p.o. tolerance test before ( ) and 3 mo after ( ) start of treatment with mifepristone in 5 postmenopausal patients with metastatic which apparently did not occur in our patients. breast cancer. Points, mean plasma glucose concentrations; bars, SEM. In conclusion, antiprogestins form a new category in the endocrine treatment of breast cancer, especially with respect to PgR-positive tumors. Randomized studies comparing the anti- tumor effects of antiprogestins with those of high-dose proges tins or other types of hormonal treatment have to be performed. 300 However, combination treatment with antiprogestins and anti- estrogens seems to be of greater interest, aiming at additive growth-inhibitory effects as observed in experimental models. 200- A disadvantage might be the frequent occurrence of side effects caused by the antiglucocorticoid properties of the presently available antiprogestins, but the use of new antiprogestins with less antiglucocorticoid activity, which are presently in an ad 100_ vanced phase of development, should overcome this problem.
ACKNOWLEDGMENTS (27) H4) (15) We thank Roussel Uclaf (Dr. M. A. Hoogslag, Dr. R. Deraedt) for TAM RU RU the supply of mifepristone and for their support, J. Munnik for prepa
TAM ration of the figures, and A. Sugiarsi and M. Drinkwaard for prepara Fig. 4. Relative effects on tumor load caused by a 3-wk treatment of mammary tion of the manuscript. tumor-bearing rats with tamoxifen (TAM, 400 ng/kg/day), mifepristone (RU, 10 mg/kg/day), or their combination. The initial tumor load in all groups set at REFERENCES 100% is indicated by the dashed line. Results are means ±SEM. Numbers in parentheses, number of rats. Statistical significance versus control group «'):.? , 1. Philibert, D., Deraedt. R., Teutsch, (,., Tourneminen, <'.. and Sakiz, E. RU P < 0.05; 1, P < 0.01 ; *, P < 0.005 (Wilcoxon's test). 38486—a new lead for steroidal antihormones. In: Proceedings of the 64th 2855
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Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1989 American Association for Cancer Research. Antiprogestins, a New Form of Endocrine Therapy for Human Breast Cancer
Jan G. M. Klijn, Frank H. de Jong, Ger H. Bakker, et al.
Cancer Res 1989;49:2851-2856.
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