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Antiprogestins, a New Form of Endocrine Therapy for Human Breast Cancer1

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Antiprogestins, a New Form of Endocrine Therapy for Human Breast Cancer1 [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
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