Abstract
Estrogens administered in high doses were commonly used for therapy of advanced breast cancer before the introduction of contemporary endocrine therapy. While the mechanism of the antitumor effect is unknown, in vitro investigations have shown estrogens in high concentrations to be toxic to cell growth. Further, it has been shown that exposure of MCF-7 cells to estrogens in low concentrations may enhance the sensitivity and also lower the toxicity threshold to estrogens. This study was designed to evaluate treatment with diethylstilbestrol (DES) in postmenopausal women with advanced breast cancer becoming resistant to estrogen deprivation. Thirty-two patients with advanced breast cancer previously exposed to multiple endocrine treatment regimens (median 4, range 2–10) were enrolled. Their tumor should have revealed evidence of endocrine sensitivity (previous partial response or at least stable disease for ≥6 months to therapy). Each patient received DES 5mg t.i.d. Four patients terminated therapy after ≤2 weeks on therapy due to side effects; another two patients terminated therapy before progression for similar reasons (one patient after SD for 15 weeks and one with a PR after 39 weeks). Four patients obtained CR and six patients PR. In addition, two patients had SD for ≥6 months duration. Five patients had an objective response and one patient a SD lasting for ≥1 year. Our results reveal estrogens administered in high doses may have antitumor effects in breast cancer patients heavily pretreated with endocrine therapy. Such treatment represents a valuable alternative to chemotherapy in selected patients.
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Buzdar AU, Jonat W, Howell A, Jones SE, Blomqvist CP, Vogel CL, Eiermann W, Wolter JM, Steinberg M, Webster A, Lee D: Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: Results of a survival update based on a combined analysis of data from two mature phase III trials. Cancer 83: 1142-1152, 1998
Dombernowsky P, Smith I, Falkson G, Leonard R, Panasci L, Bellmunt J, Bezwoda W, Gardin G, Gudgeon A, Morgan M, Fornasiero A, Hoffmann W, Michel J, Hatschek T, Tjabbes T, Chaudri HA, Hornberger U, Trunet PF: Letrozole, a new oral aromatase inhibitor for advanced breast cancer: Double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 16: 453-461, 1998
Gershanovich M, Chaudri HA, Campos D, Lurie H, Bonaventura A, Jeffrey M, Buzzi F, Bodrogi I, Ludwig H, Reichardt P, OHiggins N, Romieu G, Friederich P, Lassus M: Letrozole, a new oral aromatase inhibitor: Randomised trial comparing 2.5mg daily, 0.5mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Ann Oncol 9: 639-645, 1998
Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Cervek J, Fowst C, Polli A, Salle ED, Arkhipov A, Piscitelli G, Massimini G: Survival advantage of exemestane (AromasinR) over megestrol acetate (MA) in postmenopausal women with advanced breast cancer (ABC) refractory to tamoxifen (TAM): results of a phase III randomized double-blind study. Proc Am Soc Clin Oncol 18: Abstr 412, p. 109a, 1999
Howell A, DeFriend D, Robertson J, Blamey R, Walton P: Response to a specific antioestrogen (ICI 1827 80) in tamoxifenresistant breast cancer. Lancet 345: 29-30, 1995
Garcia-Giralt E, Ayme Y, Carton M, Daban A, Delozier T, Fargeot P, Fumoleau P, Gorins A, Guerin D, Guerin R, Maillart P, Mauriac L, May-Levin F, Metz R, Namer M, Olivier JP, Pommatau E, Pouillart P, Pujade-Lauraine E, Rouesse J, Serrou B, Vitse M, Zylberait D: Second and third line hormontherapy in advanced post-menopausal breast cancer: A multicenter randomized trial comparing medroxyprogesterone acetate with aminoglutethimide in patients who have become resistant to tamoxifen. Breast Cancer Res Treat 24: 139-145, 1992
Murray R, Pitt P: Aromatase inhibition with 4-OHandrostenedione after prior aromatase inhibition with aminoglutethimide in women with advanced breast cancer. Breast Cancer Res Treat 35: 249-253, 1995
Thurlimann B, Paridaens R, Serin D, Bonneterre J, Roche H, Murray R, diSalle E, Lanzalone S, Zurlo MG, Piscitelli G: Third-line hormonal treatment with exemestane in postmenopausal patients with advanced breast cancer progressing on aminoglutethimide: a phase II multicentre multinational study. Eur J Cancer 33: 1767-1773, 1997
Lønning PE, Bajetta E, Murray R, Tubiana-Hulin M, Eisenberg PD, Mickiewicz E, Celio L, Pitt P, Mita M, Aaronson VK, Fowst C, Arkhipov A, diSalle E, Polli A, Massimini G: Activity of exemestane in metastatic breast cancer after failure of non steridal aromatase inhibitors: a phase II trial. Clin Oncol 18: 2234-2244, 2000
Jones S, Vogel C, Arkhipov A, Fehrenbacher L, Eisenberg P, Cooper B, Honig S, Polli A, Whaley F, di Salle E, Tiffany J, Consanni A, Miller L: Multicenter, phase II trial of exemestane as third-line hormonal therapy of postmenopausal women with metastatic breast cancer. J Clin Oncol 17: 3418-3425, 1999
Haddow A, Watkinson JM, Paterson E: Influence of synthetic oestrogens upon advanced malignant disease. Br Med J 2: 393-398, 1944
Binnie GG: Regression of tumors following treatment by stilboestrol and x-ray therapy, with notes on case of breast tumour which regressede with stilboestrol alone. Brit J Radiol 17: 42-45, 1944
Carter AC, Sedransk N, Kelley RM, Ansfield FJ, Ravdin RG, Talley RW, Potter NR: Diethylstilbestrol: Recommended dosages for different categories of breast cancer patients. JAMA 237: 2079-2085, 1977
Lippman M, Bolan G, Huff K: The effects of estrogens and antiestrogens on hormone-responsive human breast cancer in long-term tissue culture. Cancer Res 36: 4595-4601, 1976
Masamura S, Santner SJ, Heitjan DF, Santen RJ: Estrogen deprivation causes estradiol hypersensitivity in human breast cancer cells. J Clin Endocrinol Metab 80: 2918-2925, 1995
Song RX, McPherson R, Yue W, Wang JP, Santen RJ: Estrogen induces apoptosis in human breast cancer cells adapted to long term estrogen deprivation. Proc Am Assoc Cancer Res 41: #2715, p427, 2000
Matelski H, Huberman M, Zipoli T, Greene R, Lokich J: Randomized trial of estrogen versus tamoxifen therapy for advanced breast cancer. J Clin Oncol 8: 128-133, 1985
Ingle JN, Ahmann DL, Green SJ, Edmonson JH, Bisel HF, Kvols LK, Nichols WC, Creagan ET, Hahn RG, Rubin J, Frytak S: Randomized clinical trial of diethylstilstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer. N Engl J Med 304: 16-21, 1981
Peethambaram PP, Ingle JN, Suman VJ, Hartmann LC, Loprinzi CL: Randomized trial of diethylstilbestrol versus tamoxifen in postmenopausal women with metastatic breast cancer. An updated analysis. Breast Cancer Res Treat 54: 117-122, 1999
Hayward JL, Rubens RD, Carbone PP, Heuson J-C, Kumaoka S, Segaloff A: Assessment of response to therapy in advanced breast cancer. Br J Cancer 35: 292-298, 1977
Simon M: Design and conduct of clinical trials. In: De Vita VT, Hellman S, Rosenberg S (eds) Cancer: Principles and Practice of Oncology. Lippincott, Philadelphia 1993, pp 418-440
Iveson TJ, Ahearn J, Smith IE: Response to third-line endocrine treatment for advanced breast cancer. Eur J Cancer 29A: 572-574, 1993
Kennedy BJ: Massive estrogen administration in premenopausal women with metastatic breast cancer. Cancer 15: 641-648, 1962
Nosaquo ND: Androgens and estrogens in the treatment of disseminated mammary carcinoma. JAMA 172: 135-147, 1960
Walpole AL, Paterson E: Synthetic oestrogens in mammary cancer. Lancet 2: 783-786, 1949
Heuson JC, Engelsman E, Blank-van der Wijst J, Maass H, Drochmans A, Michel J, Nowakowski H, Gorins A: Comparative trial of nafoxidine and ethinyloestradiol in advanced breast cancer: an E.O.R.T.C. study. Br Med J 2(5973): 711-713, 1975
Lønning PE: Pharmacology of new aromatase inhibitors. Breast 5: 202-208, 1996
Lundgren S, Helle SI, Lønning PE: Profound suppression of plasma estrogens by megestrol acetate in postmenopausal breast cancer patients. Clin Cancer Res 2: 1515-1521, 1996
Clavel M, Catimel G: Breast Cancer: Chemotherapy in the treatment of advanced disease. Eur J Cancer 29A: 598-604, 1993
Stoll BA: Rechallenging breast cancer with tamoxifen therapy. Clin Oncol 9: 347-351, 1983
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Lønning, P.E., Taylor, P.D., Anker, G. et al. High-dose estrogen treatment in postmenopausal breast cancer patients heavily exposed to endocrine therapy. Breast Cancer Res Treat 67, 111–116 (2001). https://doi.org/10.1023/A:1010619225209
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DOI: https://doi.org/10.1023/A:1010619225209