Hormonal manipulation is currently the mainstay of palliative care for metastatic breast cancer because it is well tolerated and produces significant responses in approximately one-third of unselected patients. Tamoxifen, a nonsteroidal antiestrogen, is currently considered first-line therapy. Second-line agents include progestins and aromatase inhibitors. New agents, such as the "pure" antiestrogens and the gonadotropin-releasing hormone (GnRH) agonists, are being tested. Other approaches for affecting the hormonal milieu are also under investigation, including combinations of hormonal agents, hormonal agents plus biologics, and hormonal agents plus antiproliferative agents. This review will address the basis for endocrine therapy and possible mechanisms of hormonal resistance, currently available agents and newer ones on the horizon, and areas of future interest.
Breast cancer, the most common neoplasm in American women, will result in approximately 46,000 deaths in 1995 and is second only to lung cancer as a cause of cancer-related mortality in women . At diagnosis, approximately 5% of women have metastatic disease, and current treatment for these women is only palliative. Consequently, it is important to define new therapeutic modalities and refine the therapeutic index of those already being used.
This paper reviews (1) the basis of endocrine therapy, a well-accepted treatment for metastatic breast cancer, (2) currently available and newer hormonal agents, (3) areas now under investigation, and (4) mechanisms of hormonal resistance.
Endocrine therapy generally is well tolerated by women with metastatic breast cancer and elicits a response in approximately one-third of unselected patients and in at least 50% of patients whose tumors are estrogen-receptor (ER) positive. Well-defined factors associated with a greater likelihood of response to endocrine therapy include:
- ER- and progesterone-receptor (PR) positivity
- Late premenopausal or late post-menopausal status
- Older age
- Long interval from diagnosis to first recurrence (disease-free interval)
- Disease limited to sites outside the viscera, such as bone and soft tissue
- Previous response to endocrine therapy .
Because of their favorable therapeutic index, hormonal agents are the treatment of choice for asymptomatic patients with metastatic breast cancer, especially those who are older. Randomized trials show no adverse effect on survival for patients initially treated with endocrine therapy rather than chemotherapy, although initial rates of response to chemotherapy tend to be somewhat higher [2-4]. Tamoxifen has been the drug of choice for first-line treatment of advanced disease because of its low toxicity. Second-line therapy now includes progestins and aromatase inhibitors, which have response rates similar to tamoxifen but more side effects (Tables 1 and 2).
Breast cancer cells have steroid receptors for estrogens, progestins, glucocorticoids, and androgens. Treatment of breast cancer in premenopausal women traditionally has involved removal of the ovaries, the source of estrogen, and, in postmenopausal patients, administration of pharmacologic doses of estrogen. (In postmenopausal women, large doses of estrogen can cause tumor regression.) The exact mechanism of these treatment modalities and the effects of estrogens and antiestrogens on the breast cancer cell are not fully defined. Our current understanding is that estrogen downregulates ERs and thereby decreases the hormone's effects .
Heat Shock Proteins--One speculative mechanism involves heat-shock proteins (hsps). When an estrogen antagonist (E) interacts with the ER, the ER-hsp complex dissociates. The DNA-binding domain then attaches to the estrogen-binding site on the DNA, initiating transcription of estrogen-regulated genes. Conversely, binding of an antiestrogen (AE) to the ER stabilizes the DNA-hsp, which prevents the ER-DNA interaction and thereby inhibits transcription (Figure 1).
Growth Factors--Breast cancer cells also secrete other growth factors that are autostimulatory (autocrine) and/or are stimulated by substances secreted by surrounding cells (paracrine; see Figure 2). Receptors for epidermal growth factor (EGFRs) and a closely related gene product, c-erbB2 (Her-2/neu), are found on breast cancer cells. Epidermal growth factor and transforming growth factor-alpha (TGF-alpha) interact with the EGFR and activate tyrosine kinase, a signal transduction pathway shown to induce proliferation of breast cancer cell lines in nude mice .
Transforming growth factor-alpha can act as an autocrine or paracrine growth factor. Receptors for TGF-beta also are present on breast cancer cells (primarily those that are ER-negative), and some breast cancer cells produce TGF-alpha in response to estrogens. Using antibodies against TGF-alpha or EGFR to block the effects of TGF-alpha can inhibit some breast cancer cells.
Insulin-like growth factor (IGF) also is produced by breast cancer cells in vitro and may result in both autocrine and paracrine mitogenic effects . Factors that increase IGF production include estrogen, TGF-alpha, EGF, and insulin. Antiestrogens, TGF-beta, and glucocorticoids inhibit its secretion .
Currently Available Hormonal Therapies
Currently available additive therapies include androgens, progestins, gonadotropin-releasing hormone (GnRH) agonists, corticosteroids, and, paradoxically, estrogens. Androgens, which were discovered to be effective in the 1940s, cause breast cancers to regress in approximately 20% of patients but are poorly tolerated because of virilization and other major toxicities.
Physiologic doses of estrogen (hormone replacement therapy) are generally avoided in women with breast cancer because of theoretical concerns that they might stimulate breast cancer cell growth. Higher doses yield response rates in postmenopausal women similar to those produced by other available agents, but estrogen therapy is frequently associated with nausea, vomiting, and other toxic effects [17,18]. During the 1950s, progestins were found to yield response rates of 30% in unselected patients with breast cancer .
Response rates of 20% to 25% also were reported for corticosteroid therapy alone . For example, in elderly patients in whom endocrine therapy has failed, 15 mg of prednisolone administered daily caused tumor regression in 14% of patients and tumor stabilization lasting 6 months or longer in 21% . Corticosteroids also can improve sense of well being, appetite, and functional status in seriously ill cancer patients . However, because of their long-term undesirable toxicities, corticosteroids typically are reserved for reducing inflammation and swelling in patients with intracranial metastases or the superior vena cava syndrome.
Gonadotropin-releasing hormone agonists have proven effective in pre-menopausal patients with metastatic breast cancer, but their role in standard practice has not yet been defined.
Tamoxifen, the prototypic hormonal agent used in breast cancer, is one of several antiestrogens now available and falls into the broad category of hormone antagonists. Other groups of hormone antagonists only recently introduced into the breast cancer treatment armamentarium include antiprogestins, antiandrogens, and aromatase inhibitors.
1. Cancer Facts and Figures-1995. American Cancer Society.
2. Muss HB: Endocrine therapy for advanced breast cancer: A review. Breast Cancer Res Treat 21:15-26, 1992.
3. Taylor SG, Gelman RS, Falkson G, et al: Combination chemotherapy compared to tamoxifen as initial therapy for stage IV breast cancer in elderly women. Ann Intern Med 104:455-461, 1986.
4. A randomized trial in postmenopausal patients with advanced breast cancer comparing endocrine and cytotoxic therapy given sequentially or in combination: The Australian and New Zealand Breast Cancer Trials Group, Clinical Oncological Society of Australia. J Clin Oncol 4:186-193, 1986.
5. Beatson GT: On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet 2:104-107, 1896.
6. Santen RJ, Manni A, Harvey H, et al: Endocrine treatment of breast cancer in women. Endocr Rev 11:221-265, 1990.
7. Dowsett M: Novel approaches to the endocrine therapy of breast cancer. Eur J Cancer 26:989-992, 1990.
8. Cash R, Brough AJ, Cohen MN, et al: Aminoglutethimide (Elipten-Ciba) as an inhibitor of adrenal steroidogenesis: mechanism of action and therapeutic trial. J Clin Endocrinol Metab 27:1239-1248, 1967.
9. Griffiths CT, Hall TC, Saba Z, et al: Preliminary trial of aminoglutethimide in breast cancer. Cancer 32:31-37, 1973.
10. Nemoto T, Patel J, Rosner D, et al: Tamoxifen (Nolvadex) versus adrenalectomy in metastatic breast cancer. Cancer 53:1333-1335, 1984.
11. Santen RJ, Worgul TJ, Samojlik E, et al: A randomized trial comparing surgical adrenalectomy with aminoglutethimide plus hydrocortisone in women with advanced breast cancer. N Engl J Med 305:545-551, 1981.
12. Kiang DT, Frenning DH, Vosika GJ, et al: Comparison of tamoxifen and hypophysectomy in breast cancer treatment. Cancer 45:1322-1325, 1980.
13. Harvey HA, Santen RJ, Osterman J, et al: A comparative trial of transsphenoidal hypophysectomy and estrogen suppression with aminoglutethimide in advanced breast cancer. Cancer 43:2207-2214, 1979.
14. Miller WR: Endocrine treatment for breast cancers: biological rationale and current progress. J Steroid Biochem Mol Biol 37:467-480, 1990.
15. Sutherland DJ, Mobbs BG: Hormones and cancer, in Tannock IF, Hill RP (eds): The Basic Science of Oncology, 2nd Ed, pp 207-232. New York, McGraw-Hill, 1992.
16. Lippman ME: Steroid hormone receptors and mechanisms of growth regulation of human breast cancer, in Lippman ME, Lichtner AS, Danforth DN (eds): Diagnosis and Management of Breast Cancer, pp 327-347. Philadelphia, WB Saunders, 1988.
17. Androgens and estrogens in the treatment of disseminated mammary carcinoma: Retrospective study of nine hundred forty-four patients: Report the Council on Drugs. JAMA 172:135-147, 1960.
18. Carter AC, Sedransk N, Kelley RM, et al: Diethylstilbestrol: Recommended dosages for different categories of breast cancer patients. Report of the Cooperative Breast Cancer Group. JAMA 237:2079-2085, 1977.
19. Huggins C, Yang NC: Induction and extinction of mammary cancer. Science 137:257-262, 1962.
20. Pritchard KI, Sutherland DJA: Diagnosis and therapy of breast cancer: The use of endocrine therapy. Hematol Oncol Clin North Am 3:765-805, 1989.
21. Minton MJ, Knight RK, Rubens RD: Corticosteroids for elderly patients with breast cancer. Cancer 48:883-887, 1981.
22. Bruera E, Roca E, Cedaro L, et al: Action of oral methylprednisolone in terminal cancer patients: A prospective randomized double-blind study. Cancer Treat Rep 69:751-754, 1985.
23. 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.
24. Wakeling AE. The future of new pure antiestrogens in clinical breast cancer. Breast Cancer Res Treat 25:1-9, 1993.
25. Litherland S, Jackson IM: Antioestrogens in the management of hormone-dependent cancer. Cancer Treat Rev 15:183-194, 1988.
26. Manni A: Tamoxifen therapy of metastatic breast cancer. J Lab Clin Med 109:290-299, 1987.
27. Henderson IC: Endocrine therapy of metastatic breast cancer, in Harris JR, Hellman S, Henderson IC, et al (eds): Breast Diseases, 2nd Ed, pp 559-603. New York, Lippincott, 1991.
28. Canney PA, Griffiths T, Latief TN, et al: Clinical significance of tamoxifen withdrawal response (letter). Lancet 1:36, 1987.
29. Buckley MM, Goa KL: Tamoxifen. A reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic use. Drugs 37:451-490, 1989.
30. Katzenellenbogen BS: Antiestrogen resistance: Mechanisms by which breast cancer cells undermine the effectiveness of endocrine therapy (editorial). J Natl Cancer Inst 83:1434-1435, 1991.
31. Pommier RF, Woltering EA, Keenan EJ, et al: The mechanism of hormone-sensitive breast cancer progression on antiestrogen therapy: Implications for treatment and protocol planning. Arch Surg 122:1311-1316, 1987.
32. Malet C, Gompel A, Spritzer P, et al: Tamoxifen and hydroxytamoxifen isomers versus estradiol effects on normal human breast cells in culture. Cancer Res 48:7193-7199, 1988.
33. Mauvais-Javis P, Baudot N, Castaigne D, et al: Trans-4-hydroxytamoxifen concentration and metabolism after local percutaneous administration to human breast. Cancer Res 46:1521-1525, 1986.
34. Murphy C, Fotsis T, Pantzar P, et al: Analysis of tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen levels in cytosol and KCl-nuclear extracts of breast tumours from tamoxifen treated patients by gas chromatography-mass spectrometry (GC-MS) using selected ion monitoring (SIM). J Steroid Biochem 28:609-618, 1987.
35. Osborne CK, Wiebe VJ, McGuire WL, et al: Tamoxifen and the isomers of 4-hydroxytamoxifen in tamoxifen-resistant tumors from breast cancer patients. J Clin Oncol 10: 304-310, 1992.
36. Wiebe VJ, Osborne CK, McGuire WL, et al: Identification of estrogenic tamoxifen metabolite(s) in tamoxifen-resistant human breast tumors. J Clin Oncol 10:990-994, 1992.
37. Wolf DM, Langan-Fahey SM, Parker CJ, et al: Investigation of the mechanism of tamoxifen-stimulated breast tumor growth with nonisomerizable analogues of tamoxifen and metabolites. J Natl Cancer Inst 85:806-812, 1993.
38. Karnik PS, Kulkarni S, Liu XP, et al: Estrogen receptor mutations in tamoxifen-resistant breast cancer. Cancer Res 54:349-353, 1994.
39. Clarysse A: Hormone-induced tumor flare (editorial). Eur J Cancer Clin Oncol 21:545-547, 1985.
40. Plotkin D, Lechner JJ, Jung WE, et al: Tamoxifen flare in advanced breast cancer. JAMA 240:2644-2646, 1978.
41. Rose DP, Fischer AH, Jordan VC: Activity of the antioestrogen trioxifene against N-nitrosomethylurea-induced rat mammary carcinomas. Eur J Cancer Clin Oncol 17:893-898, 1981.
42. Witte RS, Pruitt B, Tormey DC, et al: A phase I/II investigation of trioxifene mesylate in advanced breast cancer: Clinical and endocrinologic effects. Cancer 57:34-39, 1986.
43. Lee RW, Buzdar AU, Blumenschein GR, et al: Trioxifene mesylate in the treatment of advanced breast cancer. Cancer 57:40-43, 1986.
44. Anttila M, Valavaara R, Kivinen S, et al: Pharmacokinetics of toremifene. J Steroid Biochem 36:249-252, 1990.
45. Kangas L: Introduction to toremifene. Breast Cancer Res Treat 16 (suppl):S3-S7, 1990.
46. Valavaara R: Phase II trials with toremifene in advanced breast cancer: A
review. Breast Cancer Res Treat 16(suppl):S31-S35, 1990.
47. Stenbygaard LE, Herrstedt J, Thomsen JF, et al: Toremifene and tamoxifen in advanced breast cancer-a double-blind cross-over trial. Breast Cancer Res Treat 25:57-63, 1993.
48. Vogel CL, Shemano I, Schoenfelder J, et al: Multicenter phase II efficacy trial of toremifene in tamoxifen-refractory patients with advanced breast cancer. J Clin Oncol 11:345-350, 1993.
49. Kawamura I, Mizota T, Lacey E, et al: The estrogenic and antiestrogenic activities of droloxifene in human breast cancers. Jpn J Pharmacol 63:27-34, 1993.
50. Buzdar AU, Kau S, Hortobagyi GN, et al: Phase I trial of droloxifene in patients with metastatic breast cancer. Cancer Chemother Pharmacol 33:313-316, 1994.
51. Bruning PF: Droloxifene, a new anti-oestrogen in postmenopausal advanced breast cancer: Preliminary results of a double-blind dose-finding phase II trial. Eur J Cancer 28A:1404-1407, 1992.
52. Deschenes L: Droloxifene, a new antiestrogen, in advanced breast cancer. A double-blind dose-finding study. The Droloxifene 002 International Study Group. Am J Clin Oncol 14 (suppl 2):S52-55, 1991.
53. Bellmunt J, Sole L: European early phase II dose-finding study of droloxifene in advanced breast cancer. Am J Clin Oncol 14 (suppl 2):S36-39, 1991.
54. Haarstad H, Gundersen S, Wist E, et al: Droloxifene-a new anti-estrogen: A phase II study in advanced breast cancer. Acta Oncol 31:425-428, 1992.
55. Stein RC, Dowsett M, Cunningham DC, et al: Phase I/II study of the anti-oestrogen zindoxifene (Dl6726) in the treatment of advanced breast cancer: A Cancer Research Campaign Phase I/II Clinical Trials Committee study. Br J Cancer 61:451-453, 1990.
56. Coombes RC, Jarman M, Dowsett M: New endocrine agents for the treatment of breast cancer. Recent Results Cancer Res 127:267, 1993.
57. Wakeling AE: Therapeutic potential of pure antioestrogens in the treatment of breast cancer. J Steroid Biochem Mol Biol 37:771-775, 1990.
58. Wakeling AE: Novel pure antiestrogens. Mode of action and therapeutic prospects. Ann NY Acad Sci 595:348-356, 1990.
59. Poulin R, Merand Y, Poirier D, et al: Antiestrogenic properties of keoxifene, trans-4-hydroxytamoxifen, and ICI 164384, a new steroidal antiestrogen, in ZR-75-1 human breast cancer cells. Breast Cancer Res Treat 14:65-76, 1989.
60. Thompson EW, Katz D, Shima TB, et al: ICI 164,384, a pure antagonist of estrogen-stimulated MCF-7 cell proliferation and invasiveness. Cancer Res 49:6929-6934, 1989.
61. Bronzert DA, Davidson N, Lippman M: Estrogen and antiestrogen resistance in human breast cancer cell lines. Adv Exp Med Biol 196:329-345, 1986.
62. Gottardis MM, Jiang SY, Jeng MH, et al: Inhibition of tamoxifen-stimulated growth of an MCF-7 tumor variant in athymic mice by novel steroidal antiestrogens. Cancer Res 49:4090-4093, 1989.
63. Wakeling AE, Bowler J: ICI 182,780, a new antioestrogen with clinical potential. J Steroid Biochem Mol Biol 43:173-177, 1992.
64. Wakeling AE, Dukes M, Bowler J: A potent specific pure antiestrogen with clinical potential. Cancer Res 51:3867-3873, 1991.
65. DeFriend DJ, Howell A, Nicholson RI, et al: Investigation of a new pure antiestrogen (ICI 182780) in women with primary breast cancer. Cancer Res 54:408-414, 1994.
66. Bakker GH, Setyono-Han B, Portengen H, et al: Treatment of breast cancer with different antiprogestins: preclinical and clinical studies. J Steroid Biochem Mol Biol 37:789-794, 1990.
67. Schneider MR, Michna H, Nishino Y, et al: Tumor-inhibiting potential of ZK 112.993, a new progesterone antagonist, in hormone-sensitive, experimental rodent and human mammary tumors. Anticancer Res 10:683-687, 1990.
68. Cunningham D, Gazet J, Ford HT, et al: Oral gestrinone: A novel antiprogestin with no antitumor activity in endocrine-sensitive breast cancer. Cancer Treat Rep 71:1091-1092, 1987.
69. Perrault DJ, Logan DM, Stewart DJ, et al: Phase II study of flutamide in patients with metastatic breast cancer: A National Cancer Institute of Canada Clinical Trials Group study. Invest New Drugs 6:207-210, 1988.
70. Manni A, Santen RJ: Clinical use of aromatase inhibitors in the treatment of breast cancer. Cancer Treat Res 39:67-81, 1988.
71. Santen RJ, Worgul TJ, Lipton A, et al: Aminoglutethimide as treatment of postmenopausal women with advanced breast carcinoma. Ann Intern Med 96:94-101, 1982.
72. Stuart-Harris RC, Smith IE: Aminoglutethimide in the treatment of advanced breast cancer. Cancer Treat Rev 11:189-204, 1984.
73. Lawrence BV, Lipton A, Harvey HA, et al: Influence of estrogen receptor status on response of metastatic breast cancer to aminoglutethimide therapy. Cancer 45:786-791, 1980.
74. Wander HE, Blossey HC, Nagel GA: Aminoglutethimide in the treatment of premenopausal patients with metastatic breast cancer. Eur J Cancer Clin Oncol 22:1371-1374, 1986.
75. Brufman G, Biran S: Second line hormonal therapy with aminoglutethimide in metastatic breast cancer. Acta Oncol 29:717-720, 1990.
76. Messeih AA, Lipton A, Santen RJ, et al: Aminoglutethimide-induced hematologic toxicity: worldwide experience. Cancer Treat Rep 69:1003-1004, 1985.
77. Foster AB, Jarman M, Leung CS, et al: Analogues of aminoglutethimide: Selective inhibition of aromatase. J Med Chem 28:200-204, 1985.
78. Haynes BP, Jarman M, Dowsett M, et al: Pharmacokinetics and pharmacodynamics of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione in patients with postmenopausal breast cancer. Cancer Chemother Pharmacol 27:367-372, 1991.
79. Dowsett M: Inhibitors of steroidogenic enzymes for the treatment of breast cancer. J Steroid Biochem Mol Biol 39:805-809, 1991.
80. Brodie AM, Wing LY, Goss P, et al: Aromatase inhibitors and the treatment of breast cancer. J Steroid Biochem 24:91-97, 1986.
81. Pickles T, Perry L, Murray P, et al: 4-hydroxyandrostenedione-further clinical and extended endocrine observations. Br J Cancer 62:309-313, 1990.
82. Stein RC, Dowsett M, Hedley A, et al: Treatment of advanced breast cancer in postmenopausal women with 4-hydroxyandrostenedione. Cancer Chemother Pharmacol 26:75-78, 1990.
83. Hoffken K, Jonat W, Possinger K, et al: Aromatase inhibition with 4-hydroxyandrostenedione in the treatment of postmenopausal patients with advanced breast cancer: A phase II study. J Clin Oncol 8:875-880, 1990.
84. Coombes RC, Goss PE, Dowsett M, et al: 4-Hydroxyandrostenedione treatment for postmenopausal patients with advanced breast cancer. Steroids 50:245-252, 1987.
85. Lipton A, Harvey HA, Demers LM, et al: A phase I trial of CGS 16949: A new aromatase inhibitor. Cancer 65:1279-1285, 1990.
86. Santen RJ, Demers LM, Lynch J, et al: Specificity of low dose fadrozole hydrochloride (CGS 16949A) as an aromatase inhibitor. J Clin Endocrinol Metab 73:99-106, 1991.
87. Raats JI, Falkson G, Falkson HC: A study of fadrozole, a new aromatase inhibitor, in postmenopausal women with advanced metastatic breast cancer. J Clin Oncol 10:111-116, 1992.
88. Bhatnagar AS, Hausler A, Schieweck K, et al: Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new non-steroidal aromatase inhibitor. J Steroid Biochem Mol Biol 37:1021-1027, 1990.
89. Perez N, Borja J: Aromatase inhibitors: clinical pharmacology and therapeutic implications in breast cancer. J Intl Med Res 20:303-312, 1992.
90. Dowsett M, Johnston SRD, Doody D, et al: The clinical and endocrine effects of the oral aromatase inhibitor vorozole in human breast cancer (abstract). Proc Am Soc Clin Oncol 13:71, 1994
91. Goss PE, Clark R, Ambus U, et al: Phase II study of vorozole (R 83842) a new aromatase inhibitor in postmenopausal women with advanced breast cancer (abstract). Proc Am Soc Clin Oncol 13:88, 1994.
92. Vinholes J, Paridains R, Piccart MJ, et al: An EORTC breast group phase II study of vorozole (R 83842), a new aromatase inhibitor in advanced breast cancer (abstract). Proc Am Soc Clin Oncol 13:105, 1994.
93. Goldenberg IS, Waters N, Ravdin RS, et al: Androgenic therapy for advanced breast cancer in women: A report of the cooperative breast cancer group. JAMA 223:1267-1268, 1973.
94. Manni A, Arafah BM, Pearson OH: Androgen-induced remissions after antiestrogen and hypophysectomy in stage IV breast cancer. Cancer 48:2507-2509, 1981.
95. Peters TG, Lewis JD, Wilkinson EJ, et al: Danazol therapy in hormone-sensitive mammary carcinoma. Cancer 40:2797-2800, 1977.
96. Coombes RC, Dearnaley D, Humphreys J, et al: Danazol treatment of advanced breast cancer. Cancer Treat Rep 64:1073-1076, 1980.
97. Coombes RC, Perez D, Gazet JC, et al: Danazol treatment for advanced breast cancer. Cancer Chemother Pharmacol 10:194-195, 1983.
98. Pronzato P, Amoroso D, Ardizzoni A, et al: A phase II study of danazol in metastatic breast cancer. Am J Clin Oncol 10:407-409, 1987.
99. Brodovsky HS, Holroyde CP, Laucius JF, et al: Danazol in the treatment of women with metastatic breast cancer. Cancer Treat Rep 71:875-876, 1987.
100. Petru E, Schmahl D: On the role of additive hormone monotherapy with tamoxifen, medroxyprogesterone acetate and aminoglutethimide, in advanced breast cancer. Klin Wochenschrift 65:959-966, 1987.
101. Liber J, Rose C, Salimtschik M, et al: Treatment of advanced breast cancer with progestins. Acta Obstet Gynecol Scand 101(suppl):39-46, 1981.
102. Haller DG, Glick JH: Progestational agents in advanced breast cancer: an overview. Semin Oncol 13:2-8, 1986.
103. Pannuti F, Martoni A, Piana E, et al: Progestins in breast cancer, in Pannuti F (ed): Hormonotherapy: Results and Perspectives, pp 207-222. Pavia, Italy, Edizioni, 1988.
104. Sedlacek SM, Horwitz KB: The role of progestins and progesterone receptors in the treatment of breast cancer. Steroids 44:467-483, 1991.
105. Pannuti F, Martoni A, Di Marco AR, et al: Prospective, randomized clinical trial of two different high dosages of medroxyprogesterone acetate (MAP) in the treatment of metastatic breast cancer. Eur J Cancer 15:593-601, 1979.
106. Della Cuna GR, Calciati A, Strada MRB, et al: High dose medroxyprogesterone acetate (MPA) treatment in metastatic carcinoma of the breast: A dose-response evaluation. Tumori 64:I43-I49, 1978.
107. Cortes Funes H, Madrigal PL, Perez Mangas G, et al: Medroxyprogesterone acetate at two different doses for the treatment of advanced breast cancer in Campio L, Robustelli Della Cuna G, Taylor RW (eds): Role of Medroxyprogesterone in Endocrine Related Tumors, 2nd Ed, pp 77-83. New York, Raven Press, 1983.
108. Cavalli F, Goldhirsch A, Jungi F, et al: Randomized trial of low- versus high-dose medroxyprogesterone acetate in the induction treatment of postmenopausal patients with advanced breast cancer. J Clin Oncol 2:414-419, 1984.
109. Gallagher CJ, Cairnduff F, Smith IE: High dose versus low dose medroxyprogesterone acetate: a randomized trial in advanced breast cancer. Eur J Cancer Clin Oncol 23:1895-1900, 1987.
110. Sedlacek SM: An overview of megestrol acetate for the treatment of advanced breast cancer. Semin Oncol 15:3-13, 1988.
111. Muss HB, Case LD, Capizzi RL, et al: High- versus standard-dose megestrol acetate in women with advanced breast cancer: A phase III trial of the Piedmont Oncology Association. J Clin Oncol 8:1797-1805, 1990.
112. Muss HB, Case LD, Atkins JN, et al: Tamoxifen versus high dose oral medroxyprogesterone acetate as initial endocrine therapy for patients with metastatic breast cancer: A Piedmont Oncologh Association (POA) Study. J Clin Oncol 12:1630-1638, 1994.
113. DeSombre ER, Johnson ES, White WF: Regression of rat mammary tumors effected by a gonadoliberin analog. Cancer Res 36:3830-3833, 1976.
114. Klijn JG. LH-RH agonists in the treatment of metastatic breast cancer: ten years' experience. Recent Results Cancer Res 124:75-90, 1992.
115. Belchetz PE, Plant TM, Nakai Y, et al: Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone. Science 202:631-633, 1978.
116. Conn PM, Crowley WF, Jr: Gonadotropin-releasing hormone and its analogues. N Engl J Med 324:93-103, 1991.
117. Harris AL, Carmichael J, Cantwell BM, et al: Zoladex: Endocrine and therapeutic effects in postmenopausal breast cancer. Br J Cancer 59:97-99, 1989.
118. Eidne KA, Flanagan CA, Millar RP: Gonadotropin-releasing hormone binding sites in human breast carcinoma. Science 229:989-991, 1985.
119. Miller WR, Scott WN, Morris R, et al: Growth of human breast cancer cells inhibited by a luteinizing hormone-releasing hormone agonist. Nature 313:231-233, 1985.
120. Kaufmann M, Jonat W, Kleeberg U, et al: Goserelin, a depot gonadotrophin-releasing hormone agonist in the treatment of premenopausal patients with metastatic breast cancer: German Zoladex Trial Group. J Clin Oncol 7:1113-1119, 1989.
121. Hardy JR, Powles TJ, Judson IR, et al: Combination of tamoxifen, aminoglutethimide, danazol and medroxyprogesterone acetate in advanced breast cancer. Eur J Cancer 26:824-827, 1990.
122. Mouridsen HT, Salimtschik M, Dombemowsky P, et al: Therapeutic effect of tamoxifen versus combined tamoxifen and diethylstilboestrol in advanced breast cancer in postmenopausal women. Eur J Cancer 1(suppl):107-110, 1980.
123. Ingle JN, Twito DI, Schaid DJ, et al: Randomized clinical trial of tamoxifen alone or combined with fluoxymesterone in postmenopausal women with metastatic breast cancer. J Clin Oncol 6:825-831, 1988.
124. Ingle JN, Green SJ, Ahmann DL, et al: Randomized trial of tamoxifen alone or combined with aminoglutethimide and hydrocortisone in women with metastatic breast cancer. J Clin Oncol 4:958-964, 1986.
125. Bezwoda WR, Meyer K: Effect of alpha-interferon, 17 beta-estradiol, and tamoxifen on estrogen receptor concentration and cell cycle kinetics of MCF 7 cells. Cancer Res 50:5387-5391, 1990.
126. Seymour L, Bezwoda WR: Interferon plus tamoxifen treatment for advanced breast cancer: in vivo biologic effects of two growth modulators. Br J Cancer 68:352-356, 1993.
127. Cobleigh MA, Dowlatshahi K, Deutsch TA, et al: Phase I/II trial of tamoxifen with or without fenretinide, an analog of vitamin A, in women with metastatic breast cancer. J Clin
Oncol 11:474-477, 1993.
128. Hubbard SM, Henney JE, DeVita VTJ: A Computer data base for information on cancer treatment. N Engl J Med 316:315-318, 1987.
129. Binder SC, Flynn WJ, Pass LM: Endocrine ablative therapy of metastatic breast cancer. Ca Cancer J Clin 27:1-9, 1977.