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Pharmacologic suppression of estrogens with aminoglutethimide as treatment of advanced breast carcinoma

Mechanistic, hormonal, and clinical studies

  • Scandinavian Breast Cancer Symposium
  • Published:
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Summary

Recent studies suggest that estrogens are the predominant hormones required for the growth of hormonedependent breast cancers in women. Traditional methods of lowering estrogens as treatment of breast cancer involve surgical removal of the ovaries, adrenals, or pituitary. Newer investigative strategies utilize blockade of estrogen action with antiestrogens or inhibition of estrogen synthesis. As reviewed previously, a regimen for pharmacologic suppression of estrogen production was developed which utilizes the aromatase/steroidogenesis inhibitor aminoglutethimide (AG) and replacement hydrocortisone (HC). The current paper updates recent mechanistic, clinical, and hormonal data regarding AG.

The preservation of plasma androstenedione levels concomitant with marked estrone and estradiol suppression suggests that AG lowers estrogen production predominantly by blocking aromatization. The mechanism for sustained androstenedione production in the face of suppressed ketosteroids, glucocorticoids, and mineralocorticoids during AG administration was evaluated in dogs fitted with arteriovenous adrenal cannulae. Inhibition of the adrenal secretion of androstenedione with preservation of peripheral plasma levels of this steroid suggests stimulation ofextra-adrenal 3β-ol-dehydrogenase,Δ 5-Δ 4-isomerase activity by AG.

Clinical studies revealed a 32% objective response rate to AG/HC in unselected patients and a 52% response in women with estrogen receptor positive tumors. Randomized trials indicated similar response rates to AG/HC vs hypophysectomy (AG/HC 47% vs Hypox 21%,p = NS), surgical adrenalectomy (AG/HC 52% vs surgical adrenalectomy 43%,p = NS) and antiestrogen therapy (AG/HC 36% vs tamoxifen 38%,p = NS). Cross-over data revealed that 50% of 94 patients initially responding to tamoxifen later experienced an objective regression to AG/HC. Only 25% of 93 tamoxifen nonresponders benefited later from AG/HC. Trends indicate that bone metastases may respond better to AG/HC (33%) than to tamoxifen (15%).

Use of a computer-based data matrix allowed determination of whether patients escape from AG/HC induced estrogen and androgen suppression at the time of disease relapse. No trends towards escape from estrogen inhibition were apparent. However, in the objective responders to AG/HC, the weak androgens dehydroepiandrosterone-sulfate (DHEA-S) and androstenedione appeared to increase prior to disease relapse. DHEA-S but not androstenedione levels remained lower in the objective responders than in nonresponders at all phases of AG/HC therapy. Thus, the estrogens, but not androgens, remain constant during all phases of AG/HC treatment.

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References

  1. Henderson IC, Canellos GP: Cancer of the breast: the past decade. N Engl J Med 302: 17–30, 78–90, 1980.

    Google Scholar 

  2. McGuire WL, Horwitz KB, Pearson OH, Segaloff A: Current status of estrogen and progesterone receptors in breast cancer. Cancer 39: 2934–2947, 1977.

    Google Scholar 

  3. McGuire WL, Pearson OH, Segaloff A: Predicting hormone responsiveness in human breast cancer.In WL McGuire, PP Carbone, and EP Vollmer (eds). Estrogen Receptors in Breast Cancer. Raven Press, New York, 1975, pp 17–30.

    Google Scholar 

  4. Henderson IC: II. Selection of therapy for metastatic breast cancer.In RJ Santen and IC Henderson (eds). Pharmanual: A Comprehensive Guide to the Therapeutic Use of Aminoglutethimide. Karger, Basel, 1982, pp 47–100.

    Google Scholar 

  5. Santen RJ, Lipton A, Kendall J: Successful medical adrenalectomy with aminoglutethimide. Role of altered drug metabolism. J Am Med Assoc 230: 1661–1665, 1974.

    Google Scholar 

  6. Santen RJ, Samojlik E: Medical adrenalectomy for treatment of metastatic breast carcinoma.In WL McGuire (ed). Breast Cancer, Vol. 3. Plenum Publishing, New York, 1979, pp 79–114.

    Google Scholar 

  7. Harvey HA, Santen RJ, Osterman J, Samojlik E, White DS, Lipton A: A comparative trial of transsphenoidal hypophysectomy and estrogen suppression with aminoglutethimide in advanced breast cancer. Cancer 43: 2207–2214, 1979.

    Google Scholar 

  8. Santen RJ, Worgul TJ, Samojlik E, Interrante A, Boucher AE, Lipton A, Harvey HA, White DS, Smart E, Cox C, Wells SA: A randomized trial comparing surgical adrenalectomy with aminoglutethimide plus hydrocortisone in women with advanced breast cancer. N Engl J Med 305: 545–551, 1981.

    Google Scholar 

  9. Smith IE, Harris AL, Morgan M, Ford HT, Gazey J-C, Harmer CL, White H, Parsons CA, Villardo A, Walsh G, McKinna JA: Tamoxifen versus aminoglutethimide in the treatment of advanced breast carcinoma: a control randomized cross-over trial. Br Med J 283: 1432–1434, 1981.

    Google Scholar 

  10. Lipton A, Harvey HA, Santen RJ, Boucher A, White D, Bernath A, Dixon R, Richards G, Shafik A: A randomized trial of aminoglutethimide versus tamoxifen in metastatic breast cancer. Cancer Res, 1982, in press.

  11. Santen RJ, Misbin RI: Aminoglutethimide: Review of pharmacology and clinical use. Pharmacotherapy 1: 95–120, 1981.

    Google Scholar 

  12. Paesi FJA: Aminoglutethimide (Orimetene). Mechanism of Action and Clinical Results in Breast Cancer. Proceedings of an International Symposium. CIBA-GEIGY Ltd, Basel, December 11–12, 1980.

  13. Santen RJ: Suppression of estrogens with aminoglutethimide and hydrocortisone (medical adrenalectomy) as treatment of advanced breast carcinoma: A review. Breast Cancer Res Treat 1: 183–202, 1981.

    Google Scholar 

  14. Santen RJ: Suppression of estrogen production as treatment of breast carcinoma: Pharmacologic and clinical studies with aromatase inhibitors.In BJA Furr (ed). Clinics in Oncology. WB Saunders, London, March 1982, in press.

    Google Scholar 

  15. Samojlik E, Veldhuis JD, Wells SA, Santen RJ: Preservation of androgen secretion during estrogen suppression with aminoglutethimide in the treatment of metastatic breast carcinoma. J Clin Invest 65: 602–612, 1980.

    Google Scholar 

  16. Santen RJ, Samojlik E, Demers L, Badder E: Adrenal of male dog secretes androgens and estrogens. Am J Physiol E239: 109–112, 1980.

    Google Scholar 

  17. Santen RJ, Bardin CW: Episodic LH secretion in man: Pulse analysis, clinical interpretation, physiologic mechanisms. J Clin Invest 52: 2617–2628, 1973.

    Google Scholar 

  18. Siiteri PK, Williams JE, Takaki NK: Steroid abnormalities in endometrial and breast carcinoma: A unifying hypothesis. J Steroid Biochem 7: 897–903, 1976.

    Google Scholar 

  19. Adams JB, Li K: Biosynthesis of 17β-oestradiol in human breast carcinoma tissue and a novel method for its characterization. Br J Cancer 31: 429–433, 1975.

    Google Scholar 

  20. Thompson EA Jr, Siiteri PK: Utilization of oxygen and reduced nicotinamide adenine dinucleotide phosphate by human placental microsomes during aromatization of androstenedione. J Biol Chem 249: 5364–5372, 1974.

    Google Scholar 

  21. Thompson EA Jr, Siiteri PK: The involvement of human placental microsomal cytochrome P-450 in aromatization. J Biol Chem 249: 5373–5378, 1974.

    Google Scholar 

  22. Newsome HH, Brown PW, Terz JJ, Lawrence W Jr: Medical and surgical adrenalectomy in patients with advanced breast carcinoma. Cancer 39: 542–546, 1977.

    Google Scholar 

  23. Newsome HH Jr, Brown PW, Terz JJ, Lawrence W Jr: Medical adrenalectomy and plasma steroids in advanced breast carcinoma. Surgery, St Louis 83: 83–89, 1977.

    Google Scholar 

  24. Santen RJ, Santner S, Davis D, Veldhuis J, Samojlik E, Ruby E: Aminoglutethimide inhibits extraglandular estrogen production in postmenopausal women with breast carcinoma. J Clin Endocrinol Metab 47: 1257–1265, 1978.

    Google Scholar 

  25. Santner SJ, Rosen H, Osawa Y, Santen RJ: Comparison of aminoglutethimide, testololactone, 4-hydroxyandrostenedione, and brominated, chlorinated and nitrogenated androstenedione derivatives as inhibitors of aromatase. Breast Cancer Res Treat, 1982, submitted.

  26. Abul-Hajj YJ: Inhibition of androgen aromatization in human breast cancer. J Steroid Biochem 13: 1395–1400, 1980.

    Google Scholar 

  27. Abul-Hajj YJ: Significance of estrogen synthesis in human mammary tumors. Cancer Res, August 1982, in press.

  28. Santen RJ, Worgul TJ, Lipton A, Harvey H, Boucher A, Samojlik E, Wells SA: Aminoglutethimide as treatment of postmenopausal women with advanced breast carcinoma: Correlation of clinical and hormonal responses. Ann Int Med 96: 94–101, 1982.

    Google Scholar 

  29. Murray FT, Santner S, Samojlik EA, Santen RJ: Serum aminoglutethimide levels: studies of serum half-life, clearance and patient compliance. J Clin Pharmac 19: 704–711, 1979.

    Google Scholar 

  30. Santen RJ, Samojlik E, Wells SA: Resistance of the ovary to blockade of aromatization with aminoglutethimide. J Clin Endocrinol Metab 51: 473–477, 1980.

    Google Scholar 

  31. Aromatase—New Perspectives for Breast Cancer. Cancer Res (Suppl), 1982, in press.

  32. Harris A: Aminoglutethimide in 228 postmenopausal patients with advanced breast cancer. I — Clinical results. II — Plasma hormones.In FJA Paesi (ed). Aminoglutethimide (Orimetene). Mechanism of Action and Clinical Results in Breast Cancer. Proceedings of an International Symposium. CIBA-GEIGY Ltd, Basel, December 11–12, 1980.

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Authors and Affiliations

  1. Department of Medicine, Divisions of Endocrinology and Oncology, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pennsylvania, USA

    Richard J. Santen M.D., Elliott Badder M.D., Sheldon Lerman M.D., Harold Harvey M.B.B. Chr., Allan Lipton M.D., Alice E. Boucher (C.R.N.P.), Andrea Manni M.D., Howard Rosen B.S. & Samuel A. Wells M.D.

  2. Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA

    Richard J. Santen M.D., Elliott Badder M.D., Sheldon Lerman M.D., Harold Harvey M.B.B. Chr., Allan Lipton M.D., Alice E. Boucher (C.R.N.P.), Andrea Manni M.D., Howard Rosen B.S. & Samuel A. Wells M.D.

  3. Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA

    Richard J. Santen M.D., Elliott Badder M.D., Sheldon Lerman M.D., Harold Harvey M.B.B. Chr., Allan Lipton M.D., Alice E. Boucher (C.R.N.P.), Andrea Manni M.D., Howard Rosen B.S. & Samuel A. Wells M.D.

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  1. Richard J. Santen M.D.
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  2. Elliott Badder M.D.
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  3. Sheldon Lerman M.D.
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  4. Harold Harvey M.B.B. Chr.
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  5. Allan Lipton M.D.
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  6. Alice E. Boucher
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  7. Andrea Manni M.D.
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  8. Howard Rosen B.S.
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  9. Samuel A. Wells M.D.
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Santen, R.J., Badder, E., Lerman, S. et al. Pharmacologic suppression of estrogens with aminoglutethimide as treatment of advanced breast carcinoma. Breast Cancer Res Tr 2, 375–383 (1982). https://doi.org/10.1007/BF01805879

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