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Vorozole results in greater oestrogen suppression than formestane in postmenopausal women and when added to goserelin in premenopausal women with advanced breast cancer

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Abstract

The high potency and selectivity of new aromatase inhibitors has translated to greater efficacy and improved tolerability in comparison with established second‐line hormonal agents for advanced breast cancer in phase III clinical trials. Two pharmacological studies are reported which assess the use of one of these inhibitors, vorozole, in combination or comparison with well‐established methods of oestrogen deprivation in pre and postmenopausal patients. When combined with the gonadotrophin‐releasing hormone agonist (GnRHa) goserelin in 10 premenopausal patients, vorozole markedly enhanced the suppression of serum levels of oestrone, oestradiol and, oestrone sulphate beyond that achieved by goserelin alone (by a mean 74%, 83%, and 89%, respectively). The combination was well‐tolerated and had no significant effects on androgen levels. Vorozole was compared with formestane in 13 postmenopausal women and serum oestrone, oestradiol, and oestrone sulphate levels were suppressed by 47%, 30%, and 70%, respectively, more by vorozole than by the steroidal aromatase inhibitor. Again the tolerability was excellent. The plasma oestrogen levels in the postmenopausal patients on vorozole were lower than in the premenopausal patients on goserelin plus vorozole, indicating that ovarian oestrogen synthesis may be relatively resistant to aromatase inhibition, even during GnRHa treatment. Thus, in both pre and postmenopausal patients substantially greater suppression of oestrogen can be achieved by vorozole compared with alternative approaches. Existing clinical–pharmacological correlates suggest that these increases in pharmacological effectiveness may result in enhanced clinical effectiveness.

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References

  1. Howell A, Dowsett M: Recent advances in the endocrine therapy of breast cancer. BMJ 315: 863–866, 1997

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  3. Stuart-Harris R, Smith JE, Dowsett M, Bozek T, McKinna JA, Gazet J-C, Jeffcoate SL, Kurkure A, Carr L: Low-dose aminoglutethimide in treatment of advanced breast cancer. Lancet ii: 604–607, 1984

    Google Scholar 

  4. Stuart-Harris RC, Smith IE: Aminoglutethimide in the treatment of advanced breast cancer. Cancer Treatment Reviews 11: 189–204, 1984

    PubMed  Google Scholar 

  5. Kao C-Y, Can LL, Laughton CA, Zhou D, Chen S: Binding characteristics of seven inhibitors of human aromatase: a site directed mutagenesis study. Cancer Res 56: 3451–3460, 1996

    PubMed  Google Scholar 

  6. Coombes RC, Hughes SWM, Dowsett M: 4-hydroxyandrostenedione: A new treatment for postmenopausal patients with breast cancer. Eur J Cancer 28A: 1941–1945, 1992

    PubMed  Google Scholar 

  7. Jones AL, MacNeill F, Jacobs S, Lonning PE, Dowsett M, Powles TJ: The influence of intramuscular 4-hydroxyandrostenedione on peripheral aromatisation in breast cancer patients. Eur J Cancer 28: 1712–1716, 1992

    Google Scholar 

  8. Dowsett M, Jones A, Johnston SRD, Jacobs S, Trunet P, Smith IE: In vivo measurement of aromatase inhibition by letrozole (20267) in postmenopausal patients with breast cancer. Clin Cancer Res 1: 1511–1515, 1995

    PubMed  Google Scholar 

  9. Geisler J, King N, Dowsett M, Ouestad L, Lundgren S, Walton P, Kormeset PO, Lonning PE: Influence of Anastrozole (Arimidexr) a non-steroidal aromatase inhibitor, on in vivo aromatisation and plasma estrogen levels in postmenopausal women with breast cancer. Br J Cancer 74: 1286–1291, 1996

    PubMed  Google Scholar 

  10. Van der Wall E, Donker TH, DeGrankrijker E, et al.: Inhibition of the in vivo conversion of androstenedione to estrone by the aromatase inhibitor vorozole in healthy postmenopausal women. Cancer Res 53: 4563–4566, 1993

    PubMed  Google Scholar 

  11. Marty M, Gershanovich M, Campos B, Romieu G, Lurie H, Bonaventura T, Jeffery M, Buzzi F, Ludwig H, Bodrogi I, Reichardt P, O'Higgins N, Chaudri HA, Friederich P, Blachoff MA: Letrozole, a new potent, selective aromatase inhibitor superior to aminoglutethimide in postmenopausal women with advanced breast cancer previously treated with antioestrogens [abstract] Proc Am Soc Clin Oncol 544: 156a, 1997

    Google Scholar 

  12. Bergh J, Bonneterre J, Illiger HJ, Murray R, Nortier J, Paridaens R, Rubens RD, Samonigg H, Van Zyl J, Houston S: Vorozole (Rivizor) versus aminogluthimide (AG) in postmenopausal women with advanced breast cancer relapsing after tamoxifen [abstract]. Proc Am Soc Clin Oncol 543: 155a, 1997

    Google Scholar 

  13. Klijn JGM, Seymour C, Beex L, et al.: Combined estrogen suppression and receptor blockade by buserelin (LHRH-A) and tamoxifen in premenopausal metastatic breast cancer: preliminary results of a 3-arm randomised study (EORTC 10881) Eur J Cancer 32A: 49 (abstr), 1996

    Google Scholar 

  14. Jonat W, Kaufmann M, Blamey RW, Howell A, Collins JP, Coates A, Eiermann W, Janicke F, Njordenskold B, Forbes JF: A randomised study to compare the effect of the luterinising hormone releasing hormone (LHRH) analogue goserelin with or without tamoxifen in pre-and postmenopausal patients with advanced breast cancer. Eur J Cancer 31A: 137–142, 1995

    PubMed  Google Scholar 

  15. Dowsett M, Cunningham D, Nicol, S, Lal A, Evans S, Brodie AMH, Jeffcoate SL, Coombes RC: Endocrinology and pharmacokinetics of oral 4-hydroxyandrostenedione treatment for postmenopausal patients with advanced breast cancer. Steroids 50: 615–616, 1987

    Google Scholar 

  16. Johnston SRD, Smith IE, Doody D, Jacobs S, Robertshaw H, Dowsett M: Clinical and endocrine effects of the oral aromatase inhibitor vorozole in postmenopausal patients with advanced breast cancer. Cancer Res 54: 5875–5881, 1994

    PubMed  Google Scholar 

  17. Ferguson K, Hayes M, Jeffcoate SL: A standardised multicentre procedure for plasma gonadotrophin radioimmunoassay. Ann Clin Biochem 19: 358–361, 1982

    PubMed  Google Scholar 

  18. Buzdar A, Jonat W, Howell A, Blomqvist C, Vogel CL, Eirmann W, Walter JM, Azab M, Webster A, Plourde PV: Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. J Clin Oncol 14: 2000–2011, 1996

    PubMed  Google Scholar 

  19. Dombernovsky P, Smith I, Falkson G, Panasci LL, Bezwoda W: Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomised trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 16: 453–461, 1998

    PubMed  Google Scholar 

  20. Buzdar A, Jonat W, Howell A, Yin H, Lee D: Significant improved survival with Arimidex. Pro Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials [abstract]. Proc Am Soc Clin Oncol 545: 156a, 1997

    Google Scholar 

  21. Goss P, Wine E, Tannock I, Schwartz IH, Kremer AB: Vorozole versus Megace in postmenopausal patients with metastatic breast carcinoma who had relapsed following tamoxifen. Proc Am Soc Clin Oncol 542: 155a, 1997

    Google Scholar 

  22. Holzman D: Elusive estrogens may hold key to some cancer risk. J Natl Cancer Inst 87: 1207–1209, 1995

    PubMed  Google Scholar 

  23. Dowsett M, Cunningham DC, Stein RC, Evans S, Dehennin L, Hedley A, Coombes RC: Dose-related endocrine effects and pharmacokinetics of oral and intramuscular 4-hydroxyandrostenedione in postmenopausal breast cancer patients. Cancer Res 49: 1306–1312, 1989

    PubMed  Google Scholar 

  24. MacNeill FA, Jones AL, Jacobs S, Lonning P, Powles TJ, Dowsett M: The influence of aminoglutethimide and its analogue rogletimide on peripheral aromatisation in breast cancer. Br J Cancer 66: 692–697, 1992

    PubMed  Google Scholar 

  25. Dowsett M: Theoretical considerations for the ideal aromatase inhibitor. Breast Cancer Res Treat 49: 539–544. 1998

    Google Scholar 

  26. Dc Coster R, Tuman R, Bowden C, et al.: Endocrine effects of vorozole on pituitary-ovarian function. In: Motta M and Serio M (eds) Sex hormones and antihormones in endocrine dependent pathology: basic and clinical aspects. Elsevier, Amsterdam, 287–295, 1994

    Google Scholar 

  27. Santen RJ, Samojlik E, Wells SA: Resistance of the ovary to blockade of aromatization with aminoglutethimide. J Clin Endocrinol Metab 51: 473-477, 180

  28. Harris AL, Dowsett M, Jeffcoate SL, McKinna JA, Morgan M, Smith IE: Endocrine and therapeutic effects of aminoglutethimide in premenopausal patients with breast cancer. J Clin Endocrinol Metab 55: 718–722, 1982

    PubMed  Google Scholar 

  29. Wander HE, Blossey HCL, Nagel GA. Aminoglutethimide in the treatment of premenopausal patients with metastatic breast cancer. Eur J Cancer 22: 1371–1374, 1986

    Google Scholar 

  30. Wouters W, Dc Coster R, Tuman RW, Bowden CR, Bruynseels J, Vanderpas H, Van Rooy P, Amery WK, Janssen PAJ: Aromatase inhibition by R76713: experimental and clinical pharmacology. J Steroid Biochem 34: 427–430, 1989

    PubMed  Google Scholar 

  31. Stein RC, Dowsett M, Hedley A, Coombes RC: The clinical and endocrine effects of 4-hydroxyandrostenedione alone and in combination with goserelin in premenopausal women with advanced breast cancer. Br J Cancer 62: 679–683, 1990

    PubMed  Google Scholar 

  32. Dowsett M, Stein RC, Coombes RC: Aromatization inhibition alone or in combination with GnRH agonists for the treatment of premenopausal breast cancer patients. J Steroid Biochem 43: 155–159, 1992

    Google Scholar 

  33. Sakai F, Cheix F, Chavel M, Colon J, Mayer M: Increases in steroid binding globulins induced by tamoxifen in patients with carcinoma of the breast. J Endocrinol 76: 219–226, 1978

    PubMed  Google Scholar 

  34. Wakeling AE, O'Connor KM, Newboult E: Comparison of the biological effects of tamoxifen and a new antioestrogen (LY 117018) on the immature rat uterus. J Endocrinol 99: 447–453, 1983

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Academic Department of Biochemistry, Royal Marsden Hospital, London, SW3 6JJ

    Mitchell Dowsett & Debbie Doody

  2. Janssen‐Cilag Pharmaceuticals Limited, Saunderton, High Wycombe, Buckinghamshire

    Stephanie Miall & Angela Howes

  3. Department of Medical Oncology, Charing Cross Hospital, London, UK

    Jaquie English & R Charles Coombes

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  1. Mitchell Dowsett
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  2. Debbie Doody
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  3. Stephanie Miall
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  4. Angela Howes
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  5. Jaquie English
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  6. R Charles Coombes
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Dowsett, M., Doody, D., Miall, S. et al. Vorozole results in greater oestrogen suppression than formestane in postmenopausal women and when added to goserelin in premenopausal women with advanced breast cancer. Breast Cancer Res Treat 56, 25–34 (1999). https://doi.org/10.1023/A:1006289811540

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