Skip to main content
Log in

Estrogenic Effects of Toremifene and Tamoxifen in Postmenopausal Breast Cancer Patients

  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Intrinsic estrogenicities of the selective estrogen receptor modulators (SERMs) toremifene 60 mg daily or 200 mg daily and tamoxifen 20 mg daily (TOR60, TOR200 and TAM20) were compared in a randomized clinical study in postmenopausal women with advanced breast cancer. The study was open label in three parallel groups. Variables for analysis were serum follicle stimulating hormone (FSH), luteinizing hormone (LH), sex hormone binding globulin (SHBG), estradiol (E2), antithrombin III (AT III), aspartate aminotransferase (ASAT) and vaginal cytology. Clinical efficacy and safety have been reported earlier. A total of 648 patients were randomized (221 to TOR60, 212 to TOR200 and 215 to TAM20). Sera were available for the analysis from 148, 165 and 156 and for vaginal cytology from 98, 93 and 86 patients, respectively. All treatment regimens showed tissue-specific and dose-dependent estrogen agonist effect. In the primary measure of in vivo estrogenicity, effect on hypothalamus–pituitary-axis, all three treatment regimens decreased serum FSH (p < 0.001). TOR200 was more potent than the two other treatments (p < 0.05), but surprisingly, TAM20 was more estrogenic than TOR60 (p < 0.001). As could be expected in postmenopausal women, the treatments had no effect on mean serum E2 concentrations and decrease of serum LH was similar to that of FSH. Estrogenic effect on the liver was seen as dose-dependent increase of SHBG with statistically significant differences between the treatment groups (p < 0.001). Trends of transient ASAT elevations in TOR200 group (p = 0.07) and in all treatment groups AT III decrease (p = 0.1) were seen in the beginning of the treatment. TOR60 or TAM20 did not have an effect on mean ASAT values, and AT III decreased in TAM20 group more than in the two other groups (p = 0.1 compared to TOR60 and p < 0.05 compared to TOR200). Estrogenic effects on vaginal superficial cells were higher in TOR60 and TOR200 groups when compared to TAM20 (p < 0.05). Toremifene and tamoxifen had tissue-specific and partially dose-dependent estrogenic effects in hypothalamus–pituitary-axis, in the liver and in the vaginal epithelium of postmenopausal women. In some tissues tamoxifen 20 may be more estrogenic than toremifene 60 mg/day.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Anttila M, Valavaara R, Kivinen S, Mäenpää J: Pharmacokinetics of toremifene. J Steroid Biochem 36: 249–252, 1990

    Google Scholar 

  • Bergman L, Beelen MLR, Gallee MPW, Hollema H, Benraadt J, van Leeuwen FE and the Comprehensive Cancer Centers' ALERT Group: Lancet 356: 881–887, 2000

    Google Scholar 

  • Bratherton DG, Brown CH, Buchanan R, Hall V, Kingsley Pillers EM, Wheeler TK, Williams CJ: A comparison of two doses of tamoxifen (Nolvadex*) in postmenopausal women with advanced breast cancer:10 mg bd versus 20mg bd. Br J Cancer 50: 199–205, 1984

    Google Scholar 

  • Curtis ER, Boice JD, Shiner DA, Hankey BF, Fraumeni Jr JF: Second cancers after adjuvant tamoxifen therapy for breast cancer. J Natl Cancer Inst 88: 832–834, 1997

    Google Scholar 

  • Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for breast Cancer. An overview of the randomized trials. Lancet 351: 1451–1467, 1998

    Google Scholar 

  • Ellmén J, Werner D, Hakulinen P, Keiling R, Fargeot P, Falkson G, Bezwoda WR: Dose-dependent hormonal effects of toremifene in postmenopausal breast cancer patients. Cancer Chemother Pharmacol 45: 402–408, 2000

    Google Scholar 

  • Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM, Other NSABP Contributors: Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the national surgical adjuvant breast and bowel project (NSABP) B-14. J Natl Cancer Inst 86: 527–537, 1996

    Google Scholar 

  • Fisher B, Dignam J, Bryant J, DeCillis A, Wickerham DL, Wolmark N, Costantino J, Redmond C, Fisher ER, Bowman DM, Deschênes L, Dimitrov NV, Margolese RG, Robidoux A, Shibata H, Terz J, Paterson AHG, Feldman MI, Farrar W, Evans J, Lickley HL: Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor positive tumors. J Natl Cancer Inst 88: 1529–1542, 1996

    Google Scholar 

  • Fisher B, Costantino JP, Wickerham DL, Redmond Carol K, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N, and the other National Surgical Adjuvant Breast and Bowel Project Investigators: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90: 1371–1388, 1998

    Google Scholar 

  • Fornander T, Cedermark B, Mattsson A, Skoog L, Theve T, Askergren J, Rutqvist L, Glas U, Silversward C, Somell A, Wilking N, Hjalmar M: Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1: 117–120, 1989

    Google Scholar 

  • Gershanovich M, Garin A, Baltina D, Kurvet A, Kangas L, Ellmén J: A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer. Breast Cancer Res Treat 45: 251–262, 1997

    Google Scholar 

  • Gershanovich M, Hayes DF, Ellmén J, Vuorinen J: High dose toremifene v.s. tamoxifen in postmenopausal advanced breast cancer. Oncology 11(Suppl 4): 29–36, 1997

    Google Scholar 

  • Goldhirsch A, Wood WC, Senn H-J, Glick JH, Gelber RD: Meeting highlights: international consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst 87: 1441–1445, 1995

    Google Scholar 

  • Gundersen S: Toremifene, a new antiestrogenic compound in the treatment of metastatic mammary cancer. A phase II study. J Steroid Biochem 36: 233–234, 1990

    Google Scholar 

  • Hayes DF, Van Zyl JA, Hacking A, Goedhals L, Bezwoda WR, Mailliard JA, Jones SE, Vogel CL, Berris RF, Shemano I, Schoenfelder J: Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer. J Clin Oncol 13: 2556–2566, 1995

    Google Scholar 

  • Hietanen T, Hakala T, Baltina D, Johansson R, Numminen S, Helle L, Valavaara R, Thölix E: Open phase II study of high-dose toremifene as first-line therapy for advanced breast cancer. Oncology 11(Suppl 4): 37–40, 1997

    Google Scholar 

  • Holli K, Valavaara R, Blanco G, Kataja V, Hietanen P, Flander M, Pukkala E, Joensuu H for the Finnish Breast Cancer Group: Safety and efficacy results of a randomized trial comparing adjuvant toremifene and tamoxifen in postmenopausal patients with node-positive breast cancer. J Clin Oncol 18: 3487–3494, 2000

    Google Scholar 

  • Homesley HD, Shemano I, Gams R, Harry DS, Hickox PG, Rebar RW, Bump RC, Mullin TJ, Colston Wentz A, O'Toole RV, Lovelace JV, Lyden C: Antiestrogenic potency of toremifene and tamoxifen in postmenopausal women. Am J Clin Oncol 16: 117–122, 1993

    Google Scholar 

  • Joensuu H, Holli K, Oksanen H, Valavaara R: Serum lipid levels during and after adjuvant toremifene or tamoxifen therapy for breast cancer. Breast Cancer Res Treat 63: 225–234, 2000

    Google Scholar 

  • Jordan VC: Tamoxifen: toxicities and drug resistance during the treatment and prevention of breast cancer. Annu Rev Pharmacol Toxicol 35: 195–211, 1995

    Google Scholar 

  • Kangas L, Kallio S, Blanco G, Grönroos M, Kallio S, Karjalainen A, Perilä M, Södervall M, Toivola R: A new triphenylethylene compound, FC-1157a. II. Antitumor effects. Cancer Chemother Pharmacol 17: 109–114, 1986

    Google Scholar 

  • Kangas L: Agonistic and antagonistic effects of antiestrogens in different target organs. Acta Oncol 31: 143–146, 1992

    Google Scholar 

  • Kendall ME, Rose DP: The effects of diethylstilbesterol, tamoxifen, and toremifene on estrogen-inducible hepatic proteins and estrogen receptor proteins in female rats. Toxicol Appl Pharmacol 114: 127–131, 1992

    Google Scholar 

  • van Leeuwen FE, Benraadt J, Coebergh JWW, Kiemeney LALM, Gimbrère CHF, Otter R, Schouten LJ, Damhuis RAM, Bontenbal M, Diepenhorst FW, van den Belt-Dusebout AW, van Tintere H: Risk of endometrial cancer after tamoxifen treatment of breast cancer. Lancet 343: 448–452, 1994

    Google Scholar 

  • Marttunen MB, Hietanen P, Tiitinen A, Ylikorkala O: Comparison of effects of tamoxifen and toremifene on bone mineral density in postmenopausal breast cancer patients. J Clin Endocrinol Metab 83: 1158–1162, 1998

    Google Scholar 

  • Modig H, Borgström S, Nilsson I, Westman G: Phase II clinical study of toremifene in patients with metastatic breast cancer. Preliminary communication. J Steroid Biochem 36: 235–236, 1990

    Google Scholar 

  • Mouridsen H, Palshof T, Patterson J, Battersby L: Tamoxifen in advanced breast cancer. Cancer Treat Rev 5: 131–141, 1978

    Google Scholar 

  • Mäenpää J, Ellmén J, Pasanen T, Kaukonen M: Correspondence: effect of the antiestrogens tamoxifene, Toremifene, and ICI 182,780 on endometrial cancer growth. J Natl Cancer Inst 91: 972, 1999

    Google Scholar 

  • Osborne CK: Receptors. In: Harris J, Hellman S, Henderson I et al (eds) Breast Diseases. JB Lippincott, Philadelphia, 1991, pp 301–325

    Google Scholar 

  • Powles T, Eeles R, Ashley S, Easton D, Chang J, Dowsett M, Tidy A, Viggers J, Davey J: Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital: tamoxifen randomized chemoprevention trial. Lancet 352: 98–101, 1998

    Google Scholar 

  • Pukkala E, Maijanen S, Kyyrönen P, Sankila R, Holli K: Tamoxifen and toremifene treatment of breast cancer and risk of subsequent endometrial cancer-a population-based case-control study. Manuscript, 2001

  • Pyrhönen S, Valavaara R, Heikkinen M, Rissanen P, Blanco G, Nordman E, Holsti RL, Hajba A: Treatment of advanced breast cancer with 20mg toremifene, a phase II study. Preliminary communication. J Steroid Biochem 36: 227–228, 1990

    Google Scholar 

  • Pyrhönen S, Valavaara R, Modig H, Pawlicki M, Pienkowski T, Gundersen S, Bauer J, Westman G, Lundgren S, Blanco G, Mella O, Nilsson I, Hietanen T, Hindy I, Vuorinen J, Hajba A: Comparison of toremifene and tamoxifen in postmenopausal patients with advanced breast cancer: a randomised double blind, the 'Nordic' phase III study. Br J Cancer 76: 270–277, 1997

    Google Scholar 

  • Pyrhönen S, Ellmén J, Vuorinen J, Gershanovich M, Tominaga T, Kaufmann M, Hayes DF: Meta-analysis of trials comparing toremifene with tamoxifen and factors predicting outcome of antiestrogen therapy in postmenopausal women with breast cancer. Breast Cancer Res Treat 56: 133–143, 1999

    Google Scholar 

  • Rosner WA: A simplified method for the quantitative determination of testosterone-estradiol-binding globulin activity in human plasma. J Clin Endocrinol Metab 34: 983–988, 1971

    Google Scholar 

  • Rutqvist LE, Johansson H, Signomklao T, Johansson U, Fornander T, Wilking N: Adjuvant tamoxifen therapy for early stage breast cancert and second primary malignancies. J Natl Cancer Inst 87: 645–651, 1995

    Google Scholar 

  • Saarto T, Blomqvist C, Ehnholm C, Taskinen M-R, Elomaa I: Antiatherogenic effects of adjuvant antiestrogens: a randomized trial comparing the effects of tamoxifen and toremifene on plasma lipid levels in postmenopausal women with nodepositive breast cancer. J Clin Oncol 14: 429–433, 1996

    Google Scholar 

  • Saarto T, Blomqvist C, Välimäki M, Mäkelä P, Sarna S, Elomaa I: Clodronate improves bone mineral density in postmenopausal breast cancer patients treated with antioestrogens. Br J cancer 75: 602–605, 1997

    Google Scholar 

  • di Salle E, Zaccheo T, Ornati G: Antiestrogenic and antitumor properties of the new triphenylethylene derivative toremifene in the rat. J Steroid Biochem 36: 203–206, 1990

    Google Scholar 

  • Számel I, Hindy I, Vincze B, Eckhardt S, Kangas L, Hajba A: Influence of toremifene on the endocrine regulation in breast cancer patients. Eur J Cancer 30A: 154–158, 1994

    Google Scholar 

  • Valavaara R, Pyrhönen S, Heikkinen M, Rissanen P, Blanco G, Thölix E, Nordman E, Taskinen P, Holsti L, Hajba A: Estrogenic effects of toremifene and tamoxifen 111 Toremifene, a new antiestrogenic Compound, for treatment of advanced breast cancer. Phase II study. Eur J Cancer Clin Oncol 24: 785–790, 1988

    Google Scholar 

  • Veronesi U, Maisonneuve P, Costa A, Sacchini V, Maltoni C, Robertson C, Rotmensz N, Boyle P on behalf of the Italian Tamoxifen Prevention Study: Prevention of breast cancer with tamoxifen. Preliminary findings from the Italian randomized trial among hysterectomized women. Lancet 352: 93–97, 1998

    Google Scholar 

  • Wolf DM, Jordan VC: Characterization of tamoxifen stimulated MCF-7 tumor variants grown in athymic mice. Breast Cancer Res Treat 31: 117–127, 1994

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ellmén, J., Hakulinen, P., Partanen, A. et al. Estrogenic Effects of Toremifene and Tamoxifen in Postmenopausal Breast Cancer Patients. Breast Cancer Res Treat 82, 103–111 (2003). https://doi.org/10.1023/B:BREA.0000003957.54851.11

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:BREA.0000003957.54851.11

Navigation