Drug Safety

, Volume 21, Issue 4, pp 297–309 | Cite as

Risks and Benefits of Aromatase Inhibitors in Postmenopausal Breast Cancer

  • Laura Boehnke Michaud
  • Aman U. Buzdar
Review Article


Aromatase inhibitors were first reported in the early 1970s and have been used to treat breast cancer since that time. Until recently, essentially the only agent available in this class was aminoglutethimide, a nonspecific inhibitor with multiple adverse effects and drug interactions. Selective and potent aromatase inhibitors are now available (formestane, exemestane, fadrozole, anastrozole and letrozole), and we review the risks and benefits of these agents in order to assist clinicians in making treatment decisions.

Formestane is an injectable steroidal aromatase inhibitor with significant activity against metastatic breast cancer. It has been shown to have similar efficacy and superior tolerability compared with megestrol, and is similar to tamoxifen in the metastatic setting. Exemestane is an oral steroidal aromatase inhibitor. It has been shown to be effective third-line therapy after tamoxifen and megestrol in post-menopausal patients with metastatic breast cancer. All the nonsteroidal (imidazole/triazole) aromatase inhibitors are orally available. Fadrozole has similar activity to megestrol and tamoxifen in the setting of metastasis, but has been shown in phase II trials to inhibit cortisol and aldosterone production. Anastrozole and letrozole have similar toxicity profiles. Compared with megestrol, anastrozole improves overall survival and has superior tolerability. Letrozole is superior to megestrol and aminoglutethimide in terms of overall survival and time to progression, and is also better tolerated.

Although there is a strong rationale for using these agents in the treatment of breast cancer, the information presently available is insufficient to recommend any one agent over another. Direct comparative studies are lacking, and comparing agents across studies is limited by many biases and may not be valid. Formestane is only available as an injection and exemestane is not commercially available in many countries, making these agents more difficult to recommend over the other 3 agents. Fadrozole is less potent and less selective in inhibiting aromatase than letrozole. The efficacies of fadrozole, megestrol and tamoxifen appear to be similar; however, comparative data show no advantage of fadrozole over letrozole. Anastrozole and letrozole are generally considered to be similar agents.

The clinical future of the selective aromatase inhibitors is promising, and these agents may change the way postmenopausal breast cancer is treated at all stages of the disease.


Breast Cancer Tamoxifen Adis International Limited Metastatic Breast Cancer Aromatase Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Brodie A, Lu Q, Liu Y, et al. Preclinical studies using the intratumoral aromatase model for postmenopausal breast cancer. Oncology 1998; 12(3): 36–40PubMedGoogle Scholar
  2. 2.
    Santen RJ, Worgul TJ, Lipton A, et al. Aminoglutethimide as treatment of postmenopausal women with advanced breast carcinoma. Ann Intern Med 1982; 96: 94–101PubMedGoogle Scholar
  3. 3.
    Hansten PD, Horn JR, editors. Drug interactions and updates. Vancouver, Washington: Applied Therapeutics, Inc, 1997Google Scholar
  4. 4.
    Brodie A, Hendrickson J, Tsai-Morris C. Inactivation of aromatase in vitro by 4-OHA and 4-acetoxyandrostenedione and sustained effects in vivo. Steroids 1981; 38: 696–702CrossRefGoogle Scholar
  5. 5.
    Dowsett M, Coombes RC. Second generation aromatase inhibitor — 4-hydroxyandrostenedione. Breast Cancer Res Treat 1994; 30: 81–7PubMedCrossRefGoogle Scholar
  6. 6.
    Di Salle E, Ornati G, Giudici D, et al. Exemestane (FCE 24304), a new steroidal aromatase inhibitor. J Steroid Biochem Mol Biol 1992; 43(1–3): 137–43PubMedCrossRefGoogle Scholar
  7. 7.
    Brodie A, Njar V. Aromatase inhibitors and breast cancer. Semin Oncol 1996; 23: 10–20PubMedGoogle Scholar
  8. 8.
    Demers LM. Effects of fadrozole (CGS16949A) and letrozole (CGS20267) on the inhibition of aromatase activity in breast cancer patients. Breast Cancer Res Treat 1994; 30(1): 95–102PubMedCrossRefGoogle Scholar
  9. 9.
    Arimidex® (anastrozole) product information. Wilmington (DE): Zeneca Pharmaceuticals, Jan 1997Google Scholar
  10. 10.
    Femara® (letrozole) product information. East Hanover (NJ): Novartis Pharmaceutical Corporation, Jul 1997Google Scholar
  11. 11.
    Dowsett M, Pfister CU, Johnston SRD, et al. Pharmacokinetic interaction between letrozole and tamoxifen in postmenopausal patients with advanced breast cancer [abstract]. Breast 1997; 6: 245Google Scholar
  12. 12.
    Dowsett M, Welch H, Blackman GM, et al. A randomised, double blind, parallel-group trial to evaluate the effect of ‘Arimidex’ (anastrozole) on the pharmacokinetics of tamoxifen in postmenopausal breast cancer patients [abstract no. 103]. Breast Cancer Res Treat 1997; 46: 28Google Scholar
  13. 13.
    Tominaga T, Yoshida Y, Shimozuma K, et al. Effect of CGS 16949 A plus tamoxifen on induced mammary tumours in rats. Eur J Cancer 1990; 26: 600–3PubMedCrossRefGoogle Scholar
  14. 14.
    Zaccheo T, Giudici D, Di Salle E. Inhibitory effect of combined treatment with the aromatase inhibitor exemestane and tamoxifen on DMBA-induced mammary tumors in rats. J Steroid Biochem Mol Biol 1993; 44: 677–80PubMedCrossRefGoogle Scholar
  15. 15.
    Dowsett M. Aromatase inhibition: basic concepts, and the pharmacodynamics of formestane. Ann Oncol 1994; 5 Suppl. 7: S3–S5PubMedGoogle Scholar
  16. 16.
    Plourde PV, Dyroff M, Dukes M. Arimidex®: a potent and selective fourth-generation aromatase inhibitor. Breast Cancer Res Treat 1994; 30: 103–11PubMedCrossRefGoogle Scholar
  17. 17.
    Sioufi A, Gauducheau N, Pineau V, et al. Absolute bioavailability of letrozole in healthy postmenopausal women. Biopharm Drug Dispos 1997; 18(9): 779–89PubMedCrossRefGoogle Scholar
  18. 18.
    Fisher B, Dignam J, Wolmark N, et al. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 1997 Nov 19; 89(22): 1673–82PubMedCrossRefGoogle Scholar
  19. 19.
    Perez Carrion R, Alberola Candel V, Calabresi F, et al. Comparison of the selective aromatase inhibitor formestane with tamoxifen as first-line hormonal therapy in postmenopausal women with advanced breast cancer. Ann Oncol 1994; 5 Suppl. 7: S19–24PubMedGoogle Scholar
  20. 20.
    Zilembo N, Noberasco C, Bajetta E, et al. Endocrinological and clinical evaluation of exemestane, a new steroidal aromatase inhibitor. Br J Cancer 1995; 72: 1007–12PubMedCrossRefGoogle Scholar
  21. 21.
    Evans T, Di Salle E, Ornati G, et al. Phase I and endocrine study of exemestane (FCE 24304), a new aromatase inhibitor, in postmenopausal women. Cancer Res 1992; 52: 5933–9PubMedGoogle Scholar
  22. 22.
    Buzdar AU, Smith R, Vogel C, et al. Fadrozole HCl (CGS-16949A) versus megestrol acetate treatment of postmenopausal patients with metastatic breast carcinoma: results of two randomized double blind controlled multi-institutional trials. Cancer 1996 Jun 15; 77(12): 2503–13PubMedCrossRefGoogle Scholar
  23. 23.
    Buzdar A, Jonat W, Howell A, et al. 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 1996 Jul; 14(7): 2000–11PubMedGoogle Scholar
  24. 24.
    Dombernowsky P, Smith I, Falkson G, et al. Letrozole, a new oral aromatase inhibitor for advanced breast cancer: doubleblind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 1998; 16(2): 453–61PubMedGoogle Scholar
  25. 25.
    Goss PE, Powles TJ, Dowsett M, et al. Treatment of advanced postmenopausal breast cancer with an aromatase inhibitor, 4-hydroxyandrostenedione: phase II report. Cancer Res 1986; 46: 4823–6PubMedGoogle Scholar
  26. 26.
    Stein RC, Dowsett M, Hedley A, et al. Treatment of advanced breast cancer in postmenopausal women with 4-hydroxyandrostenedione. Cancer Chemother Pharmacol 1990; 26(1): 75–8PubMedCrossRefGoogle Scholar
  27. 27.
    Rose C, Freue M, Kjaer M, et al. An open, comparative randomized trial comparing formestane vs oral megestrol acetate as second-line therapy in postmenopausal advanced breast cancer patients [abstract no. PP-8-4]. Eur J Cancer 1996; 32A Suppl. 2: 49CrossRefGoogle Scholar
  28. 28.
    Dowsett M, Cunningham D, Stein R, et al. Dose-related endocrine effects and pharmacokinetics of oral and intramuscular 4-hydroxyandrostenedione in postmenopausal breast cancer patients. Cancer Res 1989; 49: 1306–12PubMedGoogle Scholar
  29. 29.
    Kvinnsland S, Anker G, Dirix LY, et al. Antitumor efficacy of exemestane, a novel, irreversible, oral, aromatase inhibitor in postmenopausal patients with metastatic breast cancer (MBC), failing tamoxifen (TAM) [abstract no. 217]. Breast Cancer Res Treat 1997 Dec; 46: 55Google Scholar
  30. 30.
    Thurlimann B, Beretta K, Bacchi M, et al. First-line fadrozole HCl (CGS 16949A) versus tamoxifen in postmenopausal women with advanced breast cancer: prospective randomised trial of the Swiss Group for Clinical Cancer Research SAKK 20/88. Ann Oncol 1996: 7(5): 471–9PubMedCrossRefGoogle Scholar
  31. 31.
    Falkson CI, Falkson HC. A randomised study of CGS 16949A (fadrozole) versus tamoxifen in previously untreated postmenopausal patients with metastatic breast cancer. Ann Oncol 1996 Jul; 7(5): 433–7CrossRefGoogle Scholar
  32. 32.
    Dowsett M, Vorobiof D, Kleeberg U, et al. A randomized comparison assessing oestrogen suppression with Arimidex® (anastrozole) and formestane in postmenopausal advanced breast cancer patients [abstract]. Eur J Cancer 1996; 32A Suppl. 2: 49–50CrossRefGoogle Scholar
  33. 33.
    Marty M, Gershanovich M, Campos B, et al. Letrozole, a new potent, selective aromatase inhibitor (AI) superior to aminoglutethimide (AG) in postmenopausal women with advanced breast cancer (ABC) previously treated with antiestrogens [abstract no. 544]. Proc Am Soc Clin Oncol 1997; 16: 156aGoogle Scholar
  34. 34.
    Fisher B, Dignam J, Bryant J, et al. 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 1996; 88(21): 1529–42PubMedCrossRefGoogle Scholar
  35. 35.
    Lonning PE. Aromatase inhibition for breast cancer treatment. Acta Oncol 1996; 35 Suppl. 5: 38–43PubMedCrossRefGoogle Scholar
  36. 36.
    Klein KO, Demers LM, Santner SJ, et al. Use of ultrasensitive recombinant cell bioassay to measure estrogen levels in women with breast cancer receiving the aromatase inhibitor, letrozole. J Clin Endocrinol Metab 1995; 80: 2658–60PubMedCrossRefGoogle Scholar
  37. 37.
    Jacobs SL, Lonning PE, Haynes B, et al. Measurement of aromatization by a urine technique suitable for the evaluation of inhibitors in vivo. J Enzyme Inhib 1991; 4: 315–25PubMedCrossRefGoogle Scholar
  38. 38.
    Jones AL, MacNeill F, Jacobs S, et al. The influence of intramuscular 4-hydroxyandrostenedione on peripheral aromatization in breast cancer patients. Eur J Cancer 1992; 28: 1712–6CrossRefGoogle Scholar
  39. 39.
    Dowsett M, Jones A, Johnston SRD, et al. In vivo measurement of aromatase inhibition by letrozole (CGS 20267) in postmenopausal patients with breast cancer. Clin Cancer Res 1995; 1: 1511–5PubMedGoogle Scholar
  40. 40.
    Geisler J, King N, Dowsett M, et al. Influence of anastrozole (Arimidex), a selective nonsteroidal aromatase inhibitor, on in vivo aromatase and plasma oestrogen levels in post-menopausal women with breast cancer. Br J Cancer 1996; 74: 1286–91PubMedCrossRefGoogle Scholar
  41. 41.
    Noberasco C, Bajetta E, Zilembo N, et al. Activity of formestane in de novo tamoxifen-resistant patients with metastatic breast cancer. Oncology 1995; 52: 454–7PubMedCrossRefGoogle Scholar
  42. 42.
    Murray R, Pitt P. Aromatase inhibition with 4-OH-androstenedione after prior aromatase inhibition with aminoglutethimide in women with advanced breast cancer. Breast Cancer Res Treat 1995; 35: 249–53PubMedCrossRefGoogle Scholar
  43. 43.
    Jones S, Vogel C, Fehrenbacher L, et al. Antitumor efficacy of exemestane (Nikidess®, EXE) as third-line hormonal therapy in the treatment of postmenopausal women with metastatic breast cancer refractory to tamoxifen and Megace® [abstract no. 573]. Proc Am Soc Clin Oncol 1998; 17: 150aGoogle Scholar
  44. 44.
    Howell A, Buzdar A, Jonat W, et al. Significantly improved survival with ‘Arimidex’ (anastrozole) (AN) compared with megestrol acetate (MA) in postmenopausal women with advanced breast cancer (ABC): updated results of two randomised trials [abstract no. 18]. Breast Cancer Res Treat 1997; 46: 27Google Scholar
  45. 45.
    Smith IE, Chaudri HA, Lassus M, et al. Comparison of overall survival (OS) in two trials comparing letrozole 2.5mg (Femara) with megestrol acetate (MA) or aminoglutethimide (AG) in patients with advanced breast cancer (ABC) [abstract no. 19]. Breast Cancer Res Treat 1997; 46: 27Google Scholar
  46. 46.
    Michaud LB, Knoche AJ, Abbott B, et al. Efficacy of anastrozole (Arimidex®) in a consecutive series of advanced breast cancer patients: M.D. Anderson Cancer Center (MDACC) experience [abstract no. 641]. Proc Am Soc Clin Oncol 1997; 16: 183aGoogle Scholar
  47. 47.
    Manni A, Arafah BU, Pearson OH. Estrogen and progesterone receptors in the prediction of response of breast cancer to endocrine therapy. Cancer 1980; 46(12 Suppl.): 2838PubMedCrossRefGoogle Scholar
  48. 48.
    Bolufer P, Ricart E, Lluch A, et al. Aromatase activity and oestradiol in human breast cancer: its relationship to oestradiol and epidermal growth factor. J Clin Oncol 1992; 10: 438–46PubMedGoogle Scholar
  49. 49.
    Gershanovich M, Chaudri HA, Hornberger U, et al. Comparison of letrozole 2.5mg (Femara®) with megestrol acetate (MA) and with aminoglutethimide (AG) in patients with visceral disease (abstract no. 212). Breast Cancer Res Treat 1997; 46: 53Google Scholar
  50. 50.
    Howell A, Mackintosh J, Jones M, et al. The definition of the ‘no change’ category in patients treated with endocrine therapy and chemotherapy for advanced carcinoma of the breast. Eur J Cancer Clin Oncol 1988; 24: 1567–72PubMedCrossRefGoogle Scholar
  51. 51.
    Robertson JFR, Williams MR, Todd J, et al. Factors predicting the response of patients with advanced breast cancer to endocrine (Megace) therapy. Eur J Cancer Clin Oncol 1989; 23: 469–75CrossRefGoogle Scholar
  52. 52.
    Kelloff GJ, Lubet RA, Lieberman R, et al. Aromatase inhibitors as potential cancer chemopreventives. Cancer Epidemiol Biomarkers Prev 1998; 7: 65–78PubMedGoogle Scholar

Copyright information

© Adis International Limited 1999

Authors and Affiliations

  1. 1.Division of PharmacyThe University of Texas M.D. Anderson Cancer CenterHoustonUSA
  2. 2.Department of Breast Medical OncologyThe University of Texas M.D. Anderson Cancer CenterHoustonUSA

Personalised recommendations