Abstract
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.
Similar content being viewed by others
References
Brodie A, Lu Q, Liu Y, et al. Preclinical studies using the intratumoral aromatase model for postmenopausal breast cancer. Oncology 1998; 12(3): 36–40
Santen RJ, Worgul TJ, Lipton A, et al. Aminoglutethimide as treatment of postmenopausal women with advanced breast carcinoma. Ann Intern Med 1982; 96: 94–101
Hansten PD, Horn JR, editors. Drug interactions and updates. Vancouver, Washington: Applied Therapeutics, Inc, 1997
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: 696–702
Dowsett M, Coombes RC. Second generation aromatase inhibitor — 4-hydroxyandrostenedione. Breast Cancer Res Treat 1994; 30: 81–7
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): 137–43
Brodie A, Njar V. Aromatase inhibitors and breast cancer. Semin Oncol 1996; 23: 10–20
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): 95–102
Arimidex® (anastrozole) product information. Wilmington (DE): Zeneca Pharmaceuticals, Jan 1997
Femara® (letrozole) product information. East Hanover (NJ): Novartis Pharmaceutical Corporation, Jul 1997
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: 245
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: 28
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: 600–3
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: 677–80
Dowsett M. Aromatase inhibition: basic concepts, and the pharmacodynamics of formestane. Ann Oncol 1994; 5 Suppl. 7: S3–S5
Plourde PV, Dyroff M, Dukes M. Arimidex®: a potent and selective fourth-generation aromatase inhibitor. Breast Cancer Res Treat 1994; 30: 103–11
Sioufi A, Gauducheau N, Pineau V, et al. Absolute bioavailability of letrozole in healthy postmenopausal women. Biopharm Drug Dispos 1997; 18(9): 779–89
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): 1673–82
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: S19–24
Zilembo N, Noberasco C, Bajetta E, et al. Endocrinological and clinical evaluation of exemestane, a new steroidal aromatase inhibitor. Br J Cancer 1995; 72: 1007–12
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: 5933–9
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): 2503–13
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): 2000–11
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): 453–61
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: 4823–6
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): 75–8
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: 49
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: 1306–12
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: 55
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): 471–9
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): 433–7
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: 49–50
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: 156a
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): 1529–42
Lonning PE. Aromatase inhibition for breast cancer treatment. Acta Oncol 1996; 35 Suppl. 5: 38–43
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: 2658–60
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: 315–25
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: 1712–6
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: 1511–5
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: 1286–91
Noberasco C, Bajetta E, Zilembo N, et al. Activity of formestane in de novo tamoxifen-resistant patients with metastatic breast cancer. Oncology 1995; 52: 454–7
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: 249–53
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: 150a
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: 27
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: 27
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: 183a
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.): 2838
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: 438–46
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: 53
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: 1567–72
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: 469–75
Kelloff GJ, Lubet RA, Lieberman R, et al. Aromatase inhibitors as potential cancer chemopreventives. Cancer Epidemiol Biomarkers Prev 1998; 7: 65–78
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Michaud, L.B., Buzdar, A.U. Risks and Benefits of Aromatase Inhibitors in Postmenopausal Breast Cancer. Drug-Safety 21, 297–309 (1999). https://doi.org/10.2165/00002018-199921040-00005
Published:
Issue Date:
DOI: https://doi.org/10.2165/00002018-199921040-00005