Aromatase Inhibitors: What May We Expect?


Synopsis: Formestane is an aromatase inhibitor that can be administered every two weeks by intramuscular injection and significantly lowers plasma estrogen levels in women with breast cancer at first relapse. About one-third of treated patients experience a tumor response.

Source: Bajetta E, et al. Ann Oncol 1997;8:649-654.

Aromatase is the enzyme that converts androgenic steroids to estrogens. It emerged as a potential target for drug development when it became more clear that aminoglutethimide, an agent with activity in patients with estrogen receptor-positive tumors who had progressed on tamoxifen, was actually working by inhibiting aromatase rather than by inhibiting adrenal steroidogenesis.1 Aminoglutethimide was toxic; thus, efforts were undertaken to develop a more specific inhibitor of aromatase with improved efficacy and better tolerability.

Formestrane is the first second-generation aromatase inhibitor to enter clinical trial. It is steroidal in structure (4-hydroxyandrostenedione) and acts as a false substrate for the enzyme. Bajetta and colleagues at the National Cancer Institute in Milan performed a randomized, multi-center study comparing administration of 250 mg or 500 mg formestrane intramuscularly every two weeks in 152 women experiencing their first recurrence of estrogen receptor positive breast cancer. This trial was felt to be necessary because of the variability of estrogen suppression noted at the 250 mg dose,2 the dose recommended for use on the basis of antitumor activity in clinical studies.3

Seventy-three patients received formestane at 250 mg every two weeks and 79 received 500 mg. After four weeks of therapy, plasma estrone, estradiol, and estrone sulphate levels were significantly suppressed in both groups and there were no significant differences between the groups. The overall response rates were not significantly different—30% for the 250 mg dose and 40% for the 500 mg dose. There were no apparent dose-related differences in toxicity noted.


Aromatase inhibitors attack hormone-dependent tumors in a different fashion than tamoxifen. This suggests that resistance to tamoxifen does not necessarily mean resistance to aromatase inhibitors. Thus, formestane has a role as a second-line hormonal manipulation in women with estrogen receptor-positive breast cancer. While some investigators have suggested that 250 mg every two weeks is not sufficient to inhibit the enzyme fully, data from this study suggest that it is sufficient.

However, formestane is not nearly as potent an aromatase inhibitor as some of the third-generation compounds that are currently being tested. Letrozole (2.5 mg/d) and anastrozole (1 mg/d), triazole (nonsteroidal) drugs that are orally bioavailable, can suppress estradiol and estrone levels below the limit of detection.4,5 Phase III trials, in general, have shown that the oral agents are much better tolerated than aminoglutethimide and have antitumor effects that are at least as good as aminoglutethimide and megestrol acetate, the drugs to which they have most commonly been compared.6 One study comparing anastrozole 1 mg/d to megestrol acetate has shown a significant survival advantage (P = 0.02) for the aromatase inhibitor.7 Even if they weren’t more effective, they would be preferable to aminoglutethimide and megestrol acetate because of their lower toxicity.

It seems logical to ask whether the third-generation aromatase inhibitors might be more effective than tamoxifen as front-line therapy. However, enthusiasm for the question is tempered by the other advantages of tamoxifen treatment over estrogen withdrawal including lowered cardiovascular mortality, improved bone strength, and more recently, the possibility of enhancing cognitive function. Is it possible that aromatase inhibitors could improve the efficacy of tamoxifen by reducing competition with endogenous estrogens?


1. Santen RJ, et al. J Clin Endocrinol Metab 1978;47: 1257-1265.

2. Dowsett M, et al. Cancer Res 1989;49:1306-1312.

3. Goss PE, et al. Cancer Res 1986;46:4823-4826.

4. Iveson TJ, et al. Cancer Res 1993;53:266-270.

5. Yates RA, et al. Br J Cancer 1996;73:543-548.

6. Buzdar A, et al. J Clin Oncol 1996;14:2000-2011.

7. Buzdar A, et al. Proc Am Soc Clin Oncol 1997;16:156a.