Commentary (Buzdar): Nonsteroidal and Steroidal Aromatase Inhibitors in Breast Cancer

Drs. Hamilton and Volm provide an excellent and concise review of the use of aromatase inhibitors in the treatment of breast cancer. There has been significant progress in hormonal therapy for this disease in the past decade. In this review, the role of aromatase (a P450 enzyme) in the production of estrogen and aromatase inhibitors in suppressing the production of estrogen in postmenopausal women is well described.

The breast tissue and breast stroma have significant aromatase activity, but the correlation between the aromatase activity in tumor or in stromal tissue and the response to aromatase inhibitors have not been established. In clinical practice, the presence of estrogen and progesterone receptors still provides the best positive and negative correlations regarding responses to all endocrine therapies, including aromatase inhibitors. Patients whose tumors have both estrogen and progesterone receptors have a higher probability of response, whereas those whose tumors lack both receptors have a very low probability of response to any endocrine therapy and are better managed by other treatment modalities.

Drs. Hamilton and Volm briefly discuss data from a small study[1] that evaluated the inhibition of total-body aromatase activity and suppression of estrogen production by two aromatase inhibitors. A washout period between crossover phases was not part of this study design. In light of these laboratory data, the authors’ implications that one aromatase inhibitor may be superior are not justified: The estrone and estradiol levels were similarly suppressed by the two agents, and the only significant change was in estrone sulfate. Most other differences in estrogen suppression between the two drugs were close to the current assay’s detection threshhold. Therefore, any implications regarding a therapeutic benefit remain to be confirmed.

Two large databases (ie, for anastrozole [Arimidex] and letrozole [Femara] studies) demonstrate that both of these newer aromatase inhibitors are superior to tamoxifen (Nolvadex) as front-line therapy in estrogen-receptor-positive patients. The data regarding exemestane (Aromasin) are too preliminary to assess this agent’s antitumor activity compared with tamoxifen.

Comparative Data

All three aromatase inhibitors available for clinical use have substantial antitumor activity, but currently there are no prospective randomized studies evaluating their antitumor activity in similar cohorts of the patient population. Appropriate clinical comparative studies of these aromatase inhibitors are needed to compare their therapeutic efficacy in a prospective manner.

The indirect comparative data (from the available studies) of these aromatase inhibitors in postmenopausal women are summarized in Table 1. These analyses do not demonstrate major differences in either second- or first-line settings. The differences between the letrozole and tamoxifen arms in the letrozole front-line study were considerably larger than the differences between anastrozole and tamoxifen in the anastrozole front-line study. This may derive from the fact that, in the letrozole study, patients who had prior tamoxifen therapy (> 18% of the total population) had a very low response rate (8%) to tamoxifen re-treatment, whereas in the anastrozole study, no significant differences were observed in response rates for patients who had prior tamoxifen therapy.

All three drugs have been evaluated at different doses and, at the present time, there are no convincing data regarding dose-dependent responses with these drugs. Some letrozole studies have demonstrated that the 2.5-mg dose of the drug may have superior antitumor activity, compared with the 0.5-mg dose. Data from a subsequent, large prospective US study failed to confirm these findings.[2] The detailed results of this study are currently in the process of being published.[3]

Safety Profiles

The safety profiles of these agents are better than those of earlier drugs (ie, progestins, aminoglutethimide [Cytadren], and tamoxifen), but there are also subtle differences between these compounds. Anastrozole and letrozole are triazole compounds, and anastrozole administered at up to 10-fold the recommended dose does not cause any significant interference in the steroid synthesis pathways,[4] but letrozole at a dose of 2.5 mg does show significant blunting of adrenocorticotropic hormone response following 1 to 3 months of therapy.[5]

Anastrozole and letrozole intrinsically do not have any hormonal properties. On the other hand, exemestane is a steroidal compound with weak androgenic properties, especially at higher doses. The implications of these differences among the three drugs in the treatment of metastatic disease might be difficult to evaluate at the present time. Prolonged administration of these agents in the adjuvant setting, however, may reveal some of the differences in their safety profiles.

The safety and efficacy data of a number of ongoing adjuvant trials, as outlined in the article by Drs. Hamilton and Volm, would provide information regarding the differences, if any, among these drugs. Appropriate, direct comparative trials in front-line and/or adjuvant therapy would be the best way to demonstrate any differences in the safety and efficacy of these drugs.

References:

1. Dowsett M, Geisler J, Haynes BP, et al: Letrozole achieves more complete inhibition of whole body aromatisation than anastrozole. Eur J Cancer 36(suppl 5):S88, 2000.

2. Data presented at the FDA Oncologic Drugs Advisory Committee Meeting on Letrozole; December 13, 2000. Available at: www.fda.gov/ohrms/dockets/ac/00/backgrd/3671b1.htm. Accessed June 26, 2001.

3. Buzdar A, Douma N, Davidson N, et al: A phase III, multicenter, double blind, randomized study of letrozole (femara), an aromatase inhibitor, for advanced breast cancer versus megestrol acetate conducted in the United States, Canada, Denmark, Germany, Italy, Netherlands, and the United Kingdom. J Clin Oncol. In press.

4. Plourde PV, Dyroff M, Dowsett M, et al: Arimidex: A new oral, once-a-day aromatase inhibitor. J Steroid Biochem Mol Biol 53:175-179, 1995.

5. Bajetta E, Zilembo N, Dowsett M, et al: Double-blind, randomized, multicentre endocrine trial comparing two letrozole doses, in postmenopausal breast cancer patients. Eur J Cancer 35:208-213, 1999.