Aromatase Inhibition in Obese Women: How Much Is Enough?

Aromatase inhibitors, which prevent peripheral conversion of adrenal androgens into estrogen, are routinely used in the adjuvant endocrine therapy of postmenopausal women. Amnioglutethimide was the first aromatase inhibitor to be developed, but its use was limited by its concomitant suppression of cortisol and aldosterone production. In the mid 1990s, aromatase inhibitors that had much greater specificity and produced no clinically relevant suppression of cortisol or aldosterone were developed. These third-generation aromatase inhibitors include the steroidal drug exemestane, which binds irreversibly to the aromatase enzyme, and the nonsteroidal drugs letrozole and anastrozole, which form covalent, reversible bonds. The aromatase inhibitors initially gained US Food and Drug Administration approval based on their efficacy as second-line therapy for metastatic breast cancer. Several randomized trials demonstrated that the third-generation aromatase inhibitors were equivalent or superior to megestrol acetate in this setting. The drugs were subsequently shown to have superior efficacy compared to tamoxifen, initially in the first-line setting in the treatment of metastatic breast cancer and later in the adjuvant treatment of postmenopausal women with hormone-receptor positive, early-stage breast cancer. Current guidelines thus recommend aromatase inhibitors as the preferred agents in metastatic breast cancer and also recommend that all postmenopausal women with hormone-receptor–positive breast cancer receive an aromatase inhibitor either as primary hormonal therapy or as part of a cross-over strategy in combination with tamoxifen. The third-generation aromatase inhibitors are potent inhibitors of aromatase and have been shown to decrease estrogen levels to below the lower level of detection of most clinical assays. Studies have demonstrated that letrozole induces more complete suppression of estradiol than anastrozole in patients with breast cancer, but the clinical relevance of this finding is unclear. A randomized phase II trial of neoadjvaunt letrozole, anastrozole, and exemestane in 377 postmenopausal women with early breast cancer demonstrated similar rates of clinical response in patients treated with anastrozole and letrozole (69.1% versus 74.8%). Surgical outcomes, suppression of Ki-67 and preoperative endocrine prognostic index (PEPI) scores were similar in the two groups, with patients treated with anastrozole having a numerically higher rate of breast-conserving surgery (48.7% versus 40.0%) and PEPI scores of 0 (17.3% versus 15.9%) and patients treated with letrozole having a slightly larger geometric mean decrease in Ki-67 ( 87.1% versus 78%). In the article that accompanies this editorial, Folkerd et al evaluate the relationship between suppression of estrogen levels and body mass index (BMI) in 54 postmenopausal women with early-stage breast cancer treated with anastrozole and letrozole in the ALIQUOT (Anastrozole v Letrozole, an Investigation of Quality of Life and Tolerability) study, in which patients were treated with 3 months of anastrozole followed by 3 months of letrozole, or the opposite sequence. Highly sensitive radioimmunoassays were used to measure plasma estradiol and estrone sulfate levels at baseline and after the 3-month exposure to each aromatase inhibitor. Folkerd et al demonstrate that baseline levels of estradiol and estrone sulfate were significantly correlated with BMI (r 0.57, P .001 and r 0.38, P .006, respectively). For example, the mean estradiol level in women with a BMI more than 35 kg/m was 55 ( 4.0) pmol/L versus 20 ( 3.2) pmol/L in individuals with a BMI less than 25 kg/m. Consistent with prior reports, letrozole induced significantly greater suppression of both estradiol and estrone sulfate as compared with anastrozole, and this finding was seen in all weight groups. Importantly, obese women were found to have less complete suppression of both estrogens as compared with leaner women. This effect was seen during treatment with each aromatase inhibitor. The relationship between BMI and estrogen levels was only statistically significant during treatment with letrozole (P .035). Estrogen levels on anastrozole were higher and standard deviations were greater, leading to limited statistical power in this group of patients. A formal analysis for the interaction of BMI, estrogen level, and specific aromatase inhibitor was not performed. Although the findings are of great interest, the clinical relevance remains unclear. Levels of estradiol and estrone sulfate were higher in obese women during treatment with aromatase inhibitors compared with leaner women treated with the drugs, but the change in estrogen levels achieved by the drugs was greater in obese patients and the absolute levels of both estradiol and estrone sulfate during aromatase inhibitor therapy were low. For example, for women with a BMI more than 35 kg/m, mean estradiol levels decreased from 55 pmol/L to 4.2 pmol/L with anastrozole and 2.4 pmol/L with letrozole compared to a decrease from a mean baseline level of 20 pmol/L to 2.8 and 1.4 pmol/L, respectively, for women with a BMI less than 25 kg/m. Data from two recent observational reports may provide some evidence that incomplete suppression of estrogen levels in obese individuals might have a clinical impact. In the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, women who had a BMI JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 24 AUGUST 2