Purpose: To evaluate the influence of the third-generation aromatase inhibitor letrozole (Femara) on breast cancer tissue levels of estrone (E 1 ), estradiol (E 2 ), and estrone sulfate (E 1 S) in postmenopausal women undergoing primary treatment for locally advanced estrogen receptor/progesterone receptor^positive breast cancers. Experimental Design: Breast cancer tissue samples were collected before and following 4 months of neoadjuvant therapy with letrozole (2.5 mg o.d.), and tissue estrogen levels measured using a highly sensitive RIA after high-pressure liquid chromatography purification. Results: Letrozole suppressed pretreatment tumor levels of E 2 , E 1 , and E 1 S by 97.6%, 90.7%, and 90.1%, respectively.These data reveal that letrozole suppresses tissue estrogen levels significantly below what has previously been recorded with anastrozole (89.0%, 83.4%, and 72.9% suppression, respectively) using the same methods. To confirm the differential effect of letrozole and anastrozole on each plasma estrogen fraction, we re-analyzed plasma samples obtained from a previous intrapatient cross-over study comparing letrozole and anastrozole using an improved RIA (detection limits of 0.67, 1.14, and 0.55 pmol/L for E 2 , E 1 , and E 1 S, respectively). Letrozole consistently suppressed each plasma estrogen fraction below the levels recorded for anastrozole: E 2 (average suppression by 95.2% versus 92.8%; P = 0.018), E 1 (98.8% suppression versus 96.3%; P = 0.003), and E 1 S (98.9% suppression versus 95.3%; P = 0.003). Conclusion: Our data reveals that letrozole (2.5 mg o.d.) is more effective compared with anastrozole (1.0 mg o.d.) with respect to tissue as well as plasma estrogen suppression in patients with postmenopausal breast cancer.Contemporary clinical studies have shown that three thirdgeneration aromatase inhibitors (anastrozole, letrozole, and exemestane) improve time to progression in metastatic disease (1 -3) and relapse-free as well as overall survival compared with tamoxifen for adjuvant therapy of patients with postmenopausal breast cancer (4 -6). These results are most likely related to their improved potency. The third-generation compounds inhibit total body aromatization by z98% in vivo (7 -10). In contrast, compounds belonging to the first and second generation of inhibitors cause 80% to 90% (11 -14) aromatase inhibition and do not improve clinical outcome compared with tamoxifen or megestrol acetate (see ref. 15).An ongoing controversy relates to potential differences between the three third-generation aromatase inhibitors with respect to mechanism of action (16) and resistance (17), as well as clinical efficacy and safety. Thus, studies in metastatic breast cancer have revealed a lack of complete cross-resistance between nonsteroidal aromatase inhibitors and the steroidal aromatase inactivators (18 -22). However, except for a single study comparing anastrozole and letrozole as second-line therapy in metastatic disease (23), we lack results from direct head-to-head comparisons.Alth...
