The Use of Early Adjuvant Aromatase Inhibitor Therapy: Contributions From the BIG 1-98 Letrozole Trial

Letrozole has proven efficacious in a variety of therapeutic scenarios, including that of extended adjuvant therapy following 5 years of tamoxifen treatment in postmenopausal women with estrogen-receptor–positive early breast cancer. The Breast International Group 1-98 trial (BIG 1-98) is the first to study the efficacy of upfront letrozole treatment and the first to evaluate the benefits of initial versus sequential aromatase inhibitor therapy. At 25.8 months of follow-up, the primary core analysis of BIG 1-98 compared the efficacy of upfront letrozole treatment with that of upfront tamoxifen treatment in 8,010 postmenopausal women with early breast cancer. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival, distant DFS, systemic DFS, and safety. Letrozole significantly increased DFS, reduced distant recurrences, and prolonged time to distant metastasis compared with tamoxifen. The advantage for letrozole was particularly evident in women at increased risk of recurrence (node-positive and/or chemotherapy treated). Compared with tamoxifen, postmenopausal women receiving letrozole treatment experienced less venous thromboembolic and endometrial events, but more skeletal and grade 3-5 cardiac events, although the frequencies of these latter events were relatively low in both arms (2.1% v 1.1%). There were more deaths from noncancer causes in the letrozole group, but the numbers were small and, overall, there were 14% fewer deaths among patients in the letrozole group. Letrozole has an efficacy advantage over tamoxifen and can now be considered part of standard adjuvant therapy for postmenopausal women with endocrine-responsive breast cancer. Women at increased risk for recurrence may obtain protective benefit from letrozole. Letrozole is generally well tolerated and is associated with a similar frequency of serious side effects, but fewer deaths, than tamoxifen.