Introduction and rationale 1 2 1 1 3 5 6 7 8 9 10 11 15 12 11 16 17 The Breast International Group (BIG) 1-98 was designed, coordinated, analyzed, and reported by an independent academic group and currently is the largest ongoing adjuvant trial in breast cancer investigating the role of an AI. This review summarizes the design and results from the primary core analysis of the BIG 1-98 trial, which compared monotherapy with letrozole to monotherapy with tamoxifen and identified letrozole as a better alternative to tamoxifen in this setting. It also summarizes some of the additional published research using the BIG 1-98 database. Trial design and patients 1 Fig. 1 BIG-98 trial design  2 Fig. 2 18  End points The primary end point of the trial was disease-free survival (DFS), defined as the time from randomization to first occurrence of: invasive recurrence in ipsilateral breast, chest wall, regional site (internal mammary/axilla), or distant site (including ipsilateral supraclavicular); contralateral breast cancer (invasive); second malignancy (non-breast); or death without prior cancer event. Protocol-specified secondary end points in the BIG 1-98 trial were: overall survival (OS), defined as time from randomization to death from any cause; systemic DFS, defined as time from randomization to distant recurrence; second non-breast malignancy or death from any cause (ignoring local and contralateral-breast events); and safety. Three additional end points were defined in the statistical analysis plan: (1) DFS excluding second, non-breast malignancies; (2) time to recurrence, defined as time from randomization to first breast cancer recurrence (excluding second, non-breast cancers and censoring data on patients who died without a prior cancer event); and (3) time to distant recurrence, defined as the time from randomization to the first breast cancer recurrence at a distant site. Efficacy analyses Primary, secondary, and additional end points P 3 P P 4 Fig. 3 18  Fig. 4 18  Subgroup analyses 4 18 19 20 18 21 21 22 P P P P P 22 Letrozole-only versus tamoxifen-only arms P P P P 1 23 Table 1 n n 23 End point Events  Hazard ratio 95% CI P Let Tam DFS (primary protocol definition) 352 418 0.82 0.71–0.95 0.007 Overall survival 194 211 0.91 0.75–1.11 0.35 Systemic DFS 331 374 0.87 0.75–1.01 0.07 DFS (ignoring second non-breast cancer) 307 364 0.83 0.71–0.96 0.01 Time to recurrence 231 291 0.78 0.65–0.92 0.004 Time to distant recurrence 193 234 0.81 0.67–0.98 0.03 DFS  Let  Tam  CI Safety 2 18 24 Table 2 18 Adverse event  Incidence of any grade (%) P n n Cerebrovascular accident or transient ischemic attack 1.0 1.0 0.91 Thromboembolic event 1.5 3.5 <0.001 Cardiac event 4.1 3.8 0.61 Other cardiovascular event 0.5 0.2 0.04 Vaginal bleeding 3.3 6.6 <0.001 Hot flashes 33.5 38.0 <0.001 Night sweats 13.9 16.2 0.004 Fracture 5.7 4.0 <0.001 Arthralgia 20.3 12.3 <0.001 P P P P P 18 18 25 P P 18 Discussion  Clinical implications of BIG 1-98 18 23 26 27 26 27 27 28 29 18 28 30 31 32 12 17 33 34 35 36 33 37 38 39 Conclusions 18