Background
BIG 1-98. Phase III RCT of 8,010 postmenopausal women with HR+ early breast cancer evaluating letrozole and tamoxifen as monotherapy and in sequence, to determine the optimal adjuvant endocrine strategy.
Interventions and follow up
Arm A: Letrozole 2.5mg/d × 5yr
Arm B: Tamoxifen 20mg/d × 5yr (612 event-free women crossed to letrozole)
Arm C: Tamoxifen 20mg/d × 2yr then Letrozole 2.5mg/d × 3yr
Arm D: Letrozole 2.5mg/d × 2yr then Tamoxifen 20mg/d × 3yr
Primary endpoint: DFS
mFollow up: 71mo (~5.9yr)
Arm B: Tamoxifen 20mg/d × 5yr (612 event-free women crossed to letrozole)
Arm C: Tamoxifen 20mg/d × 2yr then Letrozole 2.5mg/d × 3yr
Arm D: Letrozole 2.5mg/d × 2yr then Tamoxifen 20mg/d × 3yr
Primary endpoint: DFS
mFollow up: 71mo (~5.9yr)
Results
5-yr DFS (letrozole vs tamoxifen vs letrozole>>tamoxifen vs tamoxifen>>letrozole): 87.9% vs 86.2% vs 86.2% vs 87.6%; no significant differences among the sequential and monotherapy strategies.
Letrozole vs tamoxifen monotherapy: earlier monotherapy analysis favored letrozole for DFS; OS similar.
Cumulative recurrence: no significant difference between sequential strategies and letrozole monotherapy.
Letrozole vs tamoxifen monotherapy: earlier monotherapy analysis favored letrozole for DFS; OS similar.
Cumulative recurrence: no significant difference between sequential strategies and letrozole monotherapy.
Adverse events
By mechanism:
Musculoskeletal/bone: arthralgia and bone fractures more frequent with letrozole.
Cardiovascular: more cardiac events with letrozole.
Vascular/gynecologic: thromboembolism, endometrial pathology, and vaginal bleeding more frequent with tamoxifen.
Musculoskeletal/bone: arthralgia and bone fractures more frequent with letrozole.
Cardiovascular: more cardiac events with letrozole.
Vascular/gynecologic: thromboembolism, endometrial pathology, and vaginal bleeding more frequent with tamoxifen.
Conclusions
Sequential letrozole-tamoxifen strategies and letrozole monotherapy yielded similar DFS; letrozole and tamoxifen monotherapy had similar OS. Sequencing did not improve outcomes over upfront letrozole, though it remains an option for tolerability.
Key Limitations
Substantial crossover (39.5%) from tamoxifen to letrozole on intention-to-treat confounds the monotherapy comparison and a potential carryover effect could not be excluded. Treatment-by-nodal-status interaction was not significant; subgroup conclusions should be interpreted with caution.
Clinical Context
BIG 1-98 supported letrozole as effective upfront adjuvant therapy and informed FDA approval of letrozole in this setting. Together with ATAC it established AIs over tamoxifen in postmenopausal HR+ disease. ASCO and ESMO guidelines accept upfront AI or sequential AI/tamoxifen strategies based on tolerability and risk.