In the double-blind trial, conducted at 158 sites in the United States, Canada, and Ireland, 3,966 postmenopausal women with stage
I–IIIA hormone receptor–positive breast cancer who were disease-free
after approximately 5 years of treatment with an aromatase inhibitor or
tamoxifen followed by an aromatase inhibitor were randomly assigned
between September 2006 and January 2010 to receive 5 years of letrozole
2.5 mg per day (n = 1,983) or placebo (n = 1,983). The primary endpoint
was disease-free survival, defined as time from randomization to breast
cancer recurrence, second primary malignancy, or death. Follow-up
information was available for 3,903 patients for the analysis of
disease-free survival, including 1,950 in the letrozole group and 1,953
in the placebo group. The two-sided statistical significance level for
disease-free survival was set at .0418 to adjust for previous interim
Disease-free survival events were observed in 292 patients in the letrozole group vs 339 patients in the placebo group (hazard ratio
No significant difference in overall survival was observed for letrozole vs placebo (HR = 1.15, P = .22). Estimated 7-year overall
survival was 91.8% vs 92.3%. A total of 93 patients died from breast
cancer, including 46 in the letrozole group and 47 in the placebo group.
The most common grade 3 adverse events were arthralgia (3% vs 2%) and back pain (2% vs 2%). The most common grade 4 adverse events were
urinary tract infection, hypokalemia, and left ventricular systolic
dysfunction (four patients each, < 1% each) in the letrozole group
and thromboembolic events (8 patients, < 1%) in the placebo group.
The investigators concluded: “After 5 years of aromatase inhibitor–based therapy, 5 years of letrozole therapy did not
significantly prolong disease-free survival compared with placebo.
Careful assessment of potential risks and benefits is required before
recommending extended letrozole therapy to patients with early-stage