As reported by Mamounas et al in The Lancet Oncology, the phase III NRG Oncology/NSABP B-42 trial has shown no disease-free survival benefit with 5 years of letrozole (Femara) vs placebo after 5 years of aromatase inhibitor–based therapy in women with hormone receptor–positive postmenopausal breast cancer.Raw Letrozole powder
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 analyses.
Disease-free survival events were observed in 292 patients in the letrozole group vs 339 patients in the placebo group (hazard ratio [HR] = 0.85, P = .048, which did not meet the prespecified significance level). Estimated disease-free survival at 7 years was 84.7% in the letrozole group vs 81.3% in the placebo group. In multivariate analysis adjusting for the significant prognostic factors of age, pathologic node status, previous tamoxifen use, and type of surgery, the HR for disease-free survival was 0.86 (P = .0501). A beneficial effect of letrozole was more pronounced in patients who underwent mastectomy, had received previous tamoxifen, and had a lowest bone mineral density score of –2.0 or less, although the differences in these groups were not statistically significant. The largest differences in disease-free survival events for the letrozole vs placebo groups were in distant recurrence (61 vs 87 events) and contralateral breast cancer (30 vs 59 events).
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 breast cancer.