Extended Letrozole Sustains DFS Benefit at 15 Years in HR+ Breast Cancer

Extending letrozole (Femara) for 5 additional years showed a statistically significant improvement in disease-free survival (DFS) vs placebo in postmenopausal patients with hormone receptor (HR)-positive breast cancer who had completed prior adjuvant endocrine therapy that included an aromatase inhibitor (AI), according to the final 15-year analysis of the randomized, double-blind, placebo-controlled phase 3 NRG Oncology/NSABP B-42 trial (NCT00382070).

At the 2026 European Society for Medical Oncology (ESMO) Congress, Eleftherios P. Mamounas, MD, MPH, FACS, medical director of the breast program at AdventHealth Cancer Institute, presented the data during a proffered paper session on early and advanced breast cancer.¹

At a median follow-up of 15.9 years, the 15-year DFS rate was 61.6% with letrozole vs 56.5% with placebo, an absolute improvement of 5.1% (HR, 0.85; 95% CI, 0.76-0.94; P = .002). In total, 691 DFS events occurred in the letrozole arm compared with 787 in the placebo arm. At 10 years, DFS rates were 74.9% and 72.1%, respectively, representing a 2.8% absolute difference, indicating that the separation between the curves continued to widen with longer follow-up.

Extended letrozole also produced a statistically significant improvement in breast cancer-free interval (BCFI). The 15-year cumulative incidence of BCFI events was 14.7% with letrozole vs 18.3% with placebo, a 3.6% absolute improvement (HR, 0.78; 95% CI, 0.67-0.92; P = .003). Similarly, the 15-year cumulative incidence of distant recurrence was 6.9% vs 9.7%, respectively, an absolute reduction of 2.8% (HR, 0.72; 95% CI, 0.57-0.91; P = .005).

When distant recurrence was evaluated by nodal status, the benefit was most pronounced among patients with node-positive disease, in whom the 15-year cumulative incidence was 10.7% with letrozole vs 15.1% with placebo (HR, 0.69; 95% CI, 0.52-0.92; P = .011). Among patients with node-negative disease, the rates were 4.0% vs 5.6%, respectively (HR, 0.78; 95% CI, 0.52-1.16; P = .22).

Despite these improvements, extended letrozole did not significantly improve overall survival (OS). The 15-year OS rate was 74.0% in the letrozole arm and 72.3% in the placebo arm (HR, 0.92; 95% CI, 0.82-1.05; P = .21). Investigators did observe a trend toward fewer breast cancer deaths with letrozole, with a 15-year cumulative incidence of 5.0% vs 6.5% with placebo (HR, 0.78; 95% CI, 0.59-1.03; P = .08). Deaths from non-breast cancer or unknown causes were comparable between the arms, at 21.0% vs 21.2%, respectively (HR, 0.96; 95% CI, 0.84-1.11; P = .60).

Among first DFS events, distant recurrence occurred in 5.1% of patients in the letrozole arm vs 7.0% in the placebo arm, and second primary cancers occurred in 14.4% vs 17.0%, respectively; these included second breast cancers (5.0% vs 6.0%) and non-breast primary cancers (9.4% vs 11.0%). Local recurrence (3.2% vs 3.6%) and death as a first event (12.6% vs 12.7%) were similar between groups.

The DFS benefit was consistent across prespecified subgroups, with no significant treatment interactions by nodal status, prior tamoxifen use, bone mineral density (BMD) T-score, age, or type of surgery (P for interaction range, 0.21-0.98). In a multivariate analysis, treatment with letrozole remained independently associated with improved DFS (HR, 0.85; 95% CI, 0.77-0.94; P = .002).

Regarding safety outcomes, extended letrozole did not significantly increase the risk of osteoporotic fractures or arterial thrombotic events. The 15-year cumulative incidence of osteoporotic fractures was 9.2% with letrozole vs 8.7% with placebo (HR, 1.08; 95% CI, 0.87-1.35; P = .47), and the incidence of arterial thrombotic events was 5.6% vs 5.5%, respectively (HR, 1.06; 95% CI, 0.80-1.41; P = .68).

Between September 2006 and January 2010, the trial randomly assigned 3966 postmenopausal patients with estrogen receptor- or progesterone receptor-positive stage I, II, or IIIA invasive breast cancer who were disease free after 5 years of endocrine therapy, consisting of either 5 years of an AI or up to 3 years of tamoxifen followed by an AI to complete 5 years. Patients were randomly assigned to receive letrozole or placebo for 5 years, with stratification by pathologic nodal status, prior adjuvant tamoxifen, and lowest BMD T-score at the spine, hip, or femur (above –2.0 vs –2.0 or below). Follow-up was completed in August 2026, and 538 additional DFS events were recorded since the 10-year update.

The primary end point was DFS, defined as local, regional, or distant recurrence; contralateral breast cancer; second non-breast primary cancer; or death from any cause as a first event. Secondary end points included OS, BCFI, distant recurrence, osteoporotic fractures, and arterial thrombotic events. Analyses followed the intent-to-treat principle, and the DFS analysis included 3906 patients (letrozole, n = 1952; placebo, n = 1954).

Baseline patient, tumor, and prior treatment characteristics were balanced between the arms. Overall, 34% of patients were younger than 60 years, 57% had node-negative disease, 78% had HER2-negative disease (8% unknown), 25% had a lowest BMD T-score of –2.0 or below, 39% had received prior tamoxifen, and 61% had undergone breast-conserving surgery.

Previously reported 10-year results from NSABP B-42 showed that extended letrozole significantly improved DFS, BCFI, and distant recurrence without a significant improvement in OS or a significant increase in osteoporotic fractures or arterial thrombotic events.² The investigators concluded that the final 15-year results continue to support these findings, with extended letrozole producing a 15% reduction in DFS events, a 22% reduction in BCFI events, and a 28% reduction in distant recurrence.

References

1. Mamounas EP, Bandos H, Geyer CE Jr, et al. Final analysis of NRG Oncology/NSABP B-42, a randomized, double-blinded, placebo-controlled trial of extended letrozole in postmenopausal women with hormone-receptor positive breast cancer who have completed previous adjuvant therapy with an aromatase inhibitor. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA24.
2. Mamounas EP, Bandos H, Rastogi P, et al. Ten-year update: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project B-42 randomized trial extended letrozole therapy in early-stage breast cancer J Natl Cancer Inst. 2023;115(11):1302-1309. doi: 10.1093/jnci/djad078