NSABP B-42 Trial 10-Year Update: Impact of Extended Letrozole on Disease-Free Survival

Get Permission

“In the 10-year analysis of the NSABP B-42 trial, the effect of extended treatment with 5 years of letrozole on disease-free survival persisted and reached statistical significance. There was no significant improvement in overall survival with letrozole, but letrozole continued to provide a significant improvement in breast cancer–free interval and distant recurrence,” said Terry P. Mamounas, MD, MPH, Medical Director of the Comprehensive Breast Program at Orlando Health University of Florida Health Cancer Center, and Chair of the NRG Oncology Breast Committee.

Terry P. Mamounas, MD, MPH

Terry P. Mamounas, MD, MPH

The analysis revealed a 16% reduction in disease-free survival events and a 4% absolute improvement with extended letrozole. There was also a statistically significant 26% reduction in breast cancer–free interval events (3% absolute improvement) and a statistically significant 29% reduction in distant recurrences (1.8% absolute improvement) with letrozole, Dr. Mamounas reported at the 2019 San Antonio Breast Cancer Symposium.1

It is has been shown that extended adjuvant endocrine therapy after 5 years of tamoxifen, with either an aromatase inhibitor or tamoxifen, improves disease-free survival in early-stage breast cancer, but the optimal duration of adjuvant aromatase inhibitors beyond 5 years has not been well established. NSABP B-42 asked whether 5 years of letrozole improves disease-free survival in patients who have completed 5 years of hormonal therapy (with either an aromatase inhibitor or tamoxifen for ≤ 3 years, followed by an aromatase inhibitor for the remainder of 5 years).

Study Details

The study randomly assigned 3,966 postmenopausal patients with stage I to III, hormone receptor–positive breast cancer who were disease-free after 5 years of endocrine therapy to letrozole at 2.5 mg or placebo daily for an additional 5 years. The primary analysis of disease-free survival was performed after 6.9 years of follow-up and reported at the 2016 San Antonio Breast Cancer Symposium. At that time, the beneficial effect of extended letrozole treatment just missed the 0.0418 level of statistical significance (hazard ratio [HR] = 0.85, P = .048).2 Extended letrozole therapy also did not improve overall survival but did significantly improve the breast cancer–free interval (HR = 0.71, P = .003) and distant recurrence rate (HR = 0.72, P = .03), Dr. ­Mamounas said.

Letrozole did not significantly increase the risk of osteoporotic fractures. However, it did increase the risk of arterial thrombotic events after 2.5 years, he added.

10-Year Update of NSABP B-42

In San Antonio, Dr. Mamounas reported the 10-year analysis of NSABP B-42 based on the data received as of April 30, 2019. These data reflected a median follow-up of 9.3 years for 3,923 patients. At this point, disease-free survival, the primary endpoint, now significantly favored extended treatment with letrozole.


  • In the 10-year analysis of NSABP B-42, the use of extended letrozole after 5 years of hormonal therapy led to a statistically significant improvement in disease-free survival, the primary endpoint. The absolute improvement was 4%.
  • The previous 7-year update showed a nonsignificant trend for improvement.
  • There was also a 3% absolute improvement in breast cancer–free interval and a 1.8% absolute improvement in distant recurrences, both of which were statistically significant.
  • Osteoporotic fracture risk was not significantly increased with extended letrozole.

In the multivariate analysis, extended letrozole therapy remained an independent predictor of improved disease-free survival (HR = 0.84, P < .01). Additional independent predictors of disease-free survival included T scores, prior tamoxifen exposure, age, and lymph node status. Disease-free survival events were less likely among patients with T scores > 2 vs < 2 (HR = 0.86, P = .047) and among those with prior tamoxifen vs without prior tamoxifen exposure (HR = 0.76, P < .001); events were more likely for patients aged ≥ 60 years vs < 60 years (HR = 1.64, P < .001) and those with positive lymph nodes vs negative lymph nodes (HR = 1.38, P < .001).

Osteoporotic fractures numbered 209 during the study—109 on the letrozole arm and 100 with placebo (= .46); cumulative incidence over 10 years was 6.5% and 6.4%, respectively. There were 154 arterial thrombotic events—82 with letrozole and 72 with placebo (= .038)—and a cumulative incidence through 10 years of 4.7% and 4.1%, respectively, he reported.

Photo by © MedMeetingImages/Todd Buchanan 2019.

“Our findings continue to suggest that careful assessment of potential risks and benefits is necessary for selecting appropriate candidates for extended letrozole therapy in patients with early-stage breast cancer,” Dr. Mamounas concluded. “Patients should be selected based on patient- and tumor-related characteristics, existing comorbidities, bone mineral density status, and tolerance of the aromatase inhibitor during the initial 5 years. We hope that genomic classifiers that predict risk of late recurrence and/or benefit of extended endocrine therapy may further aid in this treatment decision in the future,” he said. 

DISCLOSURE: Dr. Mamounas has served as a consultant or advisor for Genentech/Roche, Genomic Health, Biotheranostics, Merck, and Daiichi Sankyo and has received non-CME service fees from commercial interests or agents related to Genentech and Genomic Health.


1. Mamounas EP, Bandos H, Lembersky BC, et al: Ten-year results from NRG Oncology/NSABP B-42: A randomized, double-blinded, placebo-controlled clinical trial of extended adjuvant endocrine therapy with letrozole in postmenopausal women with hormone-receptor+ breast cancer who have completed previous adjuvant therapy with an aromatase inhibitor. 2019 San Antonio Breast Cancer Symposium. Abstract GS4-01. Presented December 12, 2019.

2. Mamounas EP, Bandos H, Lembersky BC, et al: Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): A randomized, double-blind, placebo-controlled, phase III trial. Lancet Oncol 20:88-99, 2019.