Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2019 Jan;20(1):88-99.
doi: 10.1016/S1470-2045(18)30621-1. Epub 2018 Nov 30.

Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial

Affiliations
Clinical Trial

Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial

Eleftherios P Mamounas et al. Lancet Oncol. 2019 Jan.

Erratum in

Abstract

Background: The optimal duration of extended therapy with aromatase inhibitors in patients with postmenopausal breast cancer is unknown. In the NSABP B-42 study, we aimed to determine whether extended letrozole treatment improves disease-free survival after 5 years of aromatase inhibitor-based therapy in women with postmenopausal breast cancer.

Methods: This randomised, double-blind, placebo-controlled, phase 3 trial was done in 158 centres in the USA, Canada, and Ireland. Postmenopausal women with stage I-IIIA hormone receptor-positive breast cancer, who were disease-free after about 5 years of treatment with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor, were randomly assigned (1:1) to receive 5 years of letrozole (2·5 mg orally per day) or placebo. Randomisation was stratified by pathological node status, previous tamoxifen use, and lowest bone mineral density T score in the lumbosacral spine, total hip, or femoral neck. The primary endpoint was disease-free survival, defined as time from randomisation to breast cancer recurrence, second primary malignancy, or death, and was analysed by intention to treat. To adjust for previous interim analyses, the two-sided statistical significance level for disease-free survival was set at 0·0418. This study is registered with ClinicalTrials.gov, number NCT00382070, is active, and is no longer enrolling patients.

Findings: Between Sept 28, 2006, and Jan 6, 2010, 3966 patients were randomly assigned to receive letrozole (n=1983) or placebo (n=1983). Follow-up information was available for 3903 patients for the analyses of disease-free survival. Median follow-up was 6·9 years (IQR 6·1-7·5). Letrozole treatment did not significantly improve disease-free survival (339 disease-free survival events were reported in the placebo group and 292 disease-free survival events were reported in the letrozole group; hazard ratio 0·85, 95% CI 0·73-0·999; p=0·048). 7-year disease-free survival estimate was 81·3% (95% CI 79·3-83·1) in the placebo group and 84·7% (82·9-86·4) in the letrozole group. The most common grade 3 adverse events were arthralgia (47 [2%] of 1933 patients in the placebo group vs 50 [3%] of 1941 patients in the letrozole group) and back pain (44 [2%] vs 38 [2%]). The most common grade 4 adverse event in the placebo group was thromboembolic event (eight [<1%]) and the most common grade 4 adverse events in the letrozole group were urinary tract infection, hypokalaemia, and left ventricular systolic dysfunction (four [<1%] each).

Interpretation: 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.

Funding: National Cancer Institute, Korea Health Technology R&D Project, Novartis.

PubMed Disclaimer

Conflict of interest statement

Potential conflict(s) of interest

The following authors declare the following potential conflict(s) of interest:

EPM - - served as a consultant and speaker for Genomic Health, Inc, and consultant for Biotheranostics, outside the submitted work..

CEG, Jr. - - reports grants from National Cancer Institute, during the conduct of the study; personal fees from Celgene, personal fees from Myriad, other from AstraZeneca, outside the submitted work.

JMW - - reports personal fees from Genomic Health Inc, Biotheranostics, Roche, and Pfizer, outside the submitted work,

SMS - - reports grants, personal fees, and non-financial support from Genentech/Roche; personal fees from Novartis and AstraZeneca; personal fees and non-financial support from Eli Lilly & Co., Pieris Pharmaceuticals, and Inivata Ltd.; grants from Puma Biotechnology, Pfizer, and Merrimack Pharmaceuticals; and non-financial support from Caris Life Sciences and AstraZeneca.

Figures

Figure 1:
Figure 1:
Fig 2:
Fig 2:
Effect of letrozole vs. placebo on (A) disease-free survival and (B) overall survival. NSABP B-42
Fig 3:
Fig 3:
Cumulative Incidence of (A) breast cancer-free interval (BCFI), (B) distant recurrence, and (C) arterial thrombotic events. NSABP B-42
Fig 3:
Fig 3:
Cumulative Incidence of (A) breast cancer-free interval (BCFI), (B) distant recurrence, and (C) arterial thrombotic events. NSABP B-42
Fig 4:
Fig 4:
Letrozole effect on disease-free survival (DFS) in subgroups: NSABP B-42

Comment in

References

    1. Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 351:1451–67, 1998 - PubMed
    1. Pan H, Gray R, Braybrooke J, et al. : 20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years. N Engl J Med 377:1836–1846, 2017 - PMC - PubMed
    1. Goss PE, Ingle JN, Martino S, et al. : A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793–802, 2003 - PubMed
    1. Mamounas EP, Jeong JH, Wickerham DL, et al. : Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast And Bowel Project B-33 trial. J Clin Oncol 26:1965–71, 2008 - PubMed
    1. Davies C, Pan H, Godwin J, et al. : Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381:805–16, 2013 - PMC - PubMed

Publication types

MeSH terms

Associated data