Elsevier

The Lancet Oncology

Volume 20, Issue 1, January 2019, Pages 88-99
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(18)30621-1Get rights and content

Summary

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.

Introduction

Patients with hormone receptor-positive, early-stage breast cancer are at risk of recurrence long after the first 5 years after diagnosis of breast cancer. In an overview analysis of the Early Breast Cancer Trialist's Collaborative Group,1, 2 about half of the recurrences and more than two-thirds of the deaths from breast cancer occurred more than 5 years after diagnosis.

Extended adjuvant endocrine therapy with either tamoxifen or an aromatase inhibitor after 5 years of initial tamoxifen treatment has been shown to improve disease-free survival in early-stage breast cancer.3, 4, 5, 6 In one large trial,5 breast cancer-specific mortality and overall survival were also improved with extended adjuvant endocrine therapy. However, studies investigating the benefit of extending adjuvant aromatase inhibitor therapy beyond 5 years have only recently been reported, with mixed results.7, 8, 9, 10, 11

In the NSABP B-42 trial (henceforth referred to as B-42), we aimed to determine whether 5 years of letrozole treatment would improve disease-free survival in patients who had remained free of breast cancer after completing 5 years of endocrine therapy with either an aromatase inhibitor or initial tamoxifen for up to 3 years followed by an aromatase inhibitor for the remainder of the first 5 years.

Research in context

Evidence before this study

Results from clinical trials and overview analyses have established that patients with hormone receptor-positive, early-stage breast cancer are at considerable risk of recurrence long after the first 5 years from diagnosis of breast cancer. We searched PubMed when we designed this study, in March, 2005, to identify randomised clinical trials of adjuvant endocrine therapy in English. At that time, use of adjuvant tamoxifen for 5 years was the standard of care for patients with premenopausal breast cancer. Clinical trials such as the aTTom and ATLAS studies investigated extended adjuvant tamoxifen therapy for 10 years compared with 5 years, but had not reported results at the time we designed this study. These two trials showed that 10 years of tamoxifen improved disease-free survival (and breast cancer-specific mortality in the ATLAS trial), compared with 5 years of tamoxifen. For postmenopausal patients, several clinical trials had shown significant improvement in disease-free survival with the use of aromatase inhibitors, compared with 5 years of tamoxifen. Three different approaches had been used for the incorporation of aromatase inhibitors in the adjuvant setting, all three compared with the standard of 5 years of tamoxifen: 5 years of an upfront aromatase inhibitor (as assessed in the ATAC and BIG-1-98 trials), 2–3 years of an aromatase inhibitor after 2–3 years of tamoxifen (as assessed in the ABCSG-8/ARNO 95 and the ITA trials), or 5 years of an aromatase inhibitor after 5 years of tamoxifen (as assessed in the MA.17 and B-33 trials). All three approaches yielded significant improvements in disease-free survival compared with 5 years of adjuvant tamoxifen. Although the MA.17 and B-33 trials assessed extended aromatase inhibitor therapy after 5 years of tamoxifen, at the time our trial started the benefit of extending adjuvant aromatase inhibitor therapy for longer than 5 years in patients who had received 5 years of an aromatase inhibitor or 2–3 years of tamoxifen followed by 2–3 years of an aromatase inhibitor was unknown. Therefore, the NSABP B-42 (B-42) trial aimed to determine whether extending therapy past 5 years would improve disease-free survival in these patients.

Added value of this study

The B-42 trial showed that letrozole therapy did not significantly prolong disease-free survival after 5 years of hormonal therapy. However, extended letrozole therapy resulted in a significant reduction in breast cancer recurrence and distant recurrence. The B-42 results might appear discordant with those recently reported from the NCIC MA.17R trial, which showed a significant improvement in disease-free survival with extended letrozole therapy in patients who had already received 5 years of letrozole (preceded in most participants by 5 years of tamoxifen treatment). However, disease-free survival in MA.17R included only breast cancer recurrence and contralateral breast cancer as events, which is the definition of breast-cancer-free interval by the STandardized definitions for Efficacy End points (STEEP) criteria. When the disease-free survival endpoint is defined more closely to the STEEP criteria by including deaths as first event in MA.17R, a smaller and non-significant improvement in disease-free survival was observed with extended letrozole treatment. The results of the B-42 trial are further corroborated by two other randomised trials (DATA and IDEAL), which compared longer and shorter durations of extended aromatase inhibitor therapy.

Implications of all the available evidence

Considering all available evidence, it seems that the benefit from extended aromatase inhibitor therapy is modest. Therefore, careful assessment of potential risks and benefits is required before recommending extended letrozole therapy to patients with early-stage breast cancer who are disease-free after 5 years of hormonal therapy, primarily with an aromatase inhibitor. Further research is needed to identify biological markers that might predict risk of late recurrence or magnitude of benefit from extended aromatase inhibitor therapy, to optimise selection of candidates for extended aromatase inhibitor therapy.

Section snippets

Study design and participants

This was a randomised, double-blind, placebo-controlled, phase 3 trial done in 158 centres in the USA, Canada, and Ireland. Eligible patients were postmenopausal women with histologically confirmed, oestrogen-receptor-positive or progesterone-receptor-positive invasive ductal carcinoma (by local assessment), stage I–IIIA at diagnosis, who were disease-free after about 5 years of endocrine therapy consisting of either an aromatase inhibitor or tamoxifen for 3 years or less followed by an

Results

Between Sept 28, 2006, and Jan 6, 2010, 3966 patients were randomly assigned at 158 participating institutions (figure 1; appendix pp 3–6). Median time from original diagnosis to random assignment was 5·6 years (IQR 5·4–5·8). Distribution of baseline characteristics was well balanced between the two treatment groups (table 1). The median duration of aromatase inhibitor treatment in all patients in the first 5 years after diagnosis was 60 months (IQR 40–60); median duration of aromatase

Discussion

To our knowledge, the NSABP B-42 trial is the largest to investigate extended adjuvant aromatase inhibitor therapy in patients who were disease-free after 5 years of endocrine therapy, most of whom had been treated with an aromatase inhibitor. Our findings did not show a significant prolongation of disease-free survival with extended letrozole therapy. At first glance, our results appear discordant with those reported from the MA.17R trial,7 which enrolled 1918 postmenopausal women with primary

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