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Meta-Analysis
. 2025 Aug 9;406(10503):603-614.
doi: 10.1016/S0140-6736(25)01013-X.

Extending the duration of endocrine treatment for early breast cancer: patient-level meta-analysis of 12 randomised trials of aromatase inhibitors in 22 031 postmenopausal women already treated with at least 5 years of endocrine therapy

Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Electronic address: bc.overview@ndph.ox.ac.uk; Early Breast Cancer Trialists' Collaborative Group (EBCTCG)
Collaborators
Free article
Meta-Analysis

Extending the duration of endocrine treatment for early breast cancer: patient-level meta-analysis of 12 randomised trials of aromatase inhibitors in 22 031 postmenopausal women already treated with at least 5 years of endocrine therapy

Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Electronic address: bc.overview@ndph.ox.ac.uk et al. Lancet. .
Free article

Erratum in

  • Department of Error.
    [No authors listed] [No authors listed] Lancet. 2025 Sep 27;406(10510):1340. doi: 10.1016/S0140-6736(25)01638-1. Epub 2025 Aug 11. Lancet. 2025. PMID: 40812341 No abstract available.

Abstract

Background: In postmenopausal women with oestrogen receptor-positive early breast cancer, 5 years of adjuvant tamoxifen substantially reduces 15-year recurrence and mortality; aromatase inhibitor treatment (AIT) is even more effective. We assess the effects of further AIT among women recurrence-free after at least 5 years of endocrine therapy.

Methods: We conducted individual patient data meta-analyses of 12 randomised trials, including 22 031 women who had completed at least 5 years of tamoxifen, AIT, or tamoxifen then AIT, comparing subsequent AIT versus no further adjuvant therapy. Primary outcomes were recurrence of invasive breast cancer (local, distant, or new contralateral), breast cancer mortality, mortality from other causes, and all-cause mortality. Intention-to-treat analyses (irrespective of allocation adherence and stratified by age, nodal status, and trial, and censored at death from unrelated causes) yielded event rate ratios (RRs).

Findings: Allocation to AIT versus no further treatment reduced recurrence rates by 27% (RR 0·73 [95% CI 0·67-0·80], p<0·0001). This reduction was greater after previous tamoxifen alone than after some previous AIT, and greater in trials of 5 years of AIT versus no further AIT than in trials of 2-3 years of AIT versus no further AIT. After some previous AIT, allocation to 5 further years of AIT (with median 8·1 years [IQR 6·0-10·0] follow-up after trial treatments diverged) reduced both recurrence (RR 0·71 [0·61-0·81], p<0·0001; risk from year 5 to year 15 after diagnosis 11·6% vs 15·2%) and distant recurrence (RR 0·73 [0·61-0·88], p=0·0010; 6·6% vs 8·6%); breast cancer mortality was reduced non-significantly (RR 0·90 [0·70-1·15], p=0·40; 4·4% vs 5·0%). Tumour characteristics had no definite effects on the proportional recurrence reductions from year 5 to year 15, so the absolute recurrence reduction with 10 years vs 5 years AIT was greater for node-positive (risk 16·3% vs 20·1%) than for node-negative disease (9·1% vs 11·8%). Allocation to 5 further years of AIT increased 5-year bone fracture risk (RR 1·35 [1·13-1·61], p=0·0009; 4·6% vs 3·4%). Non-adherence to allocated treatment was widespread (39·0% further AIT vs 37·6% placebo in the placebo-controlled trials).

Interpretation: Allocation to 5 further years of AIT reduced subsequent distant recurrence rates by about a quarter despite substantial non-adherence. Longer follow-up would have been needed to help assess directly any effects on mortality.

Funding: Cancer Research UK and Breast Cancer Research Foundation.

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Conflict of interest statement

Declaration of interests SA reports consulting fees from NSABP Foundation. HB reports National Institute of Health–National Cancer Institute grants (U10CA180822), and consulting fees from Hologic including to a family member. SG reports grants from AstraZeneca for the DATA study, which was co-funded with an institutional grant. MG reports consulting fees from Veracyte, payments or honoraria from Amgen, AstraZeneca, DaiichiSankyo, EliLilly, Menarini-Stemline, MSD, Novartis, and PierreFabre, payments for expert testimony from Veracyte, support for attending meetings from AstraZeneca, DaiichiSankyo, EliLilly, Menarini-Stemline, MSD, Novartis, and PerreFabre, and other financial interests with an immediate family member employed by Sandoz. EM reports consulting fees from Merck, Genentech, Exact Sciences, Biotheranostics, and Tersera, payment or honoraria from Merck, Genentech, and Exact Sciences, support for attending meetings from SBI Alapharma, and stock or stock options from Moderna. LM reports grants from Eli Lilly, Novartis, Roche, Daiichi Sankyo, Seagen, AstraZeneca, Gilead, and Pierre Fabre, consulting fees from Eli Lilly, Gilead, Stemline, Menarini, Pfizer, and Daiichi Sankyo, payment or honoraria from Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, MSD, Seagen, Gilead, Pierre Fabre, Eisai, Exact Sciences, Ipsen, GSK, Agendia, Stemline, and Menarini, support for attending meetings from Roche, Pfizer, Eisai, Daiichi Sankyo, AstraZeneca, and Gilead, and participation on data safety monitoring boards for Novartis, Roche, Eil Lilly, Pfizer, Daiichi Sankyo, Exact Sciences, Gilead, Pierre Fabre, Eisai, AstraZeneca, Agendia, GSK and Seagen. SDP reports payment or honoraria from Novartis, Roche, AstraZeneca, Pfizer, Lilly, Seagen, Daiichi Sankyo, GSK, MSD, Gilead, and Exact Sciences, and participation on advisory boards for Novartis, AstraZeneca, Lilly, Seagen, Daiichi Sankyo, MSD, Gilead, and Exact Sciences. SSa reports grants from Taiho, Eisai, Chugai, Takeda, MSD, AstraZeneca, and Daiichi Sankyo, payments or honoraria from Chugai, Kyowa Kirin, MSD, Novartis, Eisai, Takeda, Daiichi Sankyo, Eli Lilly, AstraZeneca, Pfizer, Taiho, Ono, and Nipponkayaku, participation on data safety monitoring boards for Chuagi/Roche, AstraZeneca, Eli Lilly, Pfizer, Kyowa Kirin, Daiichi Sankyo, and MSD, and leadership role in JBCRG, JBCS, JSMO, and BIG. VTH reports grants from AstraZeneca, Novartis, Pfizer, and E Lilly. NZ reports payment or honoraria from MSD, AstraZeneca, Roche, Gilead, Lilly Australia, and Novartis, support for attending meetings from Novartis, Pfizer, and Roche, participation on data safety monitoring boards for Melanoma, and Skin Collaborative Trial Group, and leadership role in Breast Cancer Trials Scientific Advisory Committee (Chair). JBe reports grants from Amgen, AstraZeneca, Bayer, Merck, Pfizer, Roche, and Sanofi-Aventis, payments or honoraria from Roche, AstraZeneca, Novartis and Stratipath, and stock or stock options for Stratipath. SSw reports grants from Genentech/Roche and Kailos Genetics, consulting fees from Genentech/Roche, Daiichi Sankyo, Natera, Biotheranostics, Sanofi, AstraZeneca, and Molecular Templates, payments or honoraria from Genentech/Roche and AstraZeneca, support for attending meetings from Genentech/Roche, Daiichi Sankyo, Sanofi, Seagen, and NAPO, leadership role for NSABP Board of Directors, NAPO pharmaceuticals, and ASCO CCF, and stock or stock options for Seagen.

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