Aromatase inhibitors versus tamoxifen in premenopausal women with oestrogen receptor-positive early-stage breast cancer treated with ovarian suppression: a patient-level meta-analysis of 7030 women from four randomised trials
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Background: For women with early-stage oestrogen receptor (ER)-positive breast cancer, adjuvant tamoxifen reduces 15-year breast cancer mortality by a third. Aromatase inhibitors are more effective than tamoxifen in postmenopausal women but are ineffective in premenopausal women when used without ovarian suppression. We aimed to investigate whether premenopausal women treated with ovarian suppression benefit from aromatase inhibitors. Methods: We did a meta-analysis of individual patient data from randomised trials comparing aromatase inhibitors (anastrozole, exemestane, or letrozole) versus tamoxifen for 3 or 5 years in premenopausal women with ER-positive breast cancer receiving ovarian suppression (goserelin or triptorelin) or ablation. We collected data on baseline characteristics, dates and sites of any breast cancer recurrence or second primary cancer, and dates and causes of death. Primary outcomes were breast cancer recurrence (distant, locoregional, or contralateral), breast cancer mortality, death without recurrence, and all-cause mortality. As distant recurrence invariably results in death from breast cancer several years after the occurrence, whereas locoregional recurrence and new contralateral breast cancer are not usually fatal, the distant recurrence analysis is shown separately. Standard intention-to-treat log-rank analyses estimated first-event rate ratios (RR) and their confidence intervals (CIs). Findings: We obtained data from all four identified trials (ABCSG XII, SOFT, TEXT, and HOBOE trials), which included 7030 women with ER-positive tumours enrolled between June 17, 1999, and Aug 4, 2015. Median follow-up was 8·0 years (IQR 6·1–9·3). The rate of breast cancer recurrence was lower for women allocated to an aromatase inhibitor than for women assigned to tamoxifen (RR 0·79, 95% CI 0·69–0·90, p=0·0005). The main benefit was seen in years 0–4 (RR 0·68, 99% CI 0·55–0·85; p<0·0001), the period when treatments differed, with a 3·2% (95% CI 1·8–4·5) absolute reduction in 5-year recurrence risk (6·9% vs 10·1%). There was no further benefit, or loss of benefit, in years 5–9 (RR 0·98, 99% CI 0·73–1·33, p=0·89) or beyond year 10. Distant recurrence was reduced with aromatase inhibitor (RR 0·83, 95% CI 0·71–0·97; p=0·018). No significant differences were observed between treatments for breast cancer mortality (RR 1·01, 95% CI 0·82–1·24; p=0·94), death without recurrence (1·30, 0·75–2·25; p=0·34), or all-cause mortality (1·04, 0·86–1·27; p=0·68). There were more bone fractures with aromatase inhibitor than with tamoxifen (227 [6·4%] of 3528 women allocated to an aromatase inhibitor vs 180 [5·1%] of 3502 women allocated to tamoxifen; RR 1·27 [95% CI 1·04–1·54]; p=0·017). Non-breast cancer deaths (30 [0·9%] vs 24 [0·7%]; 1·30 [0·75–2·25]; p=0·36) and endometrial cancer (seven [0·2%] vs 15 [0·3%]; 0·52 [0·22–1·23]; p=0·14) were rare. Interpretation: Using an aromatase inhibitor rather than tamoxifen in premenopausal women receiving ovarian suppression reduces the risk of breast cancer recurrence. Longer follow-up is needed to assess any impact on breast cancer mortality. Funding: Cancer Research UK, UK Medical Research Council.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | The Lancet Oncology |
| Vol/bind | 23 |
| Udgave nummer | 3 |
| Sider (fra-til) | 382-392 |
| Antal sider | 11 |
| ISSN | 1470-2045 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
RG and RKH report that EBCTCG is supported by a Cancer Research UK grant paid to the University of Oxford. JBe reports institutional grants or contracts from Amgen, AstraZeneca, Bayer, Merck, Pfizer, Roche, and Sanofi-Aventis; and payment from UpToDate for a chapter on breast cancer prediction. SS reports institutional grants or contracts from Kailos Genetics, Genentech/Roche, and Breast Cancer Research Foundation; consulting fees from Molecular Templates, Silverback Therapeutics, Genentech/Roche, Athenex, Lilly Pharmaceuticals, Merck, Exact sciences, Daiichi-Sankyo, AstraZeneca, Natera, Biotheranostics, and Bejing Medical Foundation; payments for non-promotional speaking from Daiichi Sankyo and Genentech/Roche; and support for attending meetings, travel, or both from Genentech/Roche and Caris. SS also reports participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca/BIG (Olympia trial); leadership or fiduciary roles on the National Surgical Adjuvant Breast and Bowel Project Board and Conquer Cancer Foundation Board; third party medical writing from Genentech/Roche; and other financial or non-financial interests, in Scientific Advisory Board for Inivata. PF reports support for travel overseas to lecture on SOFT and TEXT trials from Novartis and Ipsen. MG reports consulting fees from DaiichiSankyo, EliLilly, and Lifebrain; payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Novartis, and PierreFabre; payment for expert testimony from Veracyte; and other financial or non-financial interests from Sandoz (an immediate family member is employed by the company). FP reports institutional grants or contracts from Roche, AstraZeneca, Pfizer, Merck Sharp & Dohme, Bayer, Incyte, Taiho Oncology, Janssen Cilag, Exelixis, Aileron, and Daiichi Sankyo; payments or honoraria for educational activities or advice on regulatory activities from Incyte, GlaxoSmithKline, Eli Lilly, Ipsen, Astellas, AstraZeneca, Roche, Bristol Myers Squibb, Bayer, Clovis, and Pierre Fabre; and a leadership or fiduciary role in the Italian Society of Medical Oncology. MMR reports support for IBCSG for SOFT and TEXT from Pfizer, Ipsen, TerSera, DebioPharm, and BCRF; grants or contracts to IBCSG from Novartis, Pfizer, Merck, Roche, AstraZeneca, and Bristol Myers Squibb; institutional grants or contracts from Bristol Myers Squibb and Bayer; consulting fees from Tolmar; and payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bristol Myers Squibb and WebMD. MMR also reports participation on a Data Safety Monitoring Board or Advisory Board for ABCSG; and a leadership or fiduciary role in IBCSG. All other authors declare no competing interests.
Funding Information:
The EBCTCG Secretariat is funded primarily by a project grant from Cancer Research UK, with additional support from core funding to the Clinical Trial Service Unit and the Population Health Research Unit, Nuffield Department of Population Health, University of Oxford from Cancer Research UK, and the UK Medical Research Council. The chief acknowledgment is to the women who took part in these trials and to the trialists who conducted the studies and shared their data.
Publisher Copyright:
© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licence
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