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Meta-Analysis
. 2022 Mar;23(3):382-392.
doi: 10.1016/S1470-2045(21)00758-0. Epub 2022 Feb 3.

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

Early Breast Cancer Trialists' Collaborative Group (EBCTCG)
Collaborators
Meta-Analysis

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

Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Lancet Oncol. 2022 Mar.

Erratum in

  • Correction to Lancet Oncol 2022; 23: 382-92.
    [No authors listed] [No authors listed] Lancet Oncol. 2022 Apr;23(4):e161. doi: 10.1016/S1470-2045(22)00132-2. Lancet Oncol. 2022. PMID: 35358463 Free PMC article. No abstract available.

Abstract

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.

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Conflict of interest statement

Declaration of interests 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.

Figures

Figure 1
Figure 1
Aromatase inhibitors versus tamoxifen in premenopausal women (A) Any recurrence, (B) distant recurrence, (C) breast cancer mortality, and (D) all-cause mortality. O–E=observed minus expected. RR=rate ratio. V=variance of O–E.
Figure 2
Figure 2
Subgroup analyses of any first recurrence (including locoregional recurrence, distant recurrence, and new contralateral disease) in premenopausal women treated with aromatase inhibitors or tamoxifen White squares represent women with unknown status within a subgroup. BMI=body-mass index. *Randomised bisphosphonate use.
Figure 3
Figure 3
Post-hoc subgroup analyses of any recurrence aromatase inhibitors versus tamoxifen during the periods where treatments differed (A) Premenopausal women. (B) Postmenopausal women (published data from EBCTCG meta-analysis2 of aromatase inhibitor versus tamoxifen in early breast cancer). (C) All women. White squares represent women with unknown status within a subgroup.
Figure 4
Figure 4
Non-breast cancer mortality, endometrial cancer incidence, and bone fracture incidence in trials of aromatase inhibitors versus tamoxifen in premenopausal women
See this image and copyright information in PMC

References

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