Summary
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.
Introduction
Aromatase inhibitors are, for postmenopausal women, an even more effective endocrine treatment than tamoxifen, with further proportional reductions in recurrence rates of about 30%.
Aromatase inhibitors, which block the conversion of androgens into oestrogens, are ineffective in premenopausal women, in the absence of ovarian suppression, because compensatory physiological responses induce ovarian oestrogen production. However, in premenopausal women treated with ovarian function suppression or ablation, another efficacious endocrine treatment,
this physiological response is overcome and aromatase inhibitors might, therefore, also be more efficacious than tamoxifen at preventing breast cancer recurrence.
To test this hypothesis, at least four randomised trials have compared aromatase inhibitors with tamoxifen in premenopausal women receiving ovarian suppression or ablation but with conflicting results.
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This collaborative meta-analysis of individual patient data from these trials aims to better define the benefits and risks of aromatase inhibitors compared with tamoxifen in women who have their ovarian function suppressed.
Evidence before this study
A previous Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis of trials of aromatase inhibitors versus tamoxifen in postmenopausal women with early-stage oestrogen receptor (ER)-positive breast cancer has shown that aromatase inhibitors reduce recurrence rates by about 30% compared with tamoxifen over the 5-year treatment period. Aromatase inhibitors have not been shown to be efficacious in premenopausal women; however, premenopausal women treated with ovarian suppression might benefit from aromatase inhibitors. The EBCTCG’s ongoing extensive searches of bibliographic databases, including MEDLINE, Embase, the Cochrane Library, and meeting abstracts, from database inception to July 31, 2020, identified four trials comparing aromatase inhibitors with tamoxifen in premenopausal women receiving ovarian suppression. Individual trials reported inconsistent results.
Added value of this study
This collaborative meta-analysis collated, checked, and analysed individual patient-level data from 7030 women in the four randomised trials. Aromatase inhibitors reduced the rate of breast cancer recurrence compared with tamoxifen. The absolute reduction in the 5-year risk of breast cancer recurrence was 3·2%, but no difference was apparent in breast cancer mortality. Few non-breast cancer deaths occurred.
Implications of all the available evidence
For premenopausal women with early-stage, ER-positive breast cancer treated with ovarian suppression, use of an aromatase inhibitor rather than tamoxifen in premenopausal women receiving ovarian suppression reduces the risk of breast cancer recurrence.
Methods
Study design and participants
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and conform to the Preferred Reporting Items for Systematic Review and Meta-Analyses (Individual Patient Data).
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TEXT,
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and HOBOE;
ABCSG XII
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used Reiner score for staining of tumour-cell nuclei to define ER positivity [score ≥3; ie, ≥10% cells are positive]) to an aromatase inhibitor plus ovarian function supression versus tamoxifen plus ovarian function supression. Most trials included a small number of women with ER-negative, progesterone receptor (PR)-positive tumours but these individuals were excluded from this meta-analysis because the benefits of endocrine therapy are uncertain for such women.
Between 2018 and 2021, we requested individual patient-level data from trial groups on randomisation date; allocated treatment; use of chemotherapy; age; body-mass index (BMI); tumour diameter; tumour grade; histology; involvement of locoregional lymph nodes; ER and PR status; human epidermal growth factor receptor 2 (HER2) status; and dates of any locoregional, contralateral, or distant breast cancer recurrence, other second primary cancer (including endometrial cancer), bone fracture, and death; and cause of death.
The primary outcomes were any recurrence of invasive breast cancer (distant, locoregional, or new primary in the contralateral breast), 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. Secondary outcomes were incidence and site of second primary cancers (including endometrial cancer), and bone fracture. Prespecified primary subgroup investigations for any recurrence, distant recurrence, and breast cancer mortality were follow-up period (years 0–1, 2–4, 5–9, and ≥10), site of recurrence, age, BMI, nodal status, PR status, tumour diameter, histological tumour grade, histology (ductal or lobular), HER2 status, use or not of neoadjuvant or adjuvant chemotherapy, and use or not of bisphosphonate.
Statistical analysis
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and in the statistical analysis plan (appendix). Briefly, time-to-event analyses were stratified by age, nodal status, and trial. Each analysis compared all women randomised, regardless of treatment compliance (intention-to-treat analyses). Log-rank statistics were used to compare the treatment effects (aromatase inhibitor versus tamoxifen) on all outcomes (primary and secondary), and, for each outcome, to estimate first-event rate ratios (RRs) and their 95% CIs. If a log-rank statistic (observed [o]–expected [e]) has variance v, then, defining z=(o–e)/sqrt(v) and b=(o–e)/v, where b has variance 1/v, the outcome RR (aromatase inhibitor vs tamoxifen) is estimated as exp(b) with SE=(RR–1)/z. 95% CIs and 99% CIs for RRs are derived from those for b (by normal approximations). Two-sided significance with p values of less than 0·05 were considered significant for analyses of the primary and secondary outcomes and, to compensate for multiple investigations, p values of less than 0·01 were considered significant for subgroup analyses. 95% CIs were estimated for meta-analyses, and 99% CIs were estimated for individual trials or subgroups. χ2 tests are used to assess tests for heterogeneity and test for trends in subgroup analyses.
Breast cancer mortality RRs are estimated by subtracting log-rank statistics for mortality without recurrence from those of overall mortality, which avoids the need to determine which deaths after recurrence were from breast cancer.
of aromatase inhibitors versus tamoxifen in postmenopausal women, almost all of the benefits of aromatase inhibitors over tamoxifen were seen in the period when the treatments differed, then subgroup analyses of any recurrence just in this period would also be undertaken as a post-hoc analysis to enhance statistical power to investigate any variability in treatment efficacy by patient or tumour characteristics. We also did post-hoc analyses comparing the nodal status subgroup finding for premenopausal women with those we have previously reported for aromatase inhibitor versus tamoxifen in postmenopausal women. Data from premenopausal and postmenopausal will also be combined to show the effects by nodal status overall. Forest plots and Kaplan-Meier graphs describe the separate trials and their combined results, and subgroup analyses explore whether proportional risk reductions depend on patient or tumour-related characteristics. In-house FORTRAN programs were used for statistical analyses.
Role of the funding source
The funders of the study had no roles in the study design, data collection, data analysis, data interpretation, or writing of the report.
Results
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including 7230 premenopausal women receiving ovarian suppression or ablation, who were enrolled between June 17, 1999, and Aug 4, 2015, and randomised between an aromatase inhibitor and tamoxifen (table). This report is restricted to 7030 (97·2%) women with ER-positive tumours. 4231 (60·2%) of 7030 women had node-negative cancer. Women in SOFT, TEXT, and HOBOE were randomly assigned to either 5 years of an aromatase inhibitor or 5 years of tamoxifen, whereas women in ABCSG XII were randomly assigned to 3 years of an aromatase inhibitor or 3 years of tamoxifen, with or without zoledronic acid. The aromatase inhibitor used was anastrozole in ABCSG XII, exemestane in SOFT and TEXT, and letrozole in HOBOE. HOBOE also included a letrozole plus zoledronic acid group, which was excluded from these analyses because was no control group receiving tamoxifen and zoledronic acid. Use of bisphosphonates for declining bone density was optional in SOFT and TEXT; however, the routine use of bisphosphonates was not permitted and only a minority of women reported bisphosphonate use during adjuvant therapy.
TableBaseline patient characteristics by trial
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included only women who remained premenopausal after completion of neoadjuvant or adjuvant chemotherapy or women in whom adjuvant tamoxifen alone was considered suitable treatment. Of 1087 patients treated with chemotherapy in SOFT, 453 (41·7%) had received tamoxifen for an average of 4 months before study entry. In TEXT, adjuvant chemotherapy was optional and, if administered, was given concurrently with triptorelin. Tamoxifen or aromatase inhibition started after completion of chemotherapy. If chemotherapy was not given, tamoxifen or the aromatase inhibitor started 6–8 weeks after the initiation of triptorelin. The proportions of women who received chemotherapy were similar in SOFT (1060 [53·1%] of 1998 women), TEXT (1578 [59·9%] of 2635 women), and HOBOE (442 [62·9%] of 703 women). Use of adjuvant chemotherapy was not allowed in ABCSG XII; 97 [5·7%] of 1694 women in this trial had neoadjuvant chemotherapy before randomisation. Adjuvant trastuzumab was allowed in women with HER2-positive tumours in TEXT, SOFT, and HOBOE; ABCSG XII predated the use of trastuzumab and HER2 status was not ascertained.
Of 7030 women included in the analysis, 888 (12·6%) had a breast cancer recurrence, and 418 (5·9%) deaths occurred, of which 54 (12·9%) were from causes unrelated to breast cancer and without recorded disease recurrence. Overall median follow-up from the four trials was 8·0 years (IQR 6·1–9·3).
Figure 1Aromatase 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 2Subgroup 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.
when there was no suggestion of any lesser benefit in N4+ disease (figure 3B). Similarly, the apparently lesser benefit from aromatase inhibitors in premenopausal women with HER2-positive compared with HER2-negative disease was not replicated in postmenopausal women. When data from premenopausal and postmenopausal women were combined, aromatase inhibitors were superior to tamoxifen in all nodal and HER2 status categories (figure 3C).
Figure 3Post-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 4Non-breast cancer mortality, endometrial cancer incidence, and bone fracture incidence in trials of aromatase inhibitors versus tamoxifen in premenopausal women
Discussion
of aromatase inhibitors versus tamoxifen in postmenopausal women, almost all the benefit of aromatase inhibitors over tamoxifen was observed in the period when treatments differed, with no further gain or loss of benefit after year 5.
However, a second meta-analysis with longer follow-up did establish a reduction in breast cancer mortality and all-cause mortality.
This late benefit highlights the importance of long-term follow-up of breast cancer trials, particularly for women with hormone receptor-positive disease whose risk of recurrence persists at about the same annual rate for up to 20 years after diagnosis.
or in direct comparisons between treatments.
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- Hiroyuki T
- Ohsumi S
- Shimozuma K
- et al.
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- Smith I
- Yardley D
- Burris H
- et al.
Patients in ABCSG XII were at somewhat lower risk than those in other trials, with 1212 (67·2%) of 1803 women node negative, but the proportional reductions in recurrence with aromatase inhibitor compared with tamoxifen were at least as big in node-negative as in node-positive disease, so this also cannot be the reason for the lesser benefit from aromatase inhibitors in the ABCSG XII trial. Another possible factor is that ovarian function supression was achieved with goserelin in ABCSG XII and triptorelin in other trials, but we are not aware of any data indicating that these drugs are any more or less efficacious in achieving ovarian function supression. There were fewer high-risk patients in ABCSG XII and few received chemotherapy (97 [5·7%] of 1694), but subgroup analyses suggest that these differences should not have much affected the proportional reductions in recurrence. So, the inconsistent trial results are most likely a chance finding: the p-value for heterogeneity (p=0·032) did not reach the 2p of less than 0·01 threshold for significance in subgroup investigations.
of aromatase inhibitors versus tamoxifen in postmenopausal women found similar proportional reductions in recurrence in HER2-positive and HER2-negative disease so the apparent lack of benefit from aromatase inhibitors over tamoxifen in HER2-positive tumours could also be a chance finding.
With no good previous reasons for anticipating that the proportional effects of treatment might be so different in these different nodal status categories, the proportional risk reduction that is suggested by the overall results of the meta-analysis (RR 0·79) might provide a better guide to the proportional risk reductions that would be achieved in different nodal subgroups than the apparent results in each subgroup.
If so, those patients at highest recurrence risk, as defined by clinicopathological characteristics, should derive the greatest benefit from aromatase inhibitors, as is usually assumed.
There were, however, too few patients in some subgroups, for example those with PR-negative or lobular tumours, for meaningful assessment of any potential differential benefit.
who have a higher risk of recurrence than older women.
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However, our subgroup analysis of recurrence by age showed no significant trend across the age groupings. Subgroup analyses of the ABCSG XII trial suggested that women with a BMI of 25kg/m2 or higher treated with anastrozole plus goserelin had worse disease-free survival and overall survival than those treated with tamoxifen plus goserelin.
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However, our analyses showed similar recurrence reductions with aromatase inhibitors compared with tamoxifen across BMI groupings.
found no strong indication to favour either exemestane plus ovarian function supression or tamoxifen plus ovarian function supression with respect to overall quality of life.
The effects of endocrine therapy and ovarian function supression on quality of life also need to be carefully considered alongside the expected improvement in disease outcomes demonstrated in this meta-analysis.
Contributors
R Bradley, J Braybrooke, R Gray, and R K Hills designed and carried out the analyses. R Bradley, R Gray, and R K Hills accessed and verified the data. R Bradley, J Braybrooke, R Gray, and R K Hills drafted the report and all other writing committee members contributed to revising it. Interim analyses were discussed by the steering committee members and by the trialists who supplied data for the analysis. The EBCTCG secretariat was responsible for maintaining collaboration, identifying trials, and obtaining and checking datasets. The EBCTCG secretariat had full access to all data and the writing committee had final responsibility for the decision to submit for publication.
Writing committee
R Bradley, J Braybrooke, R Gray, R K Hills, Z Liu, H Pan, R Peto, D Dodwell, P McGale, C Taylor (Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK); J Bergh (Karolinska Institute and University Hospital, Stockholm, Sweden); S Swain (Georgetown University Medical Center, Washington, DC, USA); P A Francis (Peter MacCallum Cancer Centre, Melbourne, VIC, Australia); M Gnant (Medical University of Vienna, Vienna, Austria); F Perrone (Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy); M M Regan (Division of Biostatistics, Dana-Farber Cancer Institute, Boston, MA, USA)
EBCTCG secretariat
R Berry, C Boddington, R Bradley, J Braybrooke, M Clarke, C Davies, L Davies, D Dodwell, F Duane, V Evans, J Gay, L Gettins, J Godwin, R Gray, R K Hills, S James, H Liu, Z Liu, E MacKinnon, G Mannu, P McGale, T McHugh, P Morris, H Pan, R Peto, S Read, E Straiton, C Taylor.
Group (lead investigators) contributing data
Austrian Breast and Colorectal Cancer Study Group (ABCSG; ABCSG Trial XII), Vienna, Austria (M Gnant, R Jakesz, C Fesl); International Breast Cancer Study Group (IBCSG; SOFT, TEXT), Bern, Switzerland (O Pagani, M M Regan, P A Francis, R Gelber); Napoli Istituto Tumori (HOBOE), Naples, Italy (F Perrone, M De Laurentiis, S De Placido, C Gallo).
EBCTCG steering committee
J Bergh, S Swain (co-chairs), D Cameron (vice-chair), K Albain, S Anderson, R Arriagada, J Bartlett, E Bergsten-Nordström, J Bliss, R Bradley, E Brain, J Braybrooke, L Carey, M Clarke, R Coleman, J Cuzick, N Davidson, L Del Mastro, A Di Leo, J Dignam, D Dodwell, M Dowsett, F Duane, B Ejlertsen, P A Francis, R Gelber, M Gnant, M Goetz, P Goodwin, R Gray, P Halpin-Murphy, D Hayes, C Hill, R K Hills, R Jagsi, W Janni, Z Liu, S Loibl, E MacKinnon, E Mamounas, G Mannu, M Martín, P McGale, H Mukai, V Nekljudova, L Norton, Y Ohashi, H Pan, R Peto, M Piccart, L Pierce, P Poortmans, K I Pritchard, V Raina, D Rea, M M Regan, J Robertson, E Rutgers, D Slamon, T Spanic, J Sparano, G Steger, C Taylor, G Tang, M Toi, A Tutt, G Viale, X Wang, T Whelan, N Wilcken, N Wolmark. EBCTCG Secretariat, Clinical Trial Service Unit, Nuffield Department of Population Health.
Data sharing
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.
Acknowledgments
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.
Supplementary Material
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Article Info
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Published: February 03, 2022
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