# 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

EBCTCG- Early Breast Cancer Trialists' Collaborative Group

► To cite this version:

EBCTCG- Early Breast Cancer Trialists' Collaborative Group. 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. The Lancet, 2025, 406 (10503), pp.603-614. 10.1016/S0140-6736(25)01013-X. inserm-05224587

HAL Id: inserm-05224587

https://inserm.hal.science/inserm-05224587v1

Submitted on 26 Aug 2025

**HAL** is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire **HAL**, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# 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)*

<figure><img src="image_2.png" /></figure>

oa

OPEN ACCESS

## Summary

**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.

**Copyright** © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

## Introduction

In postmenopausal women with recently diagnosed oestrogen receptor (ER)-positive early breast cancer, allocation to 5 years of adjuvant endocrine therapy, despite imperfect adherence, proportionally reduces breast cancer recurrence rates during the first 10 years by about 40% for tamoxifen and 50% for aromatase inhibitor treatment (AIT), with little further gain thereafter.¹⁻³ The corresponding proportional reductions in breast cancer mortality rates are about 30% and 40%, and continue beyond year 10. Even after completion of 5 years of

endocrine therapy, however, a substantial recurrence risk persists for many years.⁴ Extending tamoxifen treatment to 10 years somewhat reduces this risk, but can cause endometrial cancer or pulmonary embolism.⁵,⁶ Using AIT to extend endocrine therapy beyond year 5 also reduces the risk of recurrence, but oestrogen deprivation can cause vasomotor symptoms, musculoskeletal symptoms, osteoporosis, or fractures.¹,⁷⁻¹¹

Among women who had already received 5 years of adjuvant tamoxifen, trials that compared further AIT versus no further endocrine treatment have reported

Lancet 2025; 406: 603–14

This online publication has been corrected. The corrected version first appeared at thelancet.com on August 11, 2025

See Comment page 573

*Writing committee and collaborators listed at end of the Article

Correspondence to:
EBCTCG secretariat, Nuffield
Department of Population
Health, University of Oxford,
Old Road Campus,
Oxford OX3 7LF, UK

bc.overview@ndph.ox.ac.uk
## Research in context

### Evidence before this study

Most postmenopausal women with early-stage breast cancer have oestrogen receptor (ER)-positive disease. After any surgery, chemotherapy, or radiotherapy, 5 years of endocrine treatment with tamoxifen or, more effectively, aromatase inhibitor treatment (AIT) substantially reduces their 15-year risk of death from breast cancer. Despite this, an appreciable risk of recurrence and death remains. Trials have studied adding further years of AIT after at least 5 years of previous endocrine treatment, but current guidelines differ on optimal AIT duration, due partly to uncertainties about effects on breast cancer outcomes that could be resolved by meta-analyses of individual patient-level data from all trials. The Early Breast Cancer Trialists' Collaborative Group's network of trialists (and regular database searches up to Sept 30, 2024, including MEDLINE, Embase, the Cochrane Library, and meeting abstracts) identified 12 such trials, all now closed.

### Added value of this study

This meta-analysis, involving the more than 22 000 eligible women from 12 trials, summarises the randomised evidence on benefits and risks of 2–3 further years of AIT versus no further AIT or of 5 further years of AIT versus no further AIT for postmenopausal women who had already received at least 5 years of tamoxifen, AIT, or tamoxifen then AIT. After previous tamoxifen alone, AIT immediately halved recurrence rates, an effect greater than that seen in the trials of further tamoxifen,

reinforcing the greater efficacy of AIT. Even after some previous AIT, further AIT further reduced recurrence. Reductions were more definite, and appeared greater, in trials of 5 years versus no further AIT than in trials of 2–3 years versus no further AIT. In the placebo-controlled trials of 5 years versus no further AIT, there were substantial, but similar, levels of non-adherence in both the AIT and the placebo groups, suggesting most women discontinued for reasons not directly due to AIT. Despite this non-adherence, allocation to 5 further years reduced rates of subsequent recurrence and distant recurrence by about a quarter, with narrow CIs. More evidence is needed to assess eventual effects on breast cancer mortality. No excess of cardiovascular, or other, mortality was seen.

### Implications of all the available evidence

Despite substantial non-adherence, among women who have already completed 5 years of adjuvant AIT, allocation to 5 further years of AIT significantly reduces the risk of distant recurrence over the next decade. Substantially greater adherence should increase both the benefits and the side-effects of treatment. If further AIT reduces breast cancer mortality as well as distant recurrence then, for individual patients, the absolute effects on survival will depend on the remaining risk of death from the original tumour (which largely depends on nodal status) and on the life expectancy that would remain without breast cancer (which is greater for younger women than older women).

See Online for appendix

fewer recurrences but no significant reduction in breast cancer mortality,⁹⁻¹¹ perhaps because many participants in the two largest such trials switched from placebo to AIT soon after early findings were published. For women who had already received 5 years of adjuvant AIT, reports from the trials of then continuing versus stopping AIT were promising but inconclusive. Thus, irrespective of the drugs used during the first 5 years of endocrine therapy, uncertainties remain about whether prolonging treatment beyond year 5 is worthwhile. To help clarify the benefits and risks, we review all the trials among women who had already received at least 5 years of previous endocrine therapy that randomly allocated giving further AIT versus giving no further adjuvant treatment. Information is reviewed on outcome by allocated treatment (by intention-to-treat meta-analyses) and contextualised based upon adherence to allocated treatment (to help assess the likely effects of actually taking AIT for some years versus no further endocrine treatment).

## Methods

### Study design and participants

Methods of identifying trials, data collection, checking, analysis, and presentation are as in previous Early Breast Cancer Trialists' Collaborative Group (EBCTCG) reports,¹,¹²,¹³ and conform with PRISMA guidelines.¹⁴ The

statistical analysis plan (SAP) agreed before data collection began (appendix pp 50–57) involves all trials starting before Jan 1, 2010, that randomly assigned postmenopausal women with ER-positive early breast cancer who had already taken at least 5 years of endocrine therapy to some additional years of AIT versus no further adjuvant treatment. Some trials included women recorded as having had ER-negative, progesterone receptor (PR)-positive tumours, but the SAP excluded these women due to uncertainty about their benefits from any endocrine therapy.¹

Trial groups provided individual patient-level data on randomisation date, allocated treatment, type and duration of previous endocrine therapy, age, BMI, tumour diameter, grade, histology, axillary lymph node involvement, ER, PR, and HER2 status; follow-up duration; dates of any loco-regional, contralateral, or distant breast cancer recurrence; details of any other second primary cancer; dates of any bone fracture; and date and underlying cause of death.

### Outcomes

Protocol-specified primary outcomes were recurrence of invasive breast cancer (local, distant, or new contralateral), breast cancer mortality, mortality from other causes, and all-cause mortality. Time to first distant recurrence
(ignoring any other recurrences) was an important secondary outcome, and is used to analyse breast cancer mortality by log-rank subtraction. Other secondary outcomes were bone fractures, cardiovascular deaths, and site-specific second primary cancers.

## Statistical analysis

Forest plots and Kaplan-Meier graphs describe the separate trials and their combined results, and subgroup analyses help explore whether the proportional risk reductions produced by treatment depend strongly on patient or tumour characteristics. Statistical methods are as in previous EBCTCG reports¹,²,¹²,¹³ and in the SAP

(appendix pp 50–57). Follow-up of breast cancer outcomes is censored at death from an unrelated cause, so Kaplan-Meier graphs yield breast cancer recurrence risks in the hypothetical absence of deaths from other causes. Competing-risk analyses could allow for how other deaths curtail any treatment benefits but would confuse effects on breast cancer outcomes with consequences of mortality from other causes. Time-to-first-event analyses, stratified by age, nodal status, year of follow-up, and trial, give the log-rank observed minus expected (O-E) statistic and its variance V. These yield not only a significance test but also the first-event rate ratio, RR, and its confidence interval (using the one-step estimate $log_{e}RR=[O-E]/V$ with

<figure><img src="image_3.png" /><figcaption>**Figure 1:** Recurrence in trials of 2–3 further years of AIT versus no further AIT or of 5 further years of AIT versus no further AIT in women who had already completed at least 5 years of previous endocrine therapy</figcaption></figure>

For each trial, figure shows year started, study name, previous endocrine therapy, randomised treatment comparison, log-rank statistics, and recurrence RR (local, distant, or new contralateral invasive disease). AIT-aromatase inhibitor treatment. ANA-anastrozole. E=expected. EXE=exemestane. LET=letrozole. O=observed. TAM=tamoxifen. *Placebo-controlled trial. †Landmark analysis, excluding events before scheduled treatment divergence (appendix pp 8–11). All analyses exclude women with recurrence already diagnosed when the allocated treatments first differed. MA.17 and NSABP B-33 results were censored on Jan 1, 2005, due to crossover; post-censoring results (red font) were ignored in all analyses. Due to this censoring, median follow-up duration was only 3-4 years in (A), but 8 years in (B) and in (C). Some participants in MA.17R had received TAM for 5 years before their 5 years of previous AIT, and some participants in ABCSG 6a had received aminoglutethimide with their first 2 years of TAM.
variance, 1/V). For overall results 95% CIs are given. Results for subgroups and individual trials are not unduly emphasised, and for them 99% CIs are given. χ² tests for heterogeneity or, where appropriate, trend compare RRs in different subgroups. Median (IQR) follow-up duration

(among women who would have been survivors) was from Kaplan-Meier graphs of time to follow-up cessation. All p values are two-sided.

Breast cancer mortality RRs are estimated by subtracting the log-rank statistics (O-E and V) for

<figure><img src="image_4.png" /><figcaption>**Figure 2:** Effects on any recurrence, distant recurrence, and breast cancer mortality in the trials of 2-3 further years of AIT versus no further AIT or of 5 further years of AIT versus no further AIT following some previous AIT</figcaption></figure>

(A) 2-3 further years of AIT versus no further AIT. (B) 5 further years of AIT versus no further AIT. Results are smoothed (broken lines) after year 5 in (A) and year 8 in (B). AIT=aromatase inhibitor treatment. E=expected. O=observed. RR=rate ratio. V=variance.
mortality without distant recurrence from those for overall mortality (log-rank subtraction). This avoids having to determine which deaths after distant recurrence were from breast cancer without inappropriately assuming all were, and use of distant recurrence improves on the original plan to use any recurrence. In-house FORTRAN programmes were used.

Four trials<sup>15-18</sup> randomly assigned women well before the allocated treatments diverged and hence gave the same AIT for some years after randomisation. For these trials a landmark analysis was used that excluded women who had had a recurrence, second primary cancer, or died before the scheduled treatment divergence, or had stopped treatment more than 3 months before that time. Sensitivity analyses (appendix pp 8–11, 32–33) included all women.

In two trials of 5 years of AIT among women who had already received 5 years of tamoxifen, interim results led to widespread switching from placebo to AIT.⁹,¹¹,¹⁹ One was unblinded in October, 2003, with median follow-up only 2·4 years, with patients on placebo then offered AIT; 1579 (61%) of 2594 patients crossed over before 2005.⁹,¹⁹ Following these preliminary results, patients on placebo in the other trial were also offered AIT and 344 (44%) of 779 crossed over, most before 2005.¹¹ In the present analyses, results for both are censored from Jan 1, 2005, which limits the evidence from this dataset. Sensitivity analyses examine the effects of this widespread switching from placebo to active treatment (appendix pp 34–40).

## Role of the funding source

Funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

## Results

All 12 eligible trials provided data.<sup>9-11,15-24</sup> Their designs and patient characteristics are given in the appendix (pp 4–7). These trials enrolled 25100 women between Dec 15, 1995, and May 21, 2014, of whom 22031 are included in the analyses. As prespecified, analyses excluded 364 women with unknown tumour ER status, 656 with ER-negative disease, and 2049 in four trials<sup>15-18</sup> who did not reach the landmark time when treatment schedules diverged (appendix p 3). In these four trials, numbers of excluded women and events differed little by treatment allocation, and these exclusions made no material difference to the overall results (appendix pp 8–11, 32–33).

Median age was 63 years (IQR 56–69), and 10038 (45·6%) of 22031 participants had nodal involvement. HER2 status was known for 7676 (34·8%) of 22031 tumours, with 857 (11·2%) of 7676 being HER2-positive. Trial treatment generally began when, or soon after, previous endocrine therapy ended, although some trials allowed up to 24 intervening months (appendix p 4). Four trials compared AIT versus placebo and eight versus open control. Aromatase inhibitors

were letrozole (six trials), anastrozole (four trials), and exemestane (two trials). Meta-analyses of the randomised comparisons between aromatase inhibitors found no evidence of differing effects on outcomes (appendix pp 46–49).

For each trial, figure 1 shows year started, study name, previous endocrine therapy, randomised treatment comparison, log-rank statistics, and recurrence RR (local, distant, or new contralateral invasive disease, with each given separately in the appendix pp 12–14). For the two trials with widespread crossover from placebo to AIT, black and white squares show analyses of events before and after the censoring date. Combining information from all trials (by summing the log-rank statistics for an information-weighted average over all trials and time periods), allocation to AIT versus no further treatment reduced recurrence rates by about a quarter (RR 0·73 [95% CI 0·67–0·80], p<0·0001).

Trials are grouped by previous endocrine therapy: previous tamoxifen for 5 years with no AIT; previous tamoxifen then AIT, each for a mean of fewer than 5 years; or previous AIT for at least 5 years. The treatment effect was significantly greater in women who had previously received only tamoxifen than in women who were already taking AIT (heterogeneity: $\chi^2=10.4$, p=0.0055), so subsequent analyses are subdivided by previous treatment (only tamoxifen, or some previous AIT). In women who had previously received only tamoxifen, allocation to AIT almost halved recurrence during years 0–4 (RR 0·56 [95% CI 0·46–0·67], p<0·0001), but the early widespread crossover in the two largest such trials meant there was little follow-up thereafter, meaning longer-term effects could not be assessed (appendix p 18).

In the trials among women who had previously received AIT, follow-up was considerably longer (median 8·1 years, IQR 6·0–10·0). Figure 2 shows the risk of any recurrence, distant recurrence, and breast cancer

<figure><img src="image_5.png" /><figcaption>Figure 3: Effect of further AIT duration on recurrence or distant recurrence RR in the trials of 2–3 further years of AIT versus no further AIT or of 5 further years of AIT versus no further AIT following some previous AIT</figcaption></figure>

(A) Any recurrence. (B) Distant recurrence. In the placebo-controlled trials of 5 further years of AIT versus no further AIT (n=5743), non-adherence was 39·0% for AIT versus 37·6% for placebo. AIT=aromatase inhibitor treatment. RR=rate ratio.
<caption>**Figure 4:** Subgroup analyses of effects on any recurrence in the trials of 2-3 further years of AIT versus no further AIT or of 5 further years of AIT versus no further AIT following some previous AIT</caption>

AIT = aromatase inhibitor treatment. E = expected. O = observed. RR = rate ratio. * Comparing RRs in trials of 2-3 further years of AIT versus no further AIT against RRs in trials of 5 further years of AIT versus no further AIT, ignoring years 0-1 of follow-up. † Weighted mean duration of AIT.

Unknown results do not contribute to heterogeneity or trend tests.

<table><thead><tr><th rowspan="2"></th><th colspan="2">Events/women</th><th colspan="2">AIT events</th><th rowspan="2">Ratio of annual event rates (95% CI or 99% CI)<br>AIT vs control</th></tr><tr><th>Allocated AIT</th><th>Allocated control</th><th>Log-rank O-E</th><th>Variance of O-E</th></tr></thead><tbody><tr><td colspan="6"><strong>A Further AIT duration, and follow-up period (χ²=5.3; p=0.022*)</strong></td></tr><tr><td>2-3 further years of AIT vs no further AIT</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Years 0-1</td><td>96/3428</td><td>108/3465</td><td>-6.3</td><td>49.0</td><td>0.88 (0.61-1.27)</td></tr><tr><td>Years 2-4</td><td>142</td><td>188</td><td>-23.8</td><td>79.5</td><td>0.74 (0.55-0.99)</td></tr><tr><td>Years 5+</td><td>182</td><td>177</td><td>0.0</td><td>85.3</td><td>1.00 (0.81-1.24)</td></tr><tr><td>5 further years of AIT vs no further AIT</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Years 0-1</td><td>86/3742</td><td>102/3769</td><td>-7.9</td><td>46.0</td><td>0.84 (0.58-1.23)</td></tr><tr><td>Years 2-4</td><td>121</td><td>200</td><td>-40.4</td><td>78.1</td><td>0.60 (0.45-0.80)</td></tr><tr><td>Years 5+</td><td>116</td><td>148</td><td>-17.5</td><td>64.0</td><td>0.76 (0.55-1.05)</td></tr><tr><td colspan="6"><strong>B Further AIT duration and previous endocrine therapy duration (χ²=5.3; p=0.022*)</strong></td></tr><tr><td>2-3 further years of AIT vs no further AIT</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>5 years previous endocrine therapy</td><td>193/1439</td><td>232/1466</td><td>-23.2</td><td>102.3</td><td>0.80 (0.62-1.03)</td></tr><tr><td>7-8 years previous endocrine therapy</td><td>227/1989</td><td>241/1999</td><td>-7.0</td><td>111.6</td><td>0.94 (0.74-1.20)</td></tr><tr><td>5 further years of AIT vs no further AIT</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>5 years previous endocrine therapy</td><td>258/2838</td><td>354/2849</td><td>-49.8</td><td>149.5</td><td>0.72 (0.58-0.88)</td></tr><tr><td>10 years previous endocrine therapy</td><td>65/904</td><td>96/920</td><td>-16.0</td><td>38.5</td><td>0.66 (0.44-1.00)</td></tr><tr><td colspan="6"><strong>C Further AIT duration and previous AIT duration (χ²=5.3; p=0.022*)</strong></td></tr><tr><td>2-3 further years of AIT vs no further AIT</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;5 years previous AIT (3-1 years†)</td><td>382/3142</td><td>434/3190</td><td>-29.3</td><td>195.4</td><td>0.86 (0.72-1.03)</td></tr><tr><td>≥5 years previous AIT (7-4 years†)</td><td>38/286</td><td>39/275</td><td>-0.9</td><td>18.5</td><td></td></tr><tr><td>5 further years of AIT vs no further AIT</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;5 years previous AIT (2-5 years†)</td><td>77/904</td><td>124/897</td><td>-24.9</td><td>49.0</td><td>0.60 (0.42-0.87)</td></tr><tr><td>5 years previous AIT (5-0 years†)</td><td>246/2819</td><td>326/2852</td><td>-40.9</td><td>139.0</td><td>0.75 (0.60-0.93)</td></tr><tr><td colspan="6"><strong>D Further AIT agent and its duration†; (χ²=1.3; p=0.26)</strong></td></tr><tr><td>Anastrozole (3-4 years†)</td><td>294/2831</td><td>335/2848</td><td>-24.9</td><td>150.5</td><td>0.85 (0.69-1.05)</td></tr><tr><td>Letrozole (4-0 years†)</td><td>449/4339</td><td>588/4386</td><td>-70.9</td><td>251.4</td><td>0.75 (0.64-0.89)</td></tr><tr><td colspan="6"><strong>E Site of first recurrence (χ²=1.6; p=0.21)</strong></td></tr><tr><td>Distant</td><td>435/7170</td><td>521/7234</td><td>-47.4</td><td>231.6</td><td>0.81 (0.69-0.97)</td></tr><tr><td>Isolated local</td><td>163/7170</td><td>198/7234</td><td>-17.9</td><td>88.4</td><td>0.82 (0.62-1.07)</td></tr><tr><td>Contralateral</td><td>145/7170</td><td>204/7234</td><td>-30.5</td><td>85.7</td><td>0.70 (0.53-0.93)</td></tr><tr><td colspan="6"><strong>F Age at entry (years; trend χ²=2.0; p=0.16)</strong></td></tr><tr><td>&lt;60</td><td>264/2533</td><td>317/2577</td><td>-25.4</td><td>142.1</td><td>0.84 (0.67-1.04)</td></tr><tr><td>60-69</td><td>350/3053</td><td>414/3045</td><td>-36.3</td><td>187.2</td><td>0.82 (0.68-0.99)</td></tr><tr><td>≥70</td><td>129/1584</td><td>192/1612</td><td>-31.5</td><td>78.7</td><td>0.67 (0.50-0.90)</td></tr><tr><td colspan="6"><strong>G BMI (kg/m²; trend χ²=0.5; p=0.99)</strong></td></tr><tr><td>&lt;20</td><td>23/257</td><td>24/268</td><td>-2.9</td><td>10.0</td><td></td></tr><tr><td>20-24</td><td>147/1612</td><td>214/1684</td><td>-29.8</td><td>85.0</td><td>0.70 (0.53-0.93)</td></tr><tr><td>25-29</td><td>192/1699</td><td>221/1633</td><td>-20.9</td><td>97.4</td><td>0.81 (0.62-1.05)</td></tr><tr><td>≥30</td><td>164/1247</td><td>209/1252</td><td>-20.8</td><td>87.4</td><td>0.79 (0.60-1.04)</td></tr><tr><td>Unknown</td><td>217/2355</td><td>255/2397</td><td>-20.2</td><td>112.0</td><td>0.84 (0.65-1.07)</td></tr><tr><td colspan="6"><strong>H Nodal status (trend χ²=0.0; p=0.99)</strong></td></tr><tr><td>N0</td><td>277/3809</td><td>339/3833</td><td>-31.8</td><td>151.4</td><td>0.81 (0.66-1.00)</td></tr><tr><td>N1-3</td><td>329/2663</td><td>423/2721</td><td>-49.4</td><td>182.3</td><td>0.76 (0.63-0.92)</td></tr><tr><td>N4+</td><td>134/639</td><td>152/627</td><td>-12.9</td><td>65.9</td><td>0.82 (0.60-1.13)</td></tr><tr><td>N unknown</td><td>3/59</td><td>9/53</td><td>-1.8</td><td>2.4</td><td></td></tr><tr><td colspan="6"><strong>I Progesterone receptor status (χ²=0.5; p=0.48)</strong></td></tr><tr><td>Positive</td><td>570/5630</td><td>737/5735</td><td>-84.4</td><td>314.8</td><td>0.76 (0.66-0.88)</td></tr><tr><td>Negative</td><td>153/1364</td><td>168/1307</td><td>-12.7</td><td>73.1</td><td>0.84 (0.62-1.14)</td></tr><tr><td>Unknown</td><td>20/176</td><td>18/192</td><td>3.3</td><td>7.7</td><td></td></tr><tr><td colspan="6"><strong>J Tumour diameter (trend χ²=0.2; p=0.65)</strong></td></tr><tr><td>1-20 mm (T1)</td><td>273/3133</td><td>346/3224</td><td>-32.1</td><td>151.6</td><td>0.81 (0.66-1.00)</td></tr><tr><td>21-50 mm (T2)</td><td>214/1709</td><td>233/1649</td><td>-17.3</td><td>108.0</td><td>0.85 (0.66-1.09)</td></tr><tr><td>&gt;50 mm (T3/T4)</td><td>29/179</td><td>47/194</td><td>-8.2</td><td>16.4</td><td>0.60 (0.32-1.14)</td></tr><tr><td>Other or unknown</td><td>227/2149</td><td>297/2167</td><td>-35.0</td><td>128.0</td><td>0.76 (0.61-0.96)</td></tr><tr><td colspan="6"><strong>K Tumour grade (trend χ²=1.3; p=0.25)</strong></td></tr><tr><td>Well differentiated</td><td>44/542</td><td>61/554</td><td>-7.9</td><td>23.8</td><td>0.72 (0.42-1.22)</td></tr><tr><td>Moderately differentiated</td><td>243/1927</td><td>269/1931</td><td>-16.9</td><td>120.6</td><td>0.87 (0.69-1.10)</td></tr><tr><td>Poorly differentiated</td><td>115/804</td><td>115/801</td><td>-2.2</td><td>52.6</td><td></td></tr><tr><td>Unknown</td><td>341/3897</td><td>478/3948</td><td>-67.3</td><td>195.9</td><td>0.71 (0.59-0.85)</td></tr><tr><td colspan="6"><strong>L Histological type (χ²=0.6; p=0.44)</strong></td></tr><tr><td>Ductal</td><td>251/2427</td><td>328/2488</td><td>-40.4</td><td>138.5</td><td>0.75 (0.60-0.93)</td></tr><tr><td>Lobular</td><td>59/365</td><td>64/355</td><td>-3.0</td><td>25.3</td><td></td></tr><tr><td>Unknown</td><td>433/4378</td><td>531/4391</td><td>-51.8</td><td>229.2</td><td>0.80 (0.67-0.95)</td></tr><tr><td colspan="6"><strong>M HER2 status (χ²=0.1; p=0.75)</strong></td></tr><tr><td>Positive</td><td>45/418</td><td>58/403</td><td>-7.1</td><td>23.0</td><td>0.73 (0.43-1.26)</td></tr><tr><td>Negative</td><td>374/3268</td><td>454/3289</td><td>-48.2</td><td>199.1</td><td>0.79 (0.65-0.94)</td></tr><tr><td>Unknown</td><td>324/3484</td><td>411/3536</td><td>-40.3</td><td>173.2</td><td>0.79 (0.65-0.96)</td></tr><tr><td><strong>Total</strong></td><td><strong>743/7170</strong></td><td><strong>923/7234</strong></td><td><strong>-95.8</strong></td><td><strong>402.0</strong></td><td><strong>0.788 (0.715-0.869)<br>p&lt;0.00001</strong></td></tr></tbody></table>
mortality by scheduled duration of further AIT. Treatment effects appeared greater, and were more definite, with 5 further years of AIT than with only 2–3 further years of AIT with a highly significant, and approximately linear, relationship between the duration of further AIT and the effect on recurrence (linear trend for 0, 2·5, and 5 further years: $\chi^2_1=27·1$, p<0·00001; non-linearity: $\chi^2_1=0·2$, p=0·66, figure 3). In the hypothetical absence of deaths from other causes, the risks comparing 5 further years of AIT with control during the decade after treatment divergence were 11·6% versus 15·2% (RR 0·71 [0·61–0·81], p<0·00001, figure 2B) for any recurrence and 6·6% versus 8·6% (RR 0·73 [0·61–0·88], p=0·0010) for distant recurrence, but the reduction in breast cancer mortality was only 4·4% versus 5·0% (RR 0·90 [0·70–1·15], p=0·40). All-cause mortality was not significantly reduced (RR 0·99 [0·86–1·14], p=0·89, appendix p 20).

Figure 4 shows, for trials with some previous AIT, subgroup analyses of recurrence, with p values for interaction (unadjusted for the number of analyses).

Similar subgroup analyses for distant recurrence and for breast cancer mortality are available (appendix pp 21–22), but involve smaller numbers. The recurrence reduction appeared chiefly during years 2–4 after treatments diverged and endured for longer with 5 further years of AIT than only 2–3 further years (figure 4A). There was no good evidence of differential treatment effect by duration of either previous endocrine treatment or previous AIT (figure 4B, C). There was no significant heterogeneity by type of AIT (letrozole or anastrozole), or site of first recurrence (distant [the commonest], local, or contralateral). There was insufficient data for subgroup analyses by chemotherapy or Ki-67, and no difference in the proportional reductions by age, or BMI, or original tumour size, grade, histological type, PR status, HER2 status, or nodal status.

In current practice, many postmenopausal women are offered initial adjuvant treatment with 5 years of AIT. Figure 5 shows the effect of five further years of AIT, compared to no further adjuvant treatment, in the 5710 women from four trials who had already received

<figure><img src="image_6.png" /><figcaption>**Figure 5:** Effects on recurrence and distant recurrence in the trials of 5 further years of AIT versus no further AIT in women who had already completed 5 years of previous AIT (total of 10 years vs 5 years of AIT)</figcaption></figure>

Results are smoothed (broken lines) from year 5 since allocated treatments differed (year 10 after AIT began). (A) Any recurrence. (B) Distant recurrence. (C) Any recurrence after node-negative disease. (D) Any recurrence after node-positive disease. AIT=aromatase inhibitor treatment. E=expected. O=observed. RR=rate ratio. V=variance.
5 years of adjuvant AIT (ie, 10 years vs 5 years of AIT in total). With median follow-up of 7.1 years (IQR 5.8–9.9), the risks during the decade after treatment divergence were 12.2% versus 15.4% (RR 0.74 [0.63–0.88], p=0.0005) for any recurrence and 6.9% versus 8.8% (RR 0.75 [0.60–0.93], p=0.0082) for distant recurrence, but only 4.3% versus 4.7% for breast cancer mortality (RR 0.92 [0.68–1.23], p=0.55, appendix p 23). The proportional recurrence reduction was consistent in node-positive and node-negative disease, so the absolute reduction appeared somewhat greater for node-positive disease. For all trials analysed together, the largest absolute benefits were in the few women with four or more involved nodes (appendix p 24).

Including all 12 trials, numbers of non-breast cancer deaths without distant recurrence were similar for women allocated AIT (584 [5.3%] of 10934) and control (602 [5.4%] of 11097; appendix pp 16, 25). Mortality without any record of distant recurrence was not related to nodal status or tumour size, suggesting few such deaths involved misclassified breast cancer events (appendix p 26). To help consider 10-year reductions in breast cancer outcomes in the context of life expectancy, estimated 10-year survival in the absence of any breast cancer recurrence, combining all trials, was subdivided by age (appendix p 27). It was 96% for younger than

60 years (mean 54), 90% for ages 60–69 years (mean 64) and 69% for ages 70 years or older (mean 75).

The incidence of endometrial cancer (defined as any uterine cancer except cervix cancer) was low: 37 (0.3%) of 10934 women allocated AIT versus 52 (0.5%) of 11097 allocated control (p=0.12, appendix p 31). For women who had received some AIT in their previous endocrine therapy, figure 6 shows non-breast-cancer outcomes after treatment divergence. There was no difference in mortality from cardiovascular disease (68 vs 70 deaths, with little data available on non-fatal vascular events) or all non-breast-cancer causes, but there was a definite increase in bone fracture incidence. For women with some previous AIT, 5 further years increased the reported 5-year bone fracture risk from 3.4% to 4.6% (RR 1.35 [1.13–1.61], p=0.0009; appendix pp 28–30). Not all trials reported fractures completely after trial treatment ended, so the absolute incidence, especially after year 5, might be underestimated. Individual patient-level information on other toxicities and on quality of life was not available. Most trials monitored toxicity only during or shortly after the scheduled treatment periods. The toxicities reported in each of the trial publications showed excess vasomotor and musculoskeletal symptoms but no differences in hypercholesterolaemia, hypertension, cardiovascular

<figure><img src="image_7.png" /><figcaption>**Figure 6:** Effects of AIT allocation on non-breast cancer mortality and on bone fractures in the trials of 2–3 further years of AIT versus no further AIT or of 5 further years of AIT versus no further AIT following some previous AIT</figcaption></figure>

AIT-aromatase inhibitor treatment. E=expected. O=observed. Trials of 2–3 years of further AIT versus no further AIT generally stopped systematic monitoring for bone fractures at the end of the scheduled treatment period, and these trials are excluded from the analyses of bone fractures during years 2–4 and 5 or later. *From Kaplan-Meier graph of bone fractures (appendix p 29).
events, or thromboembolic events (appendix pp 43–45). In the two placebo-controlled trials of 5 further years of AIT among women already on AIT, 1138 (39·0%) of 2918 versus 1098 (37·6%) of 2923 became non-adherent to their random allocation, including 241 (8·3%) of 2918 discontinuations in the AIT group versus 175 (6·0%) of 2923 discontinuations in the placebo group attributed to adverse events and 897 (30·7%) of 2918 for AIT versus 923 (31·6%) of 2923 for placebo attributed to other reasons, mostly during the first year.²¹,²² In the non-placebo-controlled trials discontinuation was likewise substantial among women allocated further AIT (appendix p 42), but those trials had open-label control groups, potentially biasing symptom reporting.

Discussion

For postmenopausal women with ER-positive early
breast cancer, previous meta-analyses had shown that
5 years of tamoxifen substantially reduces breast cancer
recurrence and mortality throughout the first and into
the second decade after diagnosis, and that 5 years of AIT
is somewhat more effective.¹,² This report assesses the
effects of using AIT to continue endocrine therapy after
year 5, considering analyses by allocated treatment in the
light of reported information on adherence.

After 5 years of tamoxifen alone, trials of switching to AIT (vs no further endocrine therapy) show the subsequent recurrence rate is immediately halved. This effect is much greater than that of continuing versus stopping tamoxifen⁵,⁶ and provides strong independent confirmation of the directly randomised evidence² of greater efficacy of AIT. The effect was so striking that women allocated placebo in the placebo-controlled trials were offered crossover to AIT,⁹,¹¹,¹⁹ limiting median follow-up to only 3·4 years for this comparison. Hence, it is not known how long these recurrence reductions would persist, how much they owed to the data-dependent stopping of the largest such trial, or what the long-term effects would be on breast cancer mortality.

Among women already receiving AIT, some further
years of AIT reduces recurrence rates, and the apparent
size of this reduction is supported by the trials of only
2–3 further years appearing to produce only about half
the effect of 5 further years (figures 3, 4A). A limitation of
these analyses is that, with hindsight, the trials
of 5 further years of AIT versus no further AIT were,
even in aggregate, under-powered for mortality, while for
recurrence those of only 2–3 further years could not
reliably determine on their own whether 7 years differs
from 5 years, or 10 years differs from 7 years, although
it is implausible that all the effect of
5 further years of AIT versus no further AIT derives from
the first 2–3 years of treatment.

Nowadays AIT is recommended for all or part of the
initial 5 years of endocrine treatment, but guidelines
differ on whether, or for whom, to recommend further
treatment. The rest of this Discussion focuses on trials

of 5 further years of AIT versus no further AIT in women
already receiving AIT.

Allocation to 5 further years of AIT reduced the rates of further recurrence, and further distant recurrence, by about a quarter, with no apparent increase in mortality from other causes. There was no evidence that the previous duration of endocrine treatment or AIT affected the benefit of further AIT on recurrence, and combining all 4 trials of 10 years of AIT versus 5 years of AIT (ie, of allocation to 5 further years of AIT vs no further AIT in women already prescribed AIT throughout the previous 5 years) also gave a reduction of about a quarter in any recurrence and in distant recurrence. In the placebo-controlled trials of 5 further years of AIT versus no further AIT, 8% of AIT-allocated versus 6% of placebo-allocated women discontinued due to adverse events and 31% of AIT-allocated versus 32% of placebo-allocated women discontinued for other reasons, many within the first year after randomisation. Analysis by allocated treatment therefore underestimates the benefits, and the side-effects, that could have been seen with substantially better adherence. These might involve recurrence reductions of about one-third rather than a quarter, and 5-year excess fracture risks of 2% rather than 1·2%.

The reduction in further recurrence with 5 further years of AIT might not yield a corresponding reduction in breast cancer mortality, but previous meta-analyses¹,² of the trials of 5 initial years of endocrine treatment versus no endocrine treatment showed that the proportional reduction in 10-year risk was about two-thirds as great for breast cancer mortality as for recurrence. This suggests that the definite reduction in distant recurrence in the present meta-analyses of the trials of 5 further years of AIT versus no further AIT might also eventually correspond to some reduction in breast cancer mortality. Ignoring non-adherence, in the present meta-analysis of 5 further years versus no further AIT the distant recurrence RR is 0·73, a proportional reduction of 27%. Using the estimate from previous meta-analyses to convert reductions in distant recurrence to breast cancer mortality, this would equate to an RR of about 0·82, compatible with the observed breast cancer mortality RR of 0·90 (with 95% CI 0·70–1·15).

The absolute further recurrence reduction from
5 further years of AIT appeared greater for women with
node-positive than node-negative disease, but limitations
of trial size and follow-up duration mean subgroup
analyses are not statistically stable. There was, however,
no convincingly significant variation with any recorded
patient or tumour characteristics in the proportional
effects of further AIT on breast cancer outcomes.

If proportional benefits are similar in most
circumstances, absolute benefits will depend on the
absolute breast cancer risk, and on life expectancy if
cured. Without mortality from breast cancer, however,
the large majority of participants younger than 70 years
(and two-thirds of older ones) in these trials would still
have been alive 10 years later, so reductions in 10-year distant recurrence risk are relevant despite any competing risks. The eventual benefit from any reduction in breast cancer mortality would, however, be substantially greater for younger than for older women because of their longer life expectancy.

No significant effects were observed on other cancers or on non-breast-cancer mortality. In particular, there was no excess cardiovascular mortality with 5 further years of AIT, but this was based on only 68 versus 70 vascular deaths. Follow-up in these trials was for only a few years after treatment ended, so longer-term effects cannot be excluded. Information on non-fatal vascular events was not sought for the present meta-analyses, but in the published data from these trials and those of AIT for breast cancer prevention²⁵,²⁶ there was no effect on myocardial infarction, stroke, or thromboembolism (appendix p 43). Also, there was no excess vascular mortality in meta-analyses of 5-year treatment with AIT versus tamoxifen (RR 0.96; 95% CI 0.78–1.19)² or of tamoxifen versus control (RR 0.98; 0.77–1.25).¹ These results are consistent with a Danish cohort study of over 30 000 post-menopausal women with early breast cancer that concluded that AIT had no clinically relevant effect on ischaemic cardiotoxicity.²⁷ However, this contrasts with published data meta-analyses²⁸⁻³⁰ that reported an increased risk of cardiovascular events with AIT, perhaps largely due to inclusion of an unpublished safety assessment from the IDEAL study that recorded “palpitations” as cardiac disorders (appendix p 43). Reliable reports of four major trials³¹⁻³⁴ showed no good evidence of hazard. Meta-analyses of individual patient data for non-fatal cardiovascular events would overcome methodological concerns about the published data meta-analyses.

For women already taking AIT, those allocated 5 further years had an absolute 1·2% excess 5-year incidence of reported bone fracture (4·6% vs 3·4%), although some trials may have somewhat under-reported fractures. Hence, the excess 5-year incidence of fractures with actual use of 5 further years of AIT might be about 2% rather than 1·2%. There was no evidence that any excess incidence continued after year 5 of further treatment. Monitoring of bone density varied and protection by bisphosphonates was generally permitted. Patient-level information was not available on symptomatic side-effects or quality of life, which are best assessed with placebo control.

In the placebo-controlled trials, as in clinical practice, many women discontinued treatment, but almost as many did so with placebo as with AIT. Strategies to support women taking long-term AIT and manage any symptoms reported (many of which may not actually be due to the AIT, even if they are symptoms that AIT can cause) might substantially improve adherence, and hence breast cancer outcomes. AIT is generally administered at a fixed daily dose, and intermittent

treatment might be as effective,³⁵ but further well-designed randomised trials are required to evaluate this.

This meta-analysis has reliably shown that allocation to five further years of AIT reduces by about one-quarter the distant recurrence rate during that further treatment, with no apparent rebound afterwards or increase in mortality from other causes. The proportional reduction in breast cancer mortality is less certain, due partly to non-adherence to allocated treatment and limited follow-up duration.

Women who have been taking AIT will know their individual experience of symptomatic side-effects, and physicians can assess bone density. Decisions about further AIT should balance absolute benefits and risks, and the absolute benefit from the reduction in distant recurrence depends on prognostic factors for subsequent recurrence, and on the use of other treatments, eg, CDK 4/6 inhibitors, as well as adherence. Outcomes in ER-positive early breast cancer continue to improve for various reasons,³⁶ reducing the expected absolute benefit from further AIT. Nevertheless, for women who have already had about 5 years of adjuvant AIT, the quantitative finding that 5 further years reduces any remaining risk of distant recurrence by about a quarter can usefully inform current and future decisions.

### Contributors

JBr, RB, RG, and RKH designed and carried out the analyses. RB, RG, and RKH accessed and verified the data. JBr, RB, RG, RP, and RKH drafted the report and all other writing committee members contributed to revising it. Interim analyses were presented and discussed at steering committee meetings. The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) secretariat (G Beake, 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, F Holt, S James, A Kerr, H Liu, Z Liu, E MacKinnon, G Mannu, P McGale, T McHugh, P Morris, M Nakahara, H Pan, R Peto, S Read, E Straiton, C Taylor, and H Taylor) was responsible for maintaining collaboration, identifying trials, and obtaining and checking datasets.

### Writing Committee

Jeremy Braybrooke, Rosie Bradley, Robert K Hills, Richard Peto, Amanda Kerr, Hongchao Pan, Mike Clarke, David Dodwell, Paul McGale, Carolyn Taylor, Stewart Anderson, Hanna Bandos, Sandra Geurts, Michael Gnant, Jim Ingle, Takuji Iwase, Gerrit-Jan Liefers, Elma Meershoek-Klein Kranenbarg, Eleftherios Mamounas, Christos Markopoulos, Lucia Del Mastro, Sabino de Placido, Wendy Parulekar, Shigehira Saji, Lois Shepherd, Guenther Steger, Gong Tang, Vivianne Tjan-Heijnen, Cornelis van de Velde, Nicholas Zdenkowski, Jonas Bergh, Sandra M Swain, Richard Gray (1949–2023).

### Collaborative groups contributing data, and lead investigators

Australia & New Zealand Breast Cancer Trials Group (LATER), Newcastle, NSW, Australia—J F Forbes, P A Francis, N Wilcken. Austrian Breast Cancer Study Group (ABCSG), Vienna, Austria—M Balic, R Bartsch, C Fesl, F Fitzal, H Fohler, M Gnant, R Greil, R Jakesz, C Marth, B Mlineritsch, G Pfeiler, C F Singer, L Sölkner, G G Steger, H Stöger. Canadian Cancer Trials Group (MA.17, MA.17R, MA.27), Kingston, ON, Canada—J M S Bartlett, V H Bramwell, B E Chen, S K L Chia, K Gelmon, P E Goss, M N Levine, W Parulekar, J L Pater, K I Pritchard, E Rakovitch, L E Shepherd, D Tu, T Whelan. Dutch Breast Cancer Trialists' Group (BOOG, for DATA trial), Utrecht and Amsterdam, Netherlands—V C G Tjan-Heijnen, P Peer, S Geurts, I E G van Hellemond, A Swinkels, S Lammers. (BOOG, for IDEAL trial),
Utrecht and Amsterdam, Netherlands — G J Liefers, E Meershoek-Klein Kranenbarg, C J H van de Velde. Gruppo Italiano Mammella (GIM, comprising GONO, GOCSI, GOIRC, GOL), Genoa, Italy—L Del Mastro, M Venturini. Hellenic Breast Surgeons Society (ATENA), Athens, Greece—U Dafni, C Markopoulos. National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA—S Anderson, H Bandos, A Brown, J Bryant, R Cecchini, J Costantino, J Dignam, B Fisher, C Geyer, E P Mamounas, S Paik, C Redmond, E Romond, S M Swain, G Tang, M A Torres, L Wickerham, N Wolmark, G Yothers. National Surgical Adjuvant Study Group (N-SAS-BC, AERAS), multiple sites, Japan—T Aihara, K Higaki, Y Hozumi, T Iwase, K Iijima, H Mukai, S Ohtani, H Ohtsu, S Saji, H Takei, Y Yanagida. Tamoxifen Exemestrane Adjuvant Multinational (TEAM) trial, multiple sites, worldwide—J M S Bartlett, E Bastiaannet, P Hadji, Y Hozumi, D Rea, C J H van de Velde.

## EBCTCG Steering Committee

Jonas Bergh, Sandra M Swain (Co-Chairs), David Cameron (Vice-Chair), Kathy Albain, Stewart Anderson, Rodrigo Arriagada, Karla Ballman, John Bartlett, Elizabeth Bergsten-Nordström†, Judith Bliss, Rosie Bradley*, Etienne Brain, Jeremy Braybrooke*, Lisa Carey, Almona Choudhury†, Mike Clarke*, Robert Coleman, Jack Cuzick, Nancy Davidson, Lucia Del Mastro, James Dignam, David Dodwell*, Mitch Dowsett, Fran Duane*, Bent Ejlertsen, Theodoros Foukakis, Prudence A Francis, Jose Angel Garcia-Saenz, Richard Gelber, Michael Gnant, Matthew P Goetz, Pamela Goodwin, Richard Gray*, Daniel Hayes, Catherine Hill, Robert K Hills*, Reshma Jagsi, Wolfgang Janni, Sibylle Loibl, Elizabeth MacKinnon*, Eleftherios Mamounas, Gurdeep Mannu*, Paul McGale*, Stuart A McIntosh, Allison Meisner, Hirofumi Mukai, Valentina Nekljudova, Larry Norton, Hongchao Pan*, Richard Peto*, Martine Piccart, Philip Poortmans, Kathy I Pritchard, Vinod Raina, Daniel Rea, Meredith M Regan, John Robertson, Shigehira Saji, Roberto Salgado, Priyanka Sharma, Dennis Slamon, Tanja Spanic†, Joseph Sparano, Patty Spears†, Guenther Steger, Gong Tang, Carolyn Taylor*, Masakazu Toi, Andrew Tutt, Frederieke van Duijnhoven, Giuseppe Viale, Xiang Wang, Tim Whelan, Nicholas Wilcken, Antonio Wolff, Norman Wolmark, Ke-Da Yu.
*EBCTCG secretariat, Nuffield Department of Population Health, Oxford, UK. †Patient representative

## 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 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, Eli 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.

## Data sharing

All datasets provided to the EBCTCG remain the property of the trial groups sending them, to whom data sharing requests should be made. The EBCTCG data sharing policy is available at https://www.ctsu.ox.ac.uk/research/the-early-breast-cancer-trialists-collaborative-group-ebctcg/data-policy-for-the-early-breast-cancer-trialists2019-collaborative-group-ebctcg.

## Acknowledgments

The chief acknowledgement is to the women who participated in these trials, those treating them, local and central staff working on the trials, and collaborating trialists who shared data. The EBCTCG secretariat is funded by the charity Cancer Research UK grant 27691, and the Breast Cancer Research Foundation, with additional support from core funding to the Nuffield Department of Population Health, University of Oxford, from Cancer Research UK and from the UK Medical Research Council. CT, DD, and PMcG received funding from Cancer Research UK grants C8225/A21133 and PRCRPg-Nov21/100001.

## References

1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. *Lancet* 2011; **378**: 771–84.

2. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. *Lancet* 2015; **386**: 1341–52.

3. Murphy CC, Bartholomew KL, Carpentier MY et al. Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review. *Breast Cancer Res Treat* 2012; **134**: 459–78.

4. Pan H, Gray R, Braybrooke J, et al. 20-year risks of breast cancer recurrence after stopping endocrine therapy at 5 years. *N Engl J Med* 2017; **377**: 1836–46.

5. Gray R, Rea D, Handley K et al. aTTom: long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. *J Clin Oncol* 2013; **31**: (suppl 15): 5.

6. Davies C, Pan H, Godwin J et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. *Lancet* 2013; **381**: 805–16.

7. Johnell O, Kanis JA, Odén A et al. Mortality after osteoporotic fractures. *Osteoporosis Int* 2004; **15**: 38–42.

8. Colzani E, Clements M, Johansson ALV et al. Risk of hospitalisation and death due to bone fractures after breast cancer: a registry-based cohort study. *Br J Cancer* 2016; **115**: 1400–07.

9. Goss PE, Ingle JN, Martino S et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. *N Engl J Med* 2003; **349**: 1793–1802.
10 Jakesz R, Greil R, Gnant M, et al. Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a. *J Natl Cancer Inst* 2007; **99**: 1845–53.

11 Mamounas EP, Jeong JH, Wickerham DL et al. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen; intention-to-treat analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-33 trial. *J Clin Oncol* 2008; **26**: 1965–71.

12 Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Comparisons between different poly-chemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials. *Lancet* 2012; **379**: 432–44.

13 Early Breast Cancer Trialists' Collaborative Group. Treatment of early breast cancer: worldwide evidence, 1985–1990. http://www.ctsu.ox.ac.uk/reports/ebctcg-1990/index_html (accessed Aug 21, 2024).

14 Stewart LA, Clarke M, Rovers M, et al. Preferred Reporting Items for a Systematic Review and Meta-Analysis of Individual Participant Data: the PRISMA-IPD statement. *JAMA* 2015; **313**: 1657–65.

15 Tjan-Heijnen VC, Lammers SW, Geurts SM, et al. Extended adjuvant aromatase inhibition after sequential endocrine therapy in postmenopausal women with breast cancer: follow up analysis of the randomised, phase 3 DATA trial. *eClinicalMedicine* 2023; **5**: 101901.

16 Del Mastro L, Mansutti M, Bisagni G, et al. Extended therapy with letrozole as adjuvant treatment of postmenopausal patients with early-stage breast cancer: a multicentre, open-label, randomised phase 3 trial. *Lancet Oncol* 2021; **22**: 1458–67.

17 Blok EJ, Kroep JR, Kranenbarg EM, et al. Optimal duration of extended adjuvant endocrine therapy for early breast cancer; results of the IDEAL trial (BOOG 2006–5). *J Natl Cancer Inst* 2018; **110**: 40–48.

18 Gnant M, Fitzal F, Rinnerthaler G, et al. Duration of adjuvant aromatase-inhibitor therapy in postmenopausal breast cancer. *N Engl J Med* 2021; **385**: 395–405.

19 Jin H, Tu D, Zhao N et al. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 Trial: analyses adjusting for treatment crossover. *J Clin Oncol* 2012; **30**: 718–21.

20 Markopoulos C, Dafni U, Misitzis J. et al. Extended adjuvant hormonal therapy with exemestane has no detrimental effect on the lipid profile of postmenopausal breast cancer patients: final results of the ATENA lipid sub-study. *Breast Cancer Res* 2009; **11**: R35.

21 Goss PE, Ingle JN, Pritchard KI, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. *N Engl J Med* 2016; **375**: 209–19.

22 Mamounas EP, Bandos H, Lembersky BC, et al. Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial. *Lancet Oncol* 2019; **20**: 88–99.

23 Zdenkowski N, Forbes JF, Boyle FM, et al. Observation versus late reintroduction of letrozole as adjuvant endocrine therapy for hormone receptor-positive breast cancer (ANZ0501 LATER): an open-label randomised, controlled trial. *Ann Oncol* 2016; **27**: 806–12.

24 Iwase T, Saji S, Iijima K, et al. Postoperative adjuvant anastrozole for 10 or 5 years in patients with hormone receptor-positive breast cancer: AERAS, a randomized multicenter open-label phase III trial. *J Clin Oncol* 2023; **41**: 3329–38.

25 Cuzick J, Sestak I, Forbes JF, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. *Lancet* 2014; **383**: 1041–48.

26 Goss PE, Ingle JN, Ales-Martines JE et al. Exemestane for breast cancer prevention in postmenopausal women. *N Engl J Med* 2011; **364**: 2381–91.

27 Lund M, Corn G, Jensen M, et al. Ischaemic cardiotoxicity of aromatase inhibitors in postmenopausal patients with early breast cancer in Denmark: a cohort study of real-world data. *Lancet Oncol* 2024; **25**:1496–506

28 Goldvaser H, Barnes TA, Seruga B, et al. Toxicity of extended adjuvant therapy with aromatase inhibitors in early breast cancer: a systematic review and meta-analysis. *J Natl Cancer Inst* 2018; **110**(1): dix141.

29 Matthews A, Stanway S, Farmer RE, et al. Long term adjuvant endocrine therapy and risk of cardiovascular disease in female breast cancer survivors: a systematic review. *BMJ* 2018; **363**: k3845.

30 Zhao F, Ren D, Shen G, et al. Toxicity of extended adjuvant endocrine with aromatase inhibitors in patients with postmenopausal breast cancer: a systematic review and meta-analysis. *Crit Rev Oncol Haem* 2020; **156**: 10311

31 Forbes JF, Cuzick J, Buzdar A, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. *Lancet Oncol* 2008; **9**: 45–53.

32 Colleoni M, Giobbie-Hurder A, Regan MM, et al. Analyses adjusting for selective crossover show improved overall survival with adjuvant letrozole compared with tamoxifen in the BIG 1–98 study. *J Clin Oncol* 2011; **29**: 1117–24.

33 Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. *J Natl Cancer Inst* 2005; **97**: 1262–71.

34 Pagani O, Regan MM, Walley BA, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. *N Engl J Med* 2014; **371**: 107–18.

35 Colleoni M, Luo W, Karlsson P, et al. Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, phase 3 trial. *Lancet Oncol* 2018; **19**: 127–38.

36 Early Breast Cancer Trialists' Collaborative Group. Reductions in recurrence in women with early breast cancer entering clinical trials between 1990 and 2009: a pooled analyses of 155746 women in 151 trials. *Lancet* 2024; **404**: 1407–18.