Skip to main content
Download PDF
  • Systematic Review
  • Open access
  • Published:

Optimal extension time after initial endocrine therapy for postmenopausal hormone receptor-positive early-stage breast cancer: a systematic review and meta-analysis

BMC Women's Health volume 25, Article number: 156 (2025) Cite this article

Abstract

Background

The optimal duration of extended endocrine therapy (ET) for women with hormone receptor-positive (HR-positive) early-stage postmenopausal breast cancer remains uncertain. This meta-analysis systematically evaluated the optimal time to prolong aromatase inhibitors ( AIs) therapy for postmenopausal early stage breast cancer who received initial endocrine therapy.

Methods

PubMed, Web of Science, Ovid, Scopus, EmBase, and Cochrane Library were searched for randomized controlled trials (RCTs) using keywords related to breast cancer, HR-positive, AIs, and tamoxifen (TAM). Disease-free survival (DFS) was used as the primary endpoint. Meta-analysis was performed using STATA 16.0 and Revman 5.4 statistical software. Hazard ratio (HR) with its corresponding 95% confidence intervals (CI) was used as an effective indicator to assess DFS, OS, and subgroups of extended ET. Relative ratio (RR) was used to assess adverse events.

Results

The study included four RCTs involving 8,748 patients with HR-positive breast cancer. Pooled data showed an improvement in DFS when extending endocrine therapy from 5 to 7–8 years (HR = 0.82, 95% CI: 0.73 ~ 0.93), especially in patients with tumor size ≥ 2 cm (HR = 0.69, 95% CI: 0.49 ~ 0.98), estrogen receptor (ER) and progesterone receptor (PR) positive (HR = 0.77, 95% CI: 0.67 ~ 0.89), human epidermal growth factor receptor 2 (HER-2) positive or negative (HR = 0.85, 95% CI: 0.74 ~ 0.97; HR = 0.44, 95% CI: 0.22 ~ 0.89) and previous chemotherapy (HR = 0.80, 95% CI: 0.68 ~ 0.95). However, DFS has not improved with the extension from 7–8 to 10 years (HR = 0.97, 95% CI: 0.85 ~ 1.10). Furthermore, we found no significant difference in overall survival (OS), adverse events (AEs) analysis revealed a significant increase in the incidence of arthralgia, osteoporosis, bone fractures and asthenia after extended AIs.

Conclusions

The proportion of patients with breast cancer receiving ET extended beyond 5 years has increased, while the extension of AIs treatment from 5 to 7–8 years may be an option for high-risk patients with well-tolerated tumor size ≥ 2 cm, HR-positive, and previous chemotherapy. However, a variety of adverse events may accompany ET therapy, the identification of factors that may benefit breast cancer patients requires further randomized controlled studies.

PROSPERO registration number

CRD42022335497.

Peer Review reports

Introduction

Breast cancer is the most prevalent form of cancer among females, comprising around 25% of all female malignancies and surpassing lung cancer in incidence [1, 2]. About 60%-70% of all breast cancers are hormone receptor-positive (HR-positive) [3], is treated with endocrine therapy (ET) as a key component, significantly improving patient prognosis [4, 5].

For patients with HR-positive early-stage breast cancer (histologically confirmed stage I-III and operable invasive breast cancer with no recurrence or metastasis, estrogen receptor(ER) and/or progesterone receptor (PR)-positive, accounting for 10% of the nucleus) [6], selective estrogen receptor modulator tamoxifen (Tamoxifen, TAM) adjuvant therapy has the potential to decrease the likelihood of breast cancer-related death by about one-third over 15 years [7]. Aromatase inhibitors (AIs), primarily used to inhibit aromatase after menopause and block the conversion of androgen to estrogen, are more effective in ET than TAM and can reduce the recurrence rate by about 30% [8]. The ATAC [9] trial suggested that 5-year AIs treatment could substantially elevate disease-free survival (DFS) and reduce the risk of recurrence compared with 5-year TAM, which established the standard status of AIs as an adjuvant ET for postmenopausal patients with early-stage breast cancer. Despite these improvements in the prognosis, more than 50% of patients with HR + breast cancer still face the risk of recurrence after 5 years of ET [10]. Clinical trials have shown that prolonged ET can reduce the risk of recurrence rate and mortality for HR-positive breast cancer Patients [11, 12]. However, It is unclear which patients should receive extended treatment and for how long.

In recent years, the optimal duration of ET for postmenopausal patients with early-stage breast cancer has been a hot topic of significant research [13]. Several clinical trials have evaluated the effectiveness of prolonging the duration of ET [14]. The optimal duration of extended AIs therapy is still controversial [15]. This study performed a meta-analysis of RCT to evaluate the effectiveness of prolonging AIs therapy for various years following initial adjuvant ET.

Methods

Methods of literature search

The PRISMA statement was followed for reporting, offset risk assessment, and meta-analysis [16]. The study performed a literature search in May 2022 to identify relevant RCTs in PubMed, Web of Science, Ovid, Scopus, EmBase, and Cochrane Library databases. The search strategy included a combination of free words and subject words related to the extended time of ET for HR ( +) breast cancer. The keywords used were “Breast Neoplasm”, “Postmenopausal Period”, “Duration”, “Aromatase Inhibitors”, “Tamoxifen”, and “Randomized controlled trial”.

Inclusion and exclusion criteria

Inclusion criteria were as follows: (1) Studies that were RCTs conducted in English. (2) Studies that enrolled patients who had received prior ET for 3–5 years, including TAM and/or AIs, no obvious disease recurrence. (3) Intervention: The experimental group received extended ET for 5–6 years, and the control group received the same treatment for 2–3 years. (4) Outcome indicators: Primary endpoint was DFS, secondary endpoints were OS(as defined as the period from randomization to death), adverse events. (5) Studies that provided complete trial data.

Excluded criteria: (1) Studies that were not RCTs. (2) Studies that had a significant risk of bias: publication bias, selection bias, extraction bias, time lag bias and reporting bias. (3) Studies in which the extended ET were not AIs. (4) Studies in which prior adjuvant ET were given longer than 5 years. (5) Ongoing studies whose results were not presented or published during the literature search.

Study screening

Using the databases above, we retrieve relevant articles, and duplicates were removed. Such as reviews, conference abstracts, updates, and meta-analyses, were excluded. Afterwards, the remaining articles were reviewed by two investigators who independently assessed their titles and abstracts to eliminate any articles that did not fulfill the inclusion and exclusion criteria. Finally, articles eligible for the study were included, and a third party resolved any discrepancies.

Data extraction

Data extraction included the following information: (1) Basic information: Authors’ names, publication dates, and scientific categories. (2) Study subjects: Total sample size, study design, follow-up time, median age, tumor size, histological grade, lymph node status, and hormone receptor (ER/PR, HER2) status of the study subjects in the trial and control groups. (3) Interventions: Treatment regimens in the trial and control groups. (4) Outcome indicators: Primary endpoint was DFS Secondary endpoints were OS and adverse events.

Quality assessment

Two academics separately evaluated the risk of bias and cross-checked the results. Study risk of bias was assessed using the Cochrane tool embedded in Review Manager 5.4. Each study was judged according to low risk, unknown risk, or high risk of bias, which included selection bias, implementation bias, measurement bias, follow-up bias, reporting bias, and other biases.

Statistical analysis

Our statistical analysis was conducted using STATA 16.0 and Revman 5.4. Outcome indicators: DFS, OS and adverse events. Additionally, the subgroup analysis of DFS was performed based on tumor size (< 2 cm, ≥ 2 cm), lymph node status (negative, positive), hormone receptor status (ER + and PR + , ER + or PR +), HER2 status (negative, positive) and chemotherapy (yes/no). Hazard ratio (HR) with its corresponding 95% confidence intervals (CI) was used as an effective indicator to assess DFS, OS, and subgroups of extended ET [17]. Relative ratio (RR) was used to assess adverse events. Heterogeneity test analysis was performed for the included studies, and the magnitude of heterogeneity was quantified using P-value and I2. A P-value < 0.1 or I2 > 50% indicated obvious heterogeneity. Whenever P ≥ 0.1 and I2 ≤ 50%, the fixed-effect model was used. Finally, funnel plots were generated, and the Egger test was performed using STATA 16.0 software to assess publication bias [18].

Results

We retrieved 5,794 articles by computer searches of PubMed, Web of Science, Ovid, Scopus, EmBase, and Cochrane Library databases. After removing duplicates, reviews, conference abstracts, updates, and meta-analyses, 56 articles remained for further evaluation based on titles and abstracts. After thoroughly assessing the full texts, the inclusion and exclusion criteria were not met by 52 articles. This study ultimately included 4 large RCTs, and the article selection process is visually represented in Fig. 1 using the PRISMA flow diagram.

Fig. 1
figure 1

Flowchart of enrolment

Full size image

Four RCTs with 8,748 patients were included in this study [24, 28,29,30]. Table 1 presents a summary of these studies’ key characteristics. We utilized the risk of bias assessment tool available in the Cochrane Evaluation Manual, and all four included studies were found to have randomized groups, reported complete trial results and were rated as A for quality of the literature, suggesting mild bias, reflecting good quality of the included literature and risk of bias assessment (Fig. 2).

Table 1 Baseline patient characteristics by trial
Full size table
Fig. 2
figure 2

Research quality evaluation chart

Full size image

Primary endpoint

Disease-free survival (DFS)

The HR and 95% CI of DFS were reported in the four RCTs. Aggregated results: the analysis of DFS included in the literature suggested no heterogeneity (P = 0.24, I2 = 29.1%, fixed-effect model). We observed that prolonging the duration of ET improved DFS (HR = 0.89, 95% CI: 0.82 ~ 0.97, P = 0.03; Z = 2.22, P < 0.05; Fig. 3A). Especially, the extension of ET from 5 to 7–8 years significantly improved DFS (HR = 0.82, 95% CI: 0.73 ~ 0.93, P = 0.002; Z = 3.14, P < 0.05; Fig. 3A). However, DFS has not improved with the extension from 7–8 to 10 years (HR = 0.97, 95% CI: 0.85 ~ 1.10, P = 0.607; Z = 0.51, P > 0.05; Fig. 3A).

Fig. 3
figure 3

Forest plot of HR in early-stage postmenopausal breast cancer patient. A HR for disease-free survival of all patients by the duration of endocrine therapy. B HR for overall survival of all patients by the duration of endocrine therapy

Full size image

Subgroups analyses of DFS

We also categorized the HR of DFS based on the following factors: tumor size (< 2 cm, ≥ 2 cm), lymph node status (negative, positive), hormone receptor status (ER + and PR + , ER + or PR +), HER2 status (negative, positive) and chemotherapy (yes, no). In the subgroup analysis of the included data, we observed an improvement in DFS when extending ET from 5 to 7–8 years in patients with tumor diameter ≥ 2 cm (HR = 0.69, 95% CI: 0.49 ~ 0.98) (Fig. 4A), PR + /ER + (HR = 0.77, 95% CI: 0.67 ~ 0.89) (Fig. 4B), HER2 ± (HR = 0.44, 95% CI: 0.22 ~ 0.89; HR = 0.85, 95% CI: 0.74 ~ 0.97) (Fig. 4C) and previous chemotherapy (HR = 0.80, 95% CI: 0.68 ~ 0.95) (Fig. 4D). The differences are summarized in Supplemental Table 1.

Fig. 4
figure 4

Subgroup analysis of DFS. (A) Tumor size groups; (B) Hormone receptor groups; (C) HER2 status groups; (D) Chemotherapy groups

Full size image

Secondary endpoint

Overall survival (OS)

All four RCTs reported HR and 95% CI for OS, with no heterogeneity among the studies (P = 0.30, I2 = 17.5%, fixed-effects model). Our meta-analysis results revealed no significant difference in the improvement of OS (HR = 0.94, 95% CI: 0.83 ~ 1.05, P = 0.30; Z = 2.22, P > 0.05; Fig. 3B).

In order to evaluate the robustness of the study, we carried out sensitivity analysis, excluded some fuzzy studies and the literature of relatively poor quality from the included studies, re-conducted meta-analysis, compared whether there were significant differences before and after the merger effect. Re-analyzed the data with different statistical methods, such as using random effect model instead of fixed effect model for sensitivity analysis. It was found that no significant impact on the overall results of the meta-analysis was observed in any of the studies included. The sensitivity analysis diagram is shown in the appendix. Furthermore, the Egger bias test yielded a P-value of 0.47, this suggests that there is no indication of publication bias in the studies we included and that our findings are reliable.

Adverse events (AEs)

The four RCTs included in this study reported adverse events. Adverse event (AE) analysis revealed a significant increase in the incidence of arthralgia (RR = 1.14, 95% CI: 1.06 ~ 1.23), osteoporosis (RR = 1.44, 95% CI: 1.07 ~ 1.93), and bone fractures (RR = 1.36, 95% CI: 1.01 ~ 1.84) in patients with ET from 5 to 7–8 years, while the incidence of osteoporosis (RR = 1.68, 95% CI: 1.27 ~ 2.22), bone fractures (RR = 1.74, 95% CI: 1.38 ~ 2.19) and asthenia (RR = 1.74, 95% CI: 1.32 ~ 2.29) is significantly increased in patients with ET from 7–8 to 10 years. The differences are summarized in Table 2.

Table 2 Summary of the meta-analysis of the incidence of adverse events
Full size table

Discussion

The optimal duration of ET for patients with HR-positive early-stage breast cancer remains controversial. Previous meta-analysis studies by Pan, Bradley [19, 20], and others have confirmed that 5 years of ET can effectively reduce the recrudescence and mortality proportion of HR( +) early-stage breast cancer. However, limited studies have investigated the extension of ET beyond 5 years.

The aTToms trial [21] showed that prolonging TAM treatment to 10 years could further reduce recrudescence and mortality proportion in female patients with HR( +) breast cancer, particularly in the second 10 years after diagnosis, with a halving of breast cancer mortality. In contrast, the NSABP-B14,NSABPB-33 trial did not find a significant survival advantage with TAM beyond 5 years [22, 23]. The DATA trial [24] included in this study revealed that the extension of AIs for 5 years after initial treatment (AI/TAM/TAM-AI) for 5 years did not significantly improve DFS and OS compared with 2.5 years. However, a study by AERAS, MA17 and Li et al. demonstrated that extending ET to 10 years after the standard 5-year ET could further improve DFS in patients with early breast cancer [25,26,27]. It is worth noting that drug toxicity and patient compliance can pose challenges with extended ET, and there is still ambiguity in choosing the optimal time for extending AIs treatment. This study aimed to analyze the best prolongation time after initial ET for early postmenopausal HR-positive breast cancer and to provide a reference for related clinical work.

The discoveries of this research demonstrate that extending the duration of AIs therapy from 5 to 7–8 years after the completion of initial adjuvant ET can significantly improve DFS (HR = 0.82, 95% CI: 0.73 ~ 0.93, P = 0.002) and decrease the disease progression by 18%, in line with the findings of the GIM4LEAD study [28]. However, ABCSG-16 and IDEAL studies demonstrated that HR( +) early breast cancer patients who completed the initial adjuvant ET continued to extend AIs therapy for 5 years without significant DFS benefit. [29, 30]. A meta-analysis evaluating OS also did not show significant benefits with extended adjuvant ET (HR = 0.94, 95% CI: 0.83 ~ 1.05, P = 0.30), regardless of whether it was 7–8 years or longer. This could be due to fewer studies and relatively short overall follow-up time, which may not capture long-term survival outcomes. Richman [31] showed that while extending adjuvant ET to 10 years could reduce recurrence risk in patients with HR( +) early breast cancer, no predictive biomarkers have been identified yet to determine which patients will benefit from ET. We also stratified the HR of DFS based on the tumor size(< 2 cm, ≥ 2 cm), hormone receptor status (ER + and PR + , ER + or PR +), HER2 status (negative or positive) and chemotherapy (yes or no). We found significant DFS benefits in patients with tumor diameter ≥ 2 cm, PR + /ER + , HER2 + , and formerly received chemotherapy. These findings shown that patients at high risk of recurrence after initial ET may benefit from extended AIs, while early-stage patients with smaller tumors and negative lymph nodes may achieve sufficient benefits from 5-year endocrine therapy alone. Nevertheless, it is crucial to ponder that the number of studies and follow-up duration may have contributed to these findings.

The clinical efficacy and side effects of drugs are crucial considerations while extending ET, as severe adverse reactions may affect its persistence [32, 33]. Although prolonging ET can reduce the risk of recurrence in such breast cancer patients, it can also increase the occurrence of other adverse events, such as fractures and cardiovascular disease [34]. The IDEAL study found that 15.7% of patients terminated Letrozole treatment for 2.5 years due to severe adverse drug reactions [30], while the MA17R [35] study showed that bone-related toxicity was more common when ET was extended to 10 years, which is consistent with our findings. Prolonged AIs treatment increases the risk of related diseases such as joint pain, osteoporosis, fracture, and fatigue [36, 37]. However, over time, poor patient compliance may limit the benefits of prolonged ET for all patients [38]. To mitigate the adverse effects on bone mineral density associated with AIs treatment, bone modifiers such as zoledronic acid and deschumab may be considered in patients undergoing extended ET [39, 40].

There are a number of limitations that must be taken into account in this study. Initially, the main limitation of this study is that the number of included studies is small, resulting in a limited overall sample size, and studies with positive results are more likely to be published, which may cause false positives or false negatives. Secondly, the definition of DFS in the included RCTs ABCSG-16 and GIM4LEAD is not clear enough, and the outcome indicators included do not report HR. There may be heterogeneity, which may lead to difficulties in data merger analysis and affect the interpretation of the results. Thirdly, there are differences in the initial ET time in the included studies, and the results of meta-analysis may be difficult to apply directly to such patients. However, considering the limited number of studies, we continue to include these studies.

To summarize, the percentage of breast cancer patients opting for extended adjuvant ET beyond 5 years has risen significantly, irrespective of whether they meet the treatment extension criteria of the current clinical guidelines [41]. For high-risk patients with good tolerance, tumor diameter ≥ 2 cm, positive tumor lymph nodes, and positive hormone receptors, extended treatment with AIs up to 7–8 years may be an option, but various adverse events may also accompany it. Further RCTs are necessary to assess the advantages and drawbacks of prolonged adjuvant ET for individuals with breast cancer.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

ET:

Endocrine therapy

HR-positive:

Hormone receptor-positive

AIs:

Aromatase inhibitors

RCTs:

Randomized controlled trials

TAM:

Tamoxifen

DFS:

Disease-free survival

HR:

Hazard ratio

CI:

Confidence intervals

RR:

Relative ratio

ER:

Estrogen receptor

PR:

Progesterone receptor

HER2:

Human epidermal growth factor receptor 2

OS:

Overall survival

AEs:

Adverse events

References

  1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA  Cancer J Clin. 2018;68(6):394–424. https://doiorg.publicaciones.saludcastillayleon.es/10.3322/caac.21492.

  2. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries .CA Cancer J Clin. 2021;71( 3):209–249. https://doiorg.publicaciones.saludcastillayleon.es/10.3322/caac.21660.

  3. Vici P, Pizzuti L, Natoli C, et al. Triple positive breast cancer: a distinct subtype?.Cancer Treat Rev. 2015;41( 2):69–76. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.ctrv.2014.12.005.

  4. Schrodi S, Braun M, Andrulat A, et al. Outcome of breast cancer patients with low hormone receptor positivity: analysis of a 15-year population-based cohort. Ann Oncol. 2021;32(11):1410–24. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.annonc.2021.08.1988.

    Article  CAS  PubMed  Google Scholar 

  5. Zeng E, He W, Sjölander A, Bergqvist J, Czene K. Determinants and Effectiveness of Extending the Duration of Adjuvant Hormone Therapy beyond 5 Years in Patients with Breast Cancer. Cancer Res. 2022;82(19):3614–21. https://doiorg.publicaciones.saludcastillayleon.es/10.1158/0008-5472.CAN-22-0900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Trabert B, Sherman ME, Kannan N, Stanczyk FZ. Progesterone and Breast Cancer. Endocr Rev. 2020;41(2):320–44. https://doiorg.publicaciones.saludcastillayleon.es/10.1210/endrev/bnz001.

    Article  PubMed  Google Scholar 

  7. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Davies C, Godwin J, et al. 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(9793):771–784. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/S0140-6736(11)60993-8.

  8. 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(10001):1341–1352. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/S1470-2045(21)00758-0.

  9. Cuzick J, Sestak I, Baum M, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial[J]. Lancet Oncol. 2010;11(12):1135–41. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/S1470-2045(10)70257-6.

    Article  CAS  PubMed  Google Scholar 

  10. Lee HJ, Park IA, Park SY, et al. Two histopathologically different diseases: hormone receptor-positive and hormone receptor-negative tumors in HER2-positive breast cancer. Breast Cancer Res Treat. 2014;145( 3):615–623. https://doiorg.publicaciones.saludcastillayleon.es/10.1007/s10549-014-2983-x.

  11. Burstein HJ, Somerfield MR, Barton DL, et al. Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: ASCO Guideline Update. J Clin Oncol. 2021;39(35):3959–77. https://doiorg.publicaciones.saludcastillayleon.es/10.1200/JCO.21.01392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cuzick J, Sestak I, Cawthorn S, et al. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol. 2015;16(1):67–75. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/S1470-2045(14)71171-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Davie A, Carter GC, Rider A, et al. Real-world patient-reported outcomes of women receiving initial endocrine-based therapy for HR+/HER2- advanced breast cancer in five European countries. BMC Cancer. 2020;20(1):855. Published 2020 Sep 7. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12885-020-07294-2.

  14. Simon J, Chaix M, Billa O, et al. Survival in patients with HR+/HER2- metastatic breast cancer treated with initial endocrine therapy versus initial chemotherapy. A French population-based study. Br J Cancer. 2020;123(7):1071–1077. https://doiorg.publicaciones.saludcastillayleon.es/10.1038/s41416-020-0979-3.

  15. Pieters HC, Green E, Sleven M, Stanton AL. Aromatase inhibitors: The unexpected breast cancer treatment. J Geriatr Oncol. 2020;11(3):431–6. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.jgo.2019.07.024.

    Article  PubMed  Google Scholar 

  16. Page MJ, McKenzie JE, Bossuyt PM, The PRISMA, et al. statement: an updated guideline for reporting systematic reviews. BMJ. 2020. https://doiorg.publicaciones.saludcastillayleon.es/10.1136/bmj.n71.

    Article  PubMed  Google Scholar 

  17. Der Simonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177.

    Article  Google Scholar 

  18. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629. https://doiorg.publicaciones.saludcastillayleon.es/10.1136/bmj.315.7109.629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pan H, Gray R, Braybrooke J, et al. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years[J]. N Engl J Med. 2017;377(19):1836–46. https://doiorg.publicaciones.saludcastillayleon.es/10.1056/NEJMoa1701830.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bradley R, Braybrooke J, Gray R, et al. 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. Lancet Oncol. 2022;23(3):382–392. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/S1470-2045(21)00758-0.

  21. 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 [published correction appears in Lancet. 2013;381(9869):804] [published correction appears in Lancet. 2017;389(10082):1884]. Lancet.2013;381(9869):805–816. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/S0140-6736(12)61963-1.

  22. Fisher B, Dignam J, Bryant J, et al. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial[J]. J Natl Cancer Inst. 2001;93(9):684–90. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/jnci/93.9.684.

    Article  CAS  PubMed  Google Scholar 

  23. 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 B-33 trial. J Clin Oncol. 2008;26(12):1965–71. https://doiorg.publicaciones.saludcastillayleon.es/10.1200/JCO.2007.14.0228.

    Article  CAS  PubMed  Google Scholar 

  24. Tjan-Heijnen VCG, van Hellemond IEG, Peer PGM, et al. Extended adjuvant aromatase inhibition after sequential endocrine therapy (DATA): a randomised, phase 3 trial [published correction appears in Lancet Oncol. 2017;18(11):e642]. Lancet Oncol. 2017;18(11):1502–1511. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/S1470-2045(17)30600-9.

  25. Mann BS, Johnson JR, Kelly R, Sridhara R, Williams G, Pazdur R. Letrozole in the extended adjuvant treatment of postmenopausal women with history of early-stage breast cancer who have completed 5 years of adjuvant tamoxifen. Clin Cancer Res. 2005;11(16):5671–7. https://doiorg.publicaciones.saludcastillayleon.es/10.1158/1078-0432.CCR-05-0354.

    Article  CAS  PubMed  Google Scholar 

  26. 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(17):1262–1271. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/jnci/dji250.

  27. Li L, Chang B, Jiang X, et al. Clinical outcomes comparison of 10 years versus 5 years of adjuvant endocrine therapy in patients with early breast cancer. BMC Cancer. 2018;18(1):977. Published 2018 Oct 12. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12885-018-4878-4.

  28. 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(10):1458–67. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/S1470-2045(21)00352-1.

    Article  PubMed  Google Scholar 

  29. Gnant M, Fitzal F, Rinnerthaler G, et al. Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer. N Engl J Med. 2021;385(5):395–405. https://doiorg.publicaciones.saludcastillayleon.es/10.1056/NEJMoa2104162.

    Article  CAS  PubMed  Google Scholar 

  30. Blok EJ, Kroep JR, Meershoek-Klein Kranenbarg E, et al. Optimal Duration of Extended Adjuvant Endocrine Therapy for Early Breast Cancer; Results of the IDEAL Trial (BOOG 2006–05). J Natl Cancer Inst. 2018;110(1):https://doiorg.publicaciones.saludcastillayleon.es/10.1093/jnci/djx134. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/jnci/djx134.

  31. Richman J, Dowsett M. Beyond 5 years: enduring risk of recurrence in oestrogen receptor-positive breast cancer. Nat Rev Clin Oncol. 2019;16(5):296–311. https://doiorg.publicaciones.saludcastillayleon.es/10.1038/s41571-018-0145-5.

    Article  CAS  PubMed  Google Scholar 

  32. Barron TI, Connolly R, Bennett K, et al. Early discontinuation of tamoxifen: a lesson for oncologists. Cancer: Interdisciplinary Int J Am Cancer Soc. 2007;109(5):832–839. https://doiorg.publicaciones.saludcastillayleon.es/10.1002/cncr.22485.

  33. Chlebowski RT, Geller ML. Adherence to endocrine therapy for breast cancer[J]. Oncology. 2006;71(1–2):1–9.

    Article  CAS  PubMed  Google Scholar 

  34. Goldvaser H, Barnes T A, Šeruga B, et al. Toxicity of extended adjuvant therapy with aromatase inhibitors in early breast cancer: a systematic review and meta-analysis. JNCI: J Natl Cancer Instit. 2018, 110(1): 31–39. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/jnci/djx141.

  35. Goss PE, Ingle JN, Pritchard KI, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years[J]. N Engl J Med. 2016;375:209–19. https://doiorg.publicaciones.saludcastillayleon.es/10.1056/NEJMoa1604700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cuzick J, Sestak I, Forbes JF, Dowsett M, Cawthorn S, Mansel RE, Loibl S, Bonanni B, Evans DG, Howell A, IBIS-II investigators,. Use of anastrozole for breast cancer prevention (IBIS-II): long-term results of a randomised controlled trial. Lancet (London, England). 2020;395(10218):117–22. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/S0140-6736(19)32955-1.

    Article  CAS  PubMed  Google Scholar 

  37. Stearns V, Chapman JA, Ma CX, et al. Treatment-associated musculoskeletal and vasomotor symptoms and relapse-free survival in the NCIC CTG MA.27 adjuvant breast cancer aromatase inhibitor trial. J Clin Oncol. 2015;33(3):265–271. https://doiorg.publicaciones.saludcastillayleon.es/10.1200/JCO.2014.57.6926.

  38. Villarreal-Garza C, Mesa-Chavez F, Ferrigno AS, et al. Adjuvant endocrine therapy for premenopausal women with breast cancer: Patient adherence and physician prescribing practices in Mexico. Breast. 2021;59:8–15. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.breast.2021.05.013.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Yu S, Jiang Z, Zhang L, et al. Chinese expert consensus statement on clinical diagnosis and treatment of malignant tumor bone metastasis and bone related diseases[J]. Chin-Ger J Clin Oncol. 2010;9(1):1–12.

    Article  CAS  Google Scholar 

  40. Tella SH, Gallagher JC. Prevention and treatment of postmenopausal osteoporosis. J Steroid Biochem Mol Biol. 2014;142:155–70. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.jsbmb.2013.09.008.

    Article  CAS  PubMed  Google Scholar 

  41. Vinayak S, Davidson NE. Extending Adjuvant Endocrine Therapy in Breast Cancer: Who, What, Why? Oncology (Williston Park). 2019;33(6):243–6.

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank all researchers who contributed to this article.

Provenance and peer review

Not commissioned; externally peer reviewed.

Patient and public involvement

Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. Patient consent for publication Not applicable.

Funding

This study was funded by the National Natural Science Foundation of China (Award No.: 82060485), the Applied Basic Research Fund Project of Qinghai Provincial Science and Technology Department (2019ZJ-7091), and the General Research Fund Project for Young and Middle-aged People in the Affiliated Hospital of Qinghai University (ASRF-2022-YB-12).

Author information

Author notes

  1. Zhang Ying and Liu Linxun contributed equally to this work.

Authors and Affiliations

  1. Department of General Surgery, Qinghai Provincial People’s Hospital, Xining, 810000, China

    Zhang Ying, Liu Linxun & Zhao kechang

  2. Department of Tumor Surgery, Affiliated Hospital of Qinghai University, Xining, 810000, China

    Wang Xiaowu, Gengzhi Huazhen & Ma Zhijun

Authors
  1. Zhang Ying
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Liu Linxun
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Zhao kechang
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Wang Xiaowu
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Gengzhi Huazhen
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Ma Zhijun
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

ZY contributed to selecting research directions and completing the manuscript, LLX conducted data statistics, ZKC conducted an electronic database search. GGHZ evaluated the evidence level, WXW established the inclusion and exclusion criteria, MZJ checked and edited manuscripts. The author(s) read and approved the final manuscript.

Corresponding authors

Correspondence to Zhang Ying or Ma Zhijun.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ying, Z., Linxun, L., kechang, Z. et al. Optimal extension time after initial endocrine therapy for postmenopausal hormone receptor-positive early-stage breast cancer: a systematic review and meta-analysis. BMC Women's Health 25, 156 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12905-025-03610-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12905-025-03610-9

Keywords

BMC Women's Health

ISSN: 1472-6874

Contact us