Efficacy and toxicity of extended aromatase inhibitors after adjuvant aromatase inhibitors-containing therapy for hormone-receptor-positive breast cancer: a literature-based meta-analysis of randomized trials

  • Xiaoying Qian
  • Zhian Li
  • GuoDong Ruan
  • Chuanjian Tu
  • Wu DingEmail author



Endocrine therapy with aromatase inhibitors (AIs) is the cornerstone of adjuvant systemic treatment for postmenopausal patients with hormone receptor-positive breast cancer. It has become clear that hormone receptor-positive breast cancer carries a consistent risk of relapse up to 15 years after diagnosis. Extended duration of adjuvant AIs therapy after completing initial standard adjuvant AIs-containing therapy may prevent late recurrence and death. We performed a meta-analysis to assess the real impact of the extended adjuvant therapy with AIs.


A literature-based meta-analysis of the randomized controlled trials (RCTs) was undertaken. Relevant publications from PubMed, Embase, Cochrane Library, and abstracts from American Society of Clinical Oncology (ASCO) and San Antonio Breast Cancer (SABCS) symposia were searched. The endpoints were disease-free survival (DFS), overall survival (OS), local recurrence, distant recurrence, contralateral breast cancer, non-breast cancer-related death, and toxicity.


Eight trials comprising 15,966 patients met the inclusion criteria. The pooled analysis revealed a significant improvement in DFS (RR = 0.79; 95% CI 0.68–0.91), distant recurrence (RR = 0.75; 95% CI 0.58–0.96), and contralateral breast cancer (RR = 0.53; 95% CI 0.40–0.70) in the extended AIs group. While there was not significant improvement in OS (RR = 1.00, 95% CI 0.99–1.01), non-breast cancer-related death (RR = 1.16, 95% CI 0.96–1.41), and local recurrence (RR = 0.82; 95% CI 0.64–1.06), the subgroup analysis showed that the patient with tumor size > 2 cm (HR = 0.74, RD = − 0.31, P = 0.05 vs. HR = 0.85, RD = − 0.16, P = 0.20), node positive status (HR = 0.77, RD = − 0.27, P = < 0.0001 vs. HR = 0.89, RD = −0.12, P = 0.19) and previous chemotherapy use (HR = 0.75, RD = − 0.29, P = 0.003 vs. HR = 0.91, RD = −0.10, P = 0.44) would get a greater DFS benefit with extended AIs. Longer treatment with AIs was associated with an increased risk ratio of bone pain (RR = 1.26, RD = 0.04, P = 0.003), bone fractures (RR = 1.59, RD = 0.02, P = 0.002), osteoporosis (RR = 1.53, RD = 0.07, P = 0.005), myalgia (RR = 1.26, RD = 0.04, P = 0.02), and treatment discontinuation for adverse events (RR = 1.51, RD = 0.06, P = 0.0009).


After initial standard AIs-containing adjuvant therapy, extended AIs therapy could further bring a DFS benefit for postmenopausal patients with early breast cancer, especially in the patients with high-risk characteristics.


Breast cancer Hormone-positive Adjuvant endocrine therapy Aromatase inhibitors Extended adjuvant AIs therapy 



Randomized controlled trials


American Society of Clinical Oncology


San Antonio Breast Cancer


Risk ratio


Hazard ratio


Risk difference


Confidence intervals


Estrogen receptor


Progesterone receptor

Node positive or negative


Disease-free survival


Overall survival


Local recurrence


Distant recurrence


Contralateral breast cancer


Non-breast cancer-related death








Aromatase inhibitors


Ovarian function suppression











We thank Luping chen for her support and guidance throughout the project.

Author contributions

W Ding designed the study and developed the analysis plan. W Ding and X.Y. Qian analyzed the data and performed meta-analysis. Z.A. Li and X.Y. Qian assessed the risk of bias. X.Y. Qian contributed in writing of the article. C.J. Tu and G.D. Ruanuan revised the manuscript and polished the language.


Not applicable.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors. Ethical approval was not applicable for this systematic review and meta-analysis.

Informed consent

Informed consent was obtained from all individual participants included in the study.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Oncological SurgeryShaoxing Second HospitalShaoxingChina
  2. 2.Department of SurgeryShaoxing Keqiao Women & Children’s HospitalShaoxingChina

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