Adjuvant endocrine treatment strategies for non-metastatic breast cancer: a network meta-analysis

Abstract

Background: Multiple trials have evaluated escalation strategies of endocrine therapy for early breast cancer, including ovarian function suppression (OFS) and aromatase inhibitors (AI) in premenopausal patients and extended endocrine therapy. However, several aspects remain controversial due to the heterogeneity of study designs and lack of statistical power in relevant subgroups. We aimed to investigate the optimal endocrine therapy strategy.

Methods: A systematic literature search was performed and last updated in August 2024 to identify randomized controlled trials (RCT) evaluating endocrine treatment strategies for hormone receptor positive breast cancer. A network meta-analysis with a frequentist framework using random-effects model was used to pool direct and indirect evidence. In addition, an extracted individual patient data meta-analysis was conducted to estimate the absolute differences between treatments. Study endpoints were disease-free survival (DFS), overall survival (OS), and safety. PROSPERO: CRD42023447979.

Findings: A total of 37 RCT that had enrolled 107,684 patients were included in the study. During the first five years, OFS + AI was the most effective strategy in premenopausal women, while AI or switch strategy showed the better efficacy results in postmenopausal ones. Following five years of tamoxifen, continuation with five additional years of AI was associated with improved 8-year DFS (85.8%) compared to no extended therapy (78.1%) or five additional years of tamoxifen (81.0%). Following five years of AI or switch strategy, extended treatment with AI improved DFS (Hazard Ratio = 0.81, 95% Confidence Interval 0.73-0.90).

Interpretation: This study provides information regarding the optimal endocrine treatment strategies for patients with resected hormone receptor positive early breast cancer.

Funding: None.

Keywords: Aromatase inhibitor; Breast cancer; Endocrine treatment; Estrogen receptor; Tamoxifen.

Fig. 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of search results. For more information, visit: http://www.prisma-statement.org/.

Fig. 2

Network graph of adjuvant endocrine therapy strategies in early breast cancer. The lines connect treatments that have been compared head-to-head, and the width of lines is proportional to the number of studies that evaluated this pairwise comparison. A) Premenopausal patients, first five years. B) Postmenopausal patients, first five years. C) Extended endocrine therapy after five years of tamoxifen. D) Extended endocrine therapy after five years of aromatase inhibitors or switch strategy. E) Addition of molecularly targeted agents. Abbreviations: OFS: ovarian function suppression; AI: aromatase inhibitor; CDK4/6i: cyclin dependent kinases 4/6 inhibitor; mTORi: mammalian target of rapamycin inhibitor.

Fig. 3

Comparison of treatment strategies during the first five postoperative years. Trial-level network meta-analysis for the disease-free survival endpoint in A) premenopausal and B) postmenopausal patients. Kaplan–Meier curves for disease-free survival, generated with extracted individual patient data, comparing C) three treatment strategies, Tamoxifen, OFS + Tamoxifen and OFS + AI in premenopausal women, and D) three treatment strategies, tamoxifen, aromatase inhibitors or switch strategy in postmenopausal women. Abbreviations: OFS: ovarian function suppression; AI: aromatase inhibitors; N: nodal status; DFS: disease-free survival; HR: hazard ratio; CI: confidence interval.

Fig. 4

Comparison of treatment strategies following five years of tamoxifen. A) trial-level network meta-analysis. Disease-free and overall survival are represented by means of hazard ratios. The hazard ratios for comparisons are in the cell in common between the column and row treatment, a hazard ratio lower than 1 favor column-defining treatment. The statistically significant comparisons are represented in color. B) Kaplan–Meier curves for disease-free survival, generated with extracted individual patient data, comparing three treatment strategies of no extended therapy, additional five years of tamoxifen and additional five years of aromatase inhibitors. Abbreviations: DFS: disease-free survival; TAM: tamoxifen; AI: aromatase inhibitor; HR: hazard ratio; CI: confidence interval.

Fig. 5

Comparison of treatment strategies following five years of aromatase inhibitor or switch strategy. A) trial-level network meta-analysis. Comparisons in terms of disease-free survival in entire population (A1) and according to nodal status (A2), progesterone receptor status (A3), receipt of (neo)adjuvant chemotherapy (A4), and type of prior endocrine treatment (A5). B) Kaplan–Meier curves for disease-free survival, generated with extracted individual patient data, comparing three treatment strategies of no extended therapy, additional two to three years and additional five years of aromatase inhibitors. Abbreviations: DFS: disease-free survival; TAM: tamoxifen; AI: aromatase inhibitor; HR: hazard ratio; CI: confidence interval; PR: progesterone receptor.