Extended adjuvant endocrine therapy in early breast cancer: finding the individual balance

Abstract

Endocrine therapy (ET) is a cornerstone in the management of patients with hormone receptor-positive early breast cancer, which accounts for over 70% of cases worldwide. The efficacy of adjuvant ET for 5 years in reducing the risk of recurrence and improving survival outcomes is well documented. However, the risk for late relapses, occurring >5 years after initial treatment, has prompted exploration of longer treatment durations. Extending ET beyond the traditional 5-year period offers additional benefit in reducing the risk of recurrence and improving long-term outcomes. Nevertheless, determining the optimal duration and identifying suitable candidates for extended therapy is often nuanced. This review aims to comprehensively evaluate the current landscape of extended ET in breast cancer management. It provides an overview of the rationale behind extending endocrine treatment in both premenopausal and postmenopausal women, with a focus on clinical trials and observational studies supporting extended therapy. Furthermore, it emphasizes the significance of considering associated toxicities in patient management. It also explores novel strategies involving the combination of ET with new drugs, leading to an evolution of treatment paradigms that may make the need for extended therapy obsolete.

Keywords: adjuvant; breast cancer; early setting; extended endocrine therapy; hormone receptor-positive; predictive tools.

Figure 1

Summary of recommendations for adjuvant endocrine therapy for hormone receptor-positive/HER2-negative breast cancer. AI, aromatase inhibitor; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; ET, endocrine therapy; OFS, ovarian function suppression; PARPi, poly (ADP-ribose) polymerase inhibitor; Tam, tamoxifen. ^aHigher-risk characteristics include intermediate to high-grade or higher-risk genomic signature, lower ER expression, higher baseline Ki67, or lack of decline in Ki67 with preoperative ET. ^bHigh-risk criteria defined according to the inclusion criteria of the monarchE, NATALEE, and OlympiA trials—for more complete information, please refer to Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2025.105057. Created with BioRender.com.

Figure 2

Summary of extended adjuvant endocrine therapy trials for hormone receptor-positive/HER2-negative breast cancer. The solid fill background represents the period before trial randomization. The pills are colour-coded as follows: orange for tamoxifen, blue for AI, and yellow for any ET before randomization. For more detailed information on the clinical trials design and results, please consult Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2025.105057. AI, aromatase inhibitor; CI, confidence interval; CT, chemotherapy; DFS, disease-free survival; ET, endocrine therapy; Exe, exemestane; HR, hazard ratio; N+, node positive disease; NR, not reported; OS, overall survival; Tam, tamoxifen. ^aThe trials of extended tamoxifen therapy showed a time-dependent HR. After 10 years (i.e. 5 years after random assignment), the HR was 0.75 for DFS, but it was lower in earlier years of follow-up. ^bAdjusted Cox models for unbalanced demographic and disease characteristics. ^cStarting 3 years after randomization.

Figure 3

Toxicity of standard duration of ET versus extended ET. AI, aromatase inhibitor; EET, extended endocrine therapy; Tam, tamoxifen. Created with BioRender.com.