On August 18, 2025, a pivotal patient-level meta-analysis was published in The Lancet, detailing research by Braybrooke et al. under the auspices of the Early Breast Cancer Trialists’ Collaborative Group. This study focused on the implications of extending aromatase inhibitor therapy (AIT) for women with early-stage estrogen receptor–positive breast cancer who’ve already completed five years of endocrine treatment. The findings indicate a noteworthy decrease in the risk of recurrence and distant recurrence, despite significant nonadherence observed among participants.
Study Overview
The analysis included a comprehensive dataset derived from 22,031 women enrolled in 12 randomized trials that explored the efficacy of extended AIT compared to the cessation of further endocrine therapy. The patient cohort had all undergone a minimum of five years of tamoxifen, AIT, or a combination of tamoxifen followed by AIT.
Key Findings
The results demonstrated that women receiving continued AIT experienced a significant drop in recurrence rates, with a relative risk (RR) of 0.73 (95% confidence interval [CI] = 0.67–0.80, P < .0001). Notably, the reduction in recurrence was more pronounced for those who had used tamoxifen alone prior to AIT than for those who had previously received AIT.
For individuals who had previously undergone some AIT, the assignment to five additional years of treatment was linked to lower risks of both recurrence (RR = 0.71, 95% CI = 0.61–0.81, P < .0001; with an observed risk from years 5 to 15 post-diagnosis of 11.6% vs 15.2%) and distant recurrence (RR = 0.73, 95% CI = 0.61–0.88, P = .0010; risk during the same interval being 6.6% vs 8.6%). A non-significant observation was made regarding breast cancer mortality (RR = 0.90, 95% CI = 0.70–1.15, P = .40; 4.4% vs 5.0%). It is noteworthy that the absolute reduction in recurrence from extending AIT to ten years was higher in node-positive patients (16.3% vs 20.1%) compared to those with node-negative disease (9.1% vs 11.8%).
Side Effects and Adherence
Despite the benefits observed, extending AIT for an additional five years was associated with an increased risk of bone fractures over five years (RR = 1.35, 95% CI = 1.13–1.61, P = .0009; 4.6% vs 3.4%). Furthermore, the study highlighted a considerable rate of nonadherence to the assigned treatment, with nonadherence recorded at 39.0% for AIT compared to 37.6% for placebo among the placebo-controlled trials.
Conclusions
The study concludes that “allocation to 5 further years of AIT reduced subsequent distant recurrence rates by about a quarter despite substantial nonadherence. Longer follow-up would have been needed to help assess directly any effects on mortality.” This significant body of evidence reframes the ongoing discourse around the long-term treatment of estrogen receptor-positive breast cancer, underscoring both risks and potential benefits.
Disclosure: Research funding was provided by Cancer Research UK and the Breast Cancer Research Foundation. For full disclosures of all authors, please visit The Lancet.
