Importance There is a need for biomarkers that predict late recurrence risk and extended endocrine therapy (EET) benefit among patients with early-stage breast cancer (EBC). MammaPrint, a 70-gene expression risk-of-recurrence assay, has been found to project significant EET benefit in patients with assay-classified low-risk tumors. Objective To determine the test’s utility in identifying which patients with EBC in the IDEAL (Investigation on the Duration of Extended Adjuvant Letrozole) trial could benefit from 5-year vs 2.5-year letrozole treatment. Design, Setting, and Participants This secondary analysis of the IDEAL randomized clinical trial evaluated postmenopausal women with hormone receptor–positive EBC who were assigned to either 2.5 or 5 years of EET, with 10 years of follow-up after randomization. A 70-gene assay was used to classify tumors as high, low, or ultralow risk. Adverse event (AE) frequency and treatment compliance were evaluated. Statistical analyses were performed from April 2022 to September 2024. Interventions After 5 years of endocrine therapy, patients were randomized to 2.5 or 5 years of EET with letrozole. Main Outcomes and Measures Primary end point was distant recurrence (DR). Cox proportional hazard regression models and likelihood ratios tested the interaction between treatment and gene expression assay. Results Among 515 women included (mean [SD] age at randomization, 59.9 [9.5] years), 265 were in the 2.5-year treatment arm and 250 in the 5-year treatment arm. Of these patients, 223 (43.3%) patients with 70-gene assay–classified low-risk tumors had a significant absolute benefit of 10.1% for DR (hazard ratio, 0.32; 95% CI, 0.12-0.87; P = .03). Treatment interaction was not significant for DR. Of patients with either 70-gene assay–classified high-risk tumors (259 [50.3%]) or ultralow risk tumors (33 [6.4%]), 5 years vs 2.5 years of EET was not associated with improved benefit for DR. As expected, rates of AEs and treatment discontinuation were comparable among the different 70-gene assay risk groups in each treatment arm. Conclusions and Relevance This secondary analysis of the IDEAL trial found that the 70-gene assay identified patients with low-risk tumors who could benefit from 5-year vs 2.5-year EET. These findings suggest that this gene expression assay could go beyond guiding neoadjuvant and adjuvant chemotherapy decisions to informing the optimal duration of adjuvant endocrine therapy. Trial Registration EU Clinical Trials Register Eudra CT: 2006-003958-16

Selection of Patients With Early-Stage Breast Cancer for Extended Endocrine Therapy