Extended Endocrine Therapy and Survival for Breast Cancer Subtypes in Premenopausal Patients

Importance: Premenopausal patients with node-positive, hormone receptor-positive, early breast cancer derive benefit from extended endocrine therapy (EET) following 5 years of luteinizing hormone-releasing hormone (LHRH) agonist-based treatment. The benefit of EET may differ according to surrogate breast cancer subtypes in postmenopausal patients. Objective: To evaluate the risk of invasive and distant recurrence across all surrogate breast cancer subtypes among patients with node-positive, hormone receptor-positive early breast cancer who remained premenopausal after completing 5 years of adjuvant therapy with an LHRH agonist who received and did not receive EET. Design, Setting, and Participants: This multicenter cohort study conducted in the United States and Italy used data from 2 prospectively maintained datasets: the Young Women's Breast Cancer Study and the European Institute of Oncology Breast Cancer cohort. Eligible patients were diagnosed with early breast cancer at 40 years of age or younger between January 2005 and December 2016, had node-positive hormone receptor-positive disease, and remained premenopausal after 5 years of adjuvant LHRH agonist therapy with no evidence of recurrence. Median (IQR) follow-up was 7.3 (4.9-10.3) years. Data were analyzed June 2025. Exposure: EET (with tamoxifen monotherapy, LHRH agonist plus tamoxifen, or LHRH agonist plus aromatase inhibitor), irrespective of the duration of EET, measured at study baseline (defined as the first day of the sixth year after the initiation of adjuvant ET). Main Outcomes and Measures: Invasive breast cancer-free survival and distant recurrence-free survival (DRFS) distributions were estimated using the adjusted Kaplan-Meier method among patients with or without the exposure, weighted through propensity score (PS) weighting analysis, with the scientific approach. Results: In total, 487 patients were included (median IQR age at diagnosis, 37 35-39 years in the EET group and 37 33-39 years in the no EET group), and 276 received EET for a median (IQR) duration of 3.7 (2.2-5.0) years. Overall, 89 patients (18%) had luminal A-like disease, 298 (61%) had luminal B-like disease, and 100 (21%) had ERBB2 (formerly HER2)-positive disease. The PS-weighted hazard ratio (HR) for invasive breast cancer-free survival comparing the EET with the no EET group was 0.68 (95% CI, 0.32-1.45) in luminal A-like, 0.63 (95% CI, 0.40-1.00) in luminal B-like/ERBB2-negative, and 0.62 (95% CI, 0.21-1.87) in ERBB2-positive subgroups. The cause-specific PS-weighted HR for DRFS was 0.25 (95% CI, 0.08-0.75) in luminal A-like, 0.54 (95% CI, 0.32-0.94) in luminal B-like/ERBB2-negative, and 0.54 (95% CI, 0.12-2.53) in ERBB2-positive subgroups. Conclusions and Relevance: In this cohort study, a lower estimated risk with EET use was observed across all surrogate breast cancer subtypes. However, the lower estimated risk was greatest among patients with luminal A-like disease, a finding that warrants confirmation in larger, prospective cohorts.