Outcomes of Anastrozole, Letrozole, and Exemestane in Patients With Postmenopausal Breast Cancer.

Importance: Third-generation aromatase inhibitors (AIs)-anastrozole, letrozole, and exemestane-are standard adjuvant endocrine therapy for women with postmenopausal hormone receptor (HR)-positive early-stage breast cancer. However, little is known about their comparative effectiveness in clinical settings. Objective: To compare adjuvant anastrozole, letrozole, and exemestane in terms of disease-free survival (DFS) and overall survival (OS) in women with postmenopausal HR-positive early-stage breast cancer. Design, Setting, and Participants: This comparative effectiveness study conducted in France emulated a target trial using national medicoadministrative data. The patient cohort was derived from the updated French Early Breast Cancer Cohort and consisted of women aged 50 to 75 years with early-stage breast cancer who were diagnosed between January 1, 2011, and December 31, 2020, and followed up through December 31, 2021. All women initiated adjuvant AI therapy without ovarian suppression. Data analysis was performed from November 2024 to May 2025. Exposures: Upfront adjuvant anastrozole, letrozole, and exemestane, evaluated under natural persistence and under a hypothetical intervention ensuring perfect persistence for 5 years. Main Outcomes and Measures: The primary end points were DFS and OS. Both DFS and OS were estimated using adjusted Kaplan-Meier curves. Results: Among 148 436 women (median [IQR] age, 64 [59-69] years) included in the analyses, 38.5% initiated anastrozole, 52.9% initiated letrozole, and 8.5% initiated exemestane. After a median (IQR) follow-up of 63 (34-94) months, the 8-year DFS under natural persistence was estimated to be lower for the exemestane group (79.1%; 95% CI, 78.1%-80.0%) compared with the anastrozole (81.0%; 95% CI, 80.6%-81.5%) and letrozole (81.1%; 95% CI, 80.7%-81.5%) groups. Similarly, the 8-year OS was 88.8% (95% CI, 88.0%-89.6%) for the exemestane group compared with 90.5% (95% CI, 90.2%-90.8%) for the anastrozole group and 89.9% (95% CI, 89.6%-90.2%) for the letrozole group. Patients who initiated exemestane were also more likely to discontinue treatment within 5 years of therapy than their counterparts taking the other AIs (39.3% [95% CI, 38.3%-40.3%] in the exemestane group vs 35.1% [95% CI, 34.7%-35.6%] in the anastrozole group and 35.0% [95% CI, 34.6%-35.4%] in the letrozole group). However, the lower DFS and OS observed for exemestane compared with letrozole and anastrozole persisted under perfect persistence. Conclusions and Relevance: The findings of this comparative effectiveness study using a target trial emulation framework suggest that adjuvant endocrine therapy with exemestane may result in slightly lower DFS and OS compared with anastrozole and letrozole in patients with postmenopausal HR-positive early-stage breast cancer. The findings favor anastrozole or letrozole as initial treatment and highlight the need for future studies to inform AI selection.