To investigate the clinicogenomic characteristics, post-ESR1 alteration treatment patterns and prognostic factors for progression-free survival (PFS) in patients with ESR1-altered advanced breast cancer in a real-world cohort.

From January 2019 to January 2025, the clinicopathological and molecular data were retrospectively collected from patients with ESR1 alterations (including point mutations, amplifications, rearrangements and other ESR1-related abnormalities) in advanced breast cancer. Variables included age, disease-free survival (DFS), recurrence status, metastasis site, prior CDK4/6 inhibitor exposure (duration and lines of therapy), PIK3CA/TP53 co-mutations, tumor mutation burden (TMB) and post-ESR1 alteration treatment groups. Kaplan-Meier analysis was used to estimate PFS. Univariate and multivariable Cox proportional hazards models were used to identify variables associated with PFS exploratively.

A total of 36 patients were included in the analysis. The median real-world progression-free survival (rwPFS) was 9.0 months (95% CI: 4.0-12.0 months). In the univariate Cox regression, prior CDK4/6 inhibitor exposure was associated with shorter PFS (HR=2.47, 95% CI: 1.12-5.44, P=0.025), and bone metastasis showed a borderline association with shorter PFS (HR=1.88, 95% CI: 0.90-3.97, P=0.095). In the exploratory multivariate model, bone metastasis (adjusted HR=2.35, 95% CI: 1.08-5.11, P=0.030) and prior CDK4/6 inhibitor exposure (adjusted HR=3.11, 95% CI: 1.35-7.14, P=0.008) were associated with shorter PFS. No significant difference was observed among treatment groups (log-rank P=0.584).

ESR1-altered advanced breast cancer shows substantial clinical and molecular heterogeneity. This study suggests that bone metastasis and prior CDK4/6 inhibitor exposure may be associated with shorter PFS after detection of ESR1 alterations. The subsequent treatment strategy needs to be comprehensively judged in combination with transfer burden, prior treatment exposure and molecular features.