The prevalence of ESR1 mutations in patients with metastatic hormone receptor (HR)-positive/ HER2-negative breast cancer is influenced by the duration and setting of prior endocrine therapy. This study utilized real-world data to investigate whether prolonged exposure to endocrine therapy in the metastatic setting, with or without cyclin-dependent kinase (CDK)4/6 inhibitors, increases the likelihood of acquiring ESR1 mutations.
Patients were identified from the IntegraConnect PrecisionQ de-identified database, which includes clinical data for adults with estrogen receptor (ER)-positive/HER2-negative metastatic breast cancer. Manual chart curation was used to include patients who initiated therapy between January 1, 2023, and December 31, 2024, following endocrine therapy in the metastatic setting. Patients were stratified into 4 groups based on the duration of endocrine therapy: ≤6 months, 6 to <12 months, 12 to <18 months, and ≥18 months. ESR1 mutation testing was assessed within 60 days prior to the start of the first or second line of therapy post–endocrine therapy. Endocrine therapy regimens included aromatase inhibitors, CDK4/6 inhibitors, selective ER modulators, or selective ER degraders. Descriptive statistics were used to calculate the proportion of patients with ESR1 mutations across groups.
A total of 191 patients were included, with 98% female and 2% male, and a median age of 68 years at the initiation of the first line of therapy post–endocrine therapy. ESR1 mutation-positivity increased with longer durations of endocrine therapy: 15% (4/26) of patients treated for ≤6 months, 24% (9/37) for 6 to <12 months, 34% (12/35) for 12 to <18 months, and 30% (28/93) for ≥18 months.
This real-world study demonstrates that longer durations of endocrine therapy in the metastatic setting are associated with an increased likelihood of acquiring ESR1 mutations. These findings underscore the importance of duration of endocrine therapy as a factor in the development of ESR1 mutations, which may serve as a clinically relevant biomarker in metastatic HR-positive/HER2-negative breast cancer.
Source: Choksi R, Gorantla V, Rosenfeld S, et al. Real-world study on ESR1 positivity rate in relation to length of exposure on endocrine therapy +/- CDK4/6i. Presented at: ESMO Congress 2025. October 20, 2025; Berlin, Germany. Abstract 521P.