Real-World Analysis of ESR1 Mutation Testing and Positivity Rates in ER-Positive/HER2-Negative Metastatic Breast Cancer

As the treatment landscape for metastatic breast cancer evolves, understanding ESR1 mutation testing patterns is critical to improving outcomes for patients with estrogen receptor (ER)-positive/HER2-negative metastatic breast cancer. Current guidelines recommend ESR1 mutation testing at disease progression to identify candidates for targeted therapies. However, real-world data on testing practices and mutation-positivity rates remain limited. A recent retrospective study analyzed ESR1 mutation testing and positivity rates among patients with ER-positive/HER2-negative metastatic breast cancer to identify gaps and opportunities for improved utilization.

This study included patients aged ≥18 years with an ER-positive/HER2-negative metastatic breast cancer diagnosis who initiated 1L therapy with aromatase inhibitors or SERDs with or without CDK4/6 inhibitors from January 2020 to December 2024. The Flatiron Health Research Database was used to estimate ESR1 mutation-positivity rates in windows defined as follows: (1) an initial early breast cancer diagnosis date or 90 days before a de novo metastatic breast cancer diagnosis to last patient contact, (2) a metastatic breast cancer diagnosis date to 1L initiation date plus 28 days, (3) during line of therapy ([LoT]; start date to end date), and (4) at LoT initiation (90 days before to 28 days after LoT initiation).

Researchers examined 12,377 patients diagnosed with ER-positive/HER2-negative metastatic breast cancer who initiated 1L therapy. Results showed that only 49% of patients underwent ESR1 mutation testing, with most tested patients receiving a single test (mean, 1.6 tests per patient). Testing rates remained low, with just 20% to 36% of patients tested at each LoT initiation. Among tested patients, approximately 60% of tests used tissue-only samples; 40% used blood-only samples.

ESR1 mutation-positivity rates increased with each LoT. At 1L initiation the ESR1 mutation-positivity rate was 25% among tested patients; at 2L initiation, the ESR1 mutation-positivity rate was 32% to 34% among tested patients.

Despite advancements, 51% of patients with metastatic breast cancer remained untested, and real-world positivity rates were lower than those observed in clinical trials. These disparities may stem from the frequent reliance on tissue-based testing, which is less sensitive than blood-based circulating tumor DNA (ctDNA) testing commonly used in trials.

This study underscores an urgent need to increase ESR1 mutation testing rates, particularly using blood-based ctDNA methods, to optimize patient identification for targeted therapies. Enhancing testing practices is essential to improving treatment outcomes for patients with ER-positive/HER2-negative metastatic breast cancer, and for addressing a significant unmet need in the real-world clinical setting.

Source: Liao C, Bansal N, John J, et al. Real-world ESR1 mutation (ESR1m) testing and positivity rates in patients with ER+, HER2- metastatic breast cancer (MBC). Presented at: San Antonio Breast Cancer Symposium 2025. December 10, 2025; San Antonio, TX. Presentation PS1-12-08.