Background
As the metastatic breast cancer treatment landscape evolves, understanding biomarker testing patterns is essential to identify patients for targeted therapies. Despite existing guidelines recommending testing of patients with metastatic breast cancer at progression for ESR1 mutation, real-world data on testing and mutation rates are limited. Herein, we described ESR1 mutation andtesting rates in patients with estrogen receptor–positive (ER+)/HER2-negative (HER2–) metastatic breast cancer to identify opportunities for improved ESR1 mutation test utilization.
Methods
This retrospective, observational study included patients 18 years or older at ER+/HER2– metastatic breast cancer diagnosis who initiated first-line therapy with aromatase inhibitors (AI) or selective estrogen receptor degraders with or without CDK4/6 inhibitors (CDK4/6i) from January 1, 2020, to March 31, 2025. The Flatiron Health Research Database was used to estimate ESR1 mutation rates in windows defined as: A) initial early breast cancer diagnosis date or 90 days before de novo metastatic breast cancer diagnosis to last patient contact, B) metastatic breast cancer diagnosis date to first-line initiation date plus 28 days, C) during line of therapy (LoT), and D) at LoT initiation (90 days before; 28 days after).
Results
Of 12,377 patients, 49% (n = 6099) had 1 or more ESR1 test, with 61% (n = 3768/6099) tested only once (mean:1.6 test/patient). At each LoT initiation, between 20% to 36% of patients received an ESR1 test. Among patients with de novo metastatic breast cancer, testing rates at second-line and third-line initiation were approximately 29%. The testing rate at first-line initiation was 36% for endocrine resistant patients, defined as those who had early breast cancer with disease progression while on adjuvant AI with or without CDK4/6i or 12 months or less after completion. Post-2023 testing rates were often higher than pre-2023, especially at first-line (33% vs 20%) and second-line initiation (37% vs 27%). Of patients with data on type of test sample (n = 2028), approximately 60% were in tissue only and approximately 40% were in blood only. ESR1 mutation rate increased with each LoT. At first-line initiation, the ESR1 mutation rate was 25% among endocrine resistant metastatic breast cancer. At second-line initiation, ESR1 mutation rates were 32% to 34% among all patients.
Conclusion
Among all patients with metastatic breast cancer, 51% were never tested and only 34% to 36% were tested at first-line and second-line initiation after 2023. Importantly, lower rates of ESR1 mutation were observed in the real-world compared to clinical trials. This may be due to suboptimal test timing, poor patient identification for testing, and frequent use of tissue-based testing, which is less sensitive than the recommended blood-based ctDNA used in clinical trials. These results highlight an unmet need for increased ESR1 mutation testing using blood-based ctDNA to optimize patient identification for targeted therapies in ER+/HER2– metastatic breast cancer.
Previously presented at SABCS 2025. Study is sponsored by Eli Lilly and Company.
