ESR1 Mutations Emerge Early in HR+/HER2- mBC, PADA-1 Finds

Approximately 40% of patients with hormone receptor–positive, HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) treated with first-line aromatase inhibitors (AIs) and palbociclib developed rising blood ESR1 mutations (bESR1 ^mut), according to new data presented by François Clément Bidard, MD, at the European Society for Medical Oncology (ESMO) Breast Cancer 2025 Annual Meeting.

The findings, drawn from the prospective PADA-1 trial, offer insights into the timing and risk factors associated with the emergence of ESR1 mutations during AI plus CDK4/6 inhibitor therapy. These mutations are known to drive resistance to endocrine treatment by restoring estrogen receptor alpha (ERα) activity.

The study included 1,017 patients with AI-sensitive HR+/HER2- mBC who received an AI and palbociclib as first-line therapy. Blood samples were collected at baseline, 1 month, and every 2 months thereafter and tested using droplet digital polymerase chain reaction. Patients were grouped according to whether they experienced disease progression with or without rising bESR1 ^mut. Patients without progression or mutation at data cutoff were excluded.

The cumulative incidence of bESR1^mut detection was 41.7%, with mutations rarely emerging within the first 6 months of treatment and detection rates declining after 3 years. Several baseline factors were independently associated with a higher likelihood of rising bESR1^mut, including bone metastases (odds ratio, 2.7 for bone-only disease), higher ER expression, younger age, and elevated baseline lactate dehydrogenase  levels.

“Younger (premenopausal) patients and tumors with high ER expression exhibit a higher likelihood of rising bESR1 ^mut, suggesting oncogenic addiction to ER signaling,” the authors concluded.

The results support the value of personalized circulating tumor DNA monitoring for ESR1 mutations in this setting and may help identify patients who could benefit most from next-generation selective ER degraders early in their treatment course.

Reference:

Bidard FC, et al. Kinetics and determinants of blood ESR1 mutation under AI and palbociclib in HR+/HER2- metastatic breast cancer patients in the PADA-1 trial. 2025 ESMO Breast Cancer Annual Congress. Abstract 1O. Presented at the 2025 ESMO Breast Cancer Annual Congress, May 14-17, 2025; Munich, Germany.