Related Experiment Video
Updated: May 13, 2026
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Kinetics and determinants of ESR1 mutation detection in metastatic breast cancer
L Cabel1, F Berger2, T Bachelot3
1Department of Medical Oncology, Institut Curie, Paris, France.
Background:
PADA-1 was the first prospective randomized trial to show that early therapeutic targeting of blood ESR1 mutations (bESR1-mut) with fulvestrant provides significant clinical benefit in patients with estrogen receptor α-positive/human epidermal growth factor receptor 2-negative advanced breast cancer treated with an aromatase inhibitor and palbociclib. Here, we describe the kinetics and determinants of bESR1-mut in the 1017 patients who participated in PADA-1.
Patients And Methods:
PADA-1 was an open-label, randomized, controlled, phase III trial conducted at 83 hospitals in France. Patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer were recruited and monitored by multiplex droplet digital PCR for rising bESR1-mut during first-line treatment with aromatase inhibitor and palbociclib, after one cycle and then every two cycles. Patients with newly present or increased bESR1-mut in circulating tumor DNA and no synchronous disease progression were randomly assigned to continue with the same therapy or to switch to fulvestrant and palbociclib.
Results:
Baseline bESR1-mut was detected in 3.2% of patients. Prior adjuvant treatment with aromatase inhibitor (6.8%) and lower body mass index were independently associated with a higher detection rate of bESR1-mut at baseline. Through real-time analysis of >12 500 blood samples, we observed that detection of rising bESR1-mut was not linear over time, occurring more frequently after 6 months and before 3 years of treatment. We found that high estrogen receptor expression, the presence of bone metastases, younger age, and lactate dehydrogenase elevation were associated with a higher rate of rising bESR1-mut detection. Finally, updated survival results of PADA-1 substantiate the clinical benefit of intercepting bESR1-mut emergence before clinical progression, with improved progression-free survival (PFS), hazard ratio 0.54, 95% confidence interval 0.38-0.75, and progression-free survival 2, hazard ratio 0.35, 95% confidence interval 0.22-0.54.
Conclusion:
We identified factors associated with the detection of bESR1-mut at baseline and during treatment that could help identify patients who may benefit from ESR1-targeted therapies.
