Serial analysis of ESR1 mutations in cell-free DNA from hormone receptor-positive, HER2-negative metastatic breast cancer during palliative endocrine therapy

Background Activating mutations in ESR1 gene are a known mechanism of endocrine resistance. We analyzed ESR1 mutations in cell-free DNA (cfDNA) from serially collected blood from hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer patients to investigate their impact on outcomes. Methods A total of 268 cfDNA samples serially collected from 25 patients who underwent palliative endocrine therapy were examined. Seven ESR1 hotspot mutations were tested in cfDNA using droplet digital polymerase chain reaction. Progression-free survival (PFS) was analyzed using the Kaplan–Meier method. Blood ESR1 mutation (b ESR1 ) results were correlated with clinical response. Results Among 25 patients, baseline b ESR1 mutation was negative for all patients (0/4) and 64.0% (16/25) was b ESR1 -positive at any time. b ESR1 positivity did not affect PFS. Those whose b ESR1 cleared in subsequent cfDNA exhibited longer PFS. Among patients with clinical progression, 57.1% (8/14) were b ESR1 -positive, and four had b ESR1 detected before clinical progression. Conclusions We observed worse outcomes in patients with persistent b ESR1 detection during first-line endocrine therapy and then sustained positive. b ESR1 was detected prior to clinical progression in half of patients. Our study suggests the benefit of b ESR1 monitoring during palliative endocrine therapy.