ORIGINAL RESEARCH article
Front. Oncol.
Sec. Breast Cancer
Serial analysis of ESR1 mutations in cell-free DNA from hormone receptor-positive, HER2-negative metastatic breast cancer during palliative endocrine therapy
Provisionally accepted
Soo Yeon Baek1
Meehyang Hong2Seungah Lee2Seulgi Joo2JungPil Jang2Chinkoo Jung2Hyein Lee3
Tae-Kyung Yoo4
Il Yong Chung4
Hee Jeong Kim4
Beom Seok Ko4Jong Won Lee4Byung Ho Son4Hyehyun Jeong4
Jae Ho Jeong4Jin-Hee Ahn4Kyung Hae Jung4Sung-Bae Kim4Hee Jin Lee4
Gyungyub Gong4Sae Byul Lee4*
Jisun Kim4*- 1Ajou University School of Medicine, Suwon-si, Republic of Korea
- 2Genopeaks Co., Ltd., Seoul, Republic of Korea
- 3Asan Medical Center Asan Institute for Life Sciences, Songpa-gu, Republic of Korea
- 4Asan Medical Center, Songpa-gu, Republic of Korea
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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 (bESR1) results were correlated with clinical response. Results: Among 25 patients, baseline bESR1 mutation was negative for all patients (0/4) and 64.0% (16/25) was bESR1-positive at any time. bESR1 positivity did not affect PFS. Those whose bESR1 cleared in subsequent cfDNA exhibited longer PFS. Among patients with clinical progression, 57.1% (8/14) were bESR1-positive, and four had bESR1 detected before clinical progression. Conclusions: We observed worse outcomes in patients with persistent bESR1 detection during first-line endocrine therapy and then sustained positive. bESR1 was detected prior to clinical progression in half of patients. Our study suggests the benefit of bESR1 monitoring during palliative endocrine therapy.
Keywords: breast cancer, cell-free DNA, circulating tumor DNA, Endocrine therapy, ESR1 mutation
Received: 20 Sep 2025; Accepted: 09 Dec 2025.
Copyright: © 2025 Baek, Hong, Lee, Joo, Jang, Jung, Lee, Yoo, Chung, Kim, Ko, Lee, Son, Jeong, Jeong, Ahn, Jung, Kim, Lee, Gong, Lee and Kim. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Sae Byul Lee
Jisun Kim
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