Research Papers:

Clinical significance of monitoring ESR1 mutations in circulating cell-free DNA in estrogen receptor positive breast cancer patients

Takashi Takeshita, Yutaka Yamamoto, Mutsuko Yamamoto-Ibusuki, Toko Inao, Aiko Sueta, Saori Fujiwara, Yoko Omoto and Hirotaka Iwase _

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Oncotarget. 2016; 7:32504-32518. https://doi.org/10.18632/oncotarget.8839

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Takashi Takeshita1, Yutaka Yamamoto1, Mutsuko Yamamoto-Ibusuki2, Toko Inao1, Aiko Sueta1, Saori Fujiwara1, Yoko Omoto1,3, Hirotaka Iwase1

1Department of Breast and Endocrine Surgery, Graduate School of Medical Science, Kumamoto University, Chuo-ku, Kumamoto, 860–8556, Japan

2Department of Molecular-Targeting Therapy for Breast Cancer, Kumamoto University Hospital, Chuo-ku, Kumamoto, 860–8556, Japan

3Department of Endocrine and Breast Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Hirokoji Agaru, Kawaramachi-dori, Kamigyo-ku, Kyoto, 602–0841, Japan

Correspondence to:

Hirotaka Iwase, email: [email protected]

Keywords: estrogen receptor-positive metastatic breast cancer, acquired endocrine therapy resistance, cell-free DNA ESR1 mutations in plasma, droplet digital PCR

Received: January 11, 2016     Accepted: March 14, 2016     Published: April 19, 2016


Background: The measurement of circulating cell-free DNA (cfDNA) may transform the management of breast cancer patients. We aimed to investigate the clinical significance of sequential measurements of ESR1 mutations in primary breast cancer (PBC) and metastatic breast cancer (MBC) patients.

Results: ESR1 mutations ratio in the PBC groups was used as the minimum cutoff for determining increases in cfDNA ESR1 mutation ratio. An increase in cfDNA ESR1 mutations was found in 13 samples of cfDNA from 12 (28.6%) out of 42 MBC patients. A total of 10 (83.3%) out of 12 MBC patients with increase cfDNA ESR1 mutations showed a poor response to treatment. In survival analysis, increase cfDNA ESR1 mutations may predict a shorter duration of post-endocrine-therapy effectiveness (P = 0.0033).

Methods: A total of 119 patients (253 plasma samples) with breast carcinoma were enrolled in this study. Cases were selected if archival plasma samples were available from PBC before and after treatment and from MBC gathered more than twice at the time of progression. cfDNA was isolated from the 77 PBC patients (154 plasma samples) and from the 42 MBC patients (99 plasma samples). To investigate any changes in each cfDNA ESR1 mutation before and after treatment, we analyzed the difference with cfDNA ESR1 mutations ratio in the first blood sample using droplet digital polymerase chain reaction (ddPCR).

Conclusions: We demonstrate that ddPCR monitoring of the recurrent ESR1 mutation in cfDNA of MBC patients is a feasible and useful method of providing relevant predictive information.

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