Research Papers:

Analysis of ESR1 and PIK3CA mutations in plasma cell-free DNA from ER-positive breast cancer patients

Takashi Takeshita, Yutaka Yamamoto, Mutsuko Yamamoto-Ibusuki, Mai Tomiguchi, Aiko Sueta, Keiichi Murakami, Yoko Omoto and Hirotaka Iwase _

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Oncotarget. 2017; 8:52142-52155. https://doi.org/10.18632/oncotarget.18479

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Takashi Takeshita1, Yutaka Yamamoto1, Mutsuko Yamamoto-Ibusuki2, Mai Tomiguchi1, Aiko Sueta1, Keiichi Murakami1, Yoko Omoto1,3 and Hirotaka Iwase1

1 Department of Breast and Endocrine Surgery, Graduate School of Medical Science, Kumamoto University, Honjo, Chuo-Ku, Kumamoto, Japan

2 Department of Molecular-Targeting Therapy for Breast Cancer, Kumamoto University Hospital, Honjo, Chuo-Ku, Kumamoto, Japan

3 Department of Endocrinological and Breast Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Hirokoji Agaru, Kawaramachi-Dori, Kamigyo-Ku, Kyoto, Japan

Correspondence to:

Hirotaka Iwase, email:

Keywords: estrogen receptor-positive metastatic breast cancer, acquired endocrine therapy resistance, cell-free DNA, ESR1 mutations, PIK3CA mutations

Received: April 27, 2017 Accepted: May 23, 2017 Published: June 14, 2017


Background: The measurement of ESR1 and PIK3CA mutations in plasma cell-free DNA (cfDNA) has been studied as a non-invasive method to quickly assess and monitor endocrine therapy (ET) resistant metastatic breast cancer (MBC) patients.

Methods: The subjects of this retrospective study were a total of 185 plasma samples from 86 estrogen receptor-positive BC patients, of which 151 plasma samples were from 69 MBC patients and 34 plasma samples were from 17 primary BC (PBC) patients. We developed multiplex droplet digital PCR assays to verify the clinical significance of ESR1 and PIK3CA mutations both in a snapshot and serially in these patients.

Results: cfDNA ESR1 and PIK3CA mutations were found in 28.9% and 24.6 % of MBC patients, respectively. The relation between ESR1 or PIK3CA mutations and clinical features showed that ESR1 mutations occurred mostly in patients previously treated by ET, which was not the case for PIK3CA mutations. The analysis of the clinical impact of those mutations on subsequent lines of treatment for the 69 MBC patients revealed that both ESR1 and PIK3CA mutations detection were related to a shorter duration of ET effectiveness in univariate analysis but only for ESR1 mutations in multivariate analysis. The monitoring of cfDNA in a subset of 52 patients showed that loss of ESR1 mutations was related to a longer duration of response, which was not the case for PIK3CA mutations.

Conclusions: We have demonstrated the clinical significance of on-treatment ESR1 mutations both in a snapshot and serially in comparison with PIK3CA mutations.

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