BRCA1 promoter methylation in breast cancer patients is associated with response to olaparib/eribulin combination therapy

Abstract

Background

A PARP inhibitor is effective in breast cancer patients with BRCA1/2 germline mutations, and in cell lines with BRCA1 promoter methylation. However, its efficacy in breast cancer patients with BRCA1 promoter methylation is still unknown.

Methods

Biopsy samples were obtained from 32 triple-negative breast cancer (TNBC) patients treated with eribulin/olaparib combination therapy in a clinical trial (UMINID: 000009498) and analyzed for their mutations by FoundationOne CDx. DNA methylation was evaluated by quantitative methylation-specific PCR and bisulfite sequencing, and its level was adjusted for tumor cell fraction.

Results

Among 20 TNBC patients evaluable for both methylation and mutations, one (5%) and five (25%) patients had a high (> 80%) and low (30–80%) BRCA1 promoter methylation levels, respectively. One patient with a high methylation level, also having a BRCA2 mutation of unknown significance, displayed complete response. Among the 5 patients with low methylation levels, only one patient with a BRCA2 mutation of unknown significance displayed long-lasting disease control (24 weeks). Patients with a BRCA1 or BRCA2 mutation, or high BRCA1 promoter methylation showed better 6-month progression-free survival (PFS) compared with the other patients (P = 0.009).

Conclusion

Quantitative methylation analysis suggested that addition of homozygous BRCA1 promoter methylation to mutations may more accurately identify TNBC patients who would benefit from olaparib/eribulin combination therapy. (209 words)

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Acknowledgements

We would like to acknowledge the study staff, Hiroyuki Yasojima, Norikazu Masuda, Kenjiro Aogi, Masato Takahashi, Yoichi Naito, Satoru Shimizu, Rikiya Nakamura, Jun Hashimoto, Harukaze Yamamoto, Hirofumi Michimae, Akinobu Hamada, Teruhiko Yoshida, Tamie Sukigara.

Funding

The research described in this report was funded by the Program for Promoting Platform of Genomics based Drug Discovery (Grant No. 18kk0305004h0003) from the Japan Agency for Medical Research and Development, AMED. This research was conducted with support from an Externally Sponsored Research Program of AstraZeneca.

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AK, TU and KT conceived the study and designed the experiments. AK, SY, and EO conducted the experiments, and AH performed statistical analysis. KY, TK and KT collected the samples. YK collected clinical information. AK and TU interpreted data and wrote the manuscript. TU and KT provided support for the studies. All the authors have read and approved the submission of the manuscript.

Corresponding author

Correspondence to Toshikazu Ushijima.

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Kawachi, A., Yamashita, S., Okochi-Takada, E. et al. BRCA1 promoter methylation in breast cancer patients is associated with response to olaparib/eribulin combination therapy. Breast Cancer Res Treat 181, 323–329 (2020). https://doi.org/10.1007/s10549-020-05647-w

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Keywords

  • BRCA1
  • RAD51C
  • DNA methylation
  • Triple-negative breast cancer
  • PARP inhibitor