Asuka Kawachi1,2, Satoshi Yamashita1, Eriko Okochi-Takada1, Akihiro Hirakawa3, Hitoshi Tsuda4, Akihiko Shimomura2, Yuki Kojima2, Kan Yonemori2, Yasuhiro Fujiwara2, Takayuki Kinoshita5, Toshikazu Ushijima6,7, Kenji Tamura2. 1. Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan. 2. Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan. 3. Department of Biostatistics and Bioinformatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 4. Department of Basic Pathology, National Defense Medical College, Tokorozawa, Japan. 5. Department of Breast Surgery, National Cancer Center Hospital, Tokyo, Japan. 6. Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan. tushijim@ncc.go.jp. 7. Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. tushijim@ncc.go.jp.
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).
BACKGROUND: A PARP inhibitor is effective in breast cancerpatients with BRCA1/2 germline mutations, and in cell lines with BRCA1 promoter methylation. However, its efficacy in breast cancerpatients 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).
Entities:
Keywords:
BRCA1; DNA methylation; PARP inhibitor; RAD51C; Triple-negative breast cancer