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

• Published in: Breast cancer research and treatment Vol. 181; no. 2; pp. 323 - 329
• Main Authors: Kawachi, Asuka, Yamashita, Satoshi, Okochi-Takada, Eriko, Hirakawa, Akihiro, Tsuda, Hitoshi, Shimomura, Akihiko, Kojima, Yuki, Yonemori, Kan, Fujiwara, Yasuhiro, Kinoshita, Takayuki, Ushijima, Toshikazu, Tamura, Kenji
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.06.2020; Springer; Springer Nature B.V
• Subjects: Analysis; Biopsy; Bisulfite; BRCA1 protein; BRCA2 protein; Breast cancer; Cancer; Cancer patients; Cancer research; Carboplatin; Care and treatment; Combination therapy; Disease control; DNA methylation; DNA sequencing; Gene mutations; Genetic aspects; Medical colleges; Medicine; Medicine & Public Health; Methylation; Mutation; Oncology; Patients; Poly(ADP-ribose) polymerase; Preclinical Study; Sulfites; DNA methylation; PARP inhibitor; Triple-negative breast cancer; RAD51C; BRCA1
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-020-05647-w

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)