Correlation of ER gene mutation in breast cancer metastasis with effect of CDK4 / 6 inhibitor

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K10474
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Keio University
• Principal Investigator: Takahashi Maiko 慶應義塾大学, 医学部(信濃町), 助教 (50348661)
• Co-Investigator(Kenkyū-buntansha): 関 朋子 慶應義塾大学, 医学部(信濃町), 助教 (70528900) ; 林田 哲 慶應義塾大学, 医学部(信濃町), 講師 (80327543)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 乳癌 / ESR1 / 遺伝子変異 / CDK4/6阻害薬

Outline of Final Research Achievements

In ER-positive advanced breast cancer, ESR1 gene mutation is found in 32%, which is considered to be one of the mechanisms for endocrine treatment resistance. In this study, mutations were found in 16 of 22 (64%) relapsed metastatic biopsy specimens, of which 7 were treated with aromatase inhibitors. Furthermore, among the mutations of exon 8, three ESR1 mutant genes of Leu536Arg, Tyr537Ser, and Asp538Gly were introduced into MCF7 to prepare mutant clones, and functional analysis was performed. As a result, in the ESR1 mutant cell line, TAM had little effect, and in the combination of FUL + PAL, the RB-E2F1 pathway was most efficiently blocked and cell cycle arrest was observed.

Free Research Field

乳腺外科

Academic Significance and Societal Importance of the Research Achievements

転移巣におけるER遺伝子変異についての研究は、欧米を中心に盛んに行われているが、本邦におけるまとまったデータは存在しない。また、内分泌治療耐性との関係を中心に研究がなされており、本研究で取り上げるCDK4/6阻害剤との関係性についての基礎・臨床データは報告が認められていない。さらに、バイオマーカーとしての有用性が示されれば、高額な薬剤費が予想されるCDK4/6阻害剤の使用に一定の根拠を示すことができ、学術的な成果のみならず、医療経済的なインパクトも高いと考えられる。