Mechanism for resistance EGFR blockade; Analysis using circulating tumor DNA and circulating tumor cell

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K10657
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Nippon Medical School
• Principal Investigator: Yamada Takeshi 日本医科大学, 医学部, 准教授 (50307948)
• Co-Investigator(Kenkyū-buntansha): 小泉 岐博 日本医科大学, 医学部, 講師 (40328802)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 抗EGFR抗体 / 循環DNA / 循環腫瘍細胞

Outline of Final Research Achievements

We evaluated the clinical utility of cfDNA to predict primary or secondary resistance to EGFR blockade in patients with metastatic colorectal cancer. Thirty metastatic colorectal cancer patients without RAS and BRAF mutations were prospectively enrolled and treated with cytotoxic agents and EGFR blockade as first-line therapy. cfDNA was analyzed for the presence of RAS, BRAF, and EGFR point mutations before initiating chemotherapy and at every 2 months during chemotherapy. Of the 30 patients, five had RAS mutations in their cfDNA before starting chemotherapy and did not respond. Twenty-four of the remaining 25 patients without cfDNA RAS mutations had response. Twenty of the 24 responders developed secondary resistance and cfDNA RAS mutations were found in 17 of the 20. cfDNA BRAF mutations were found in seven, and EGFR mutations were found in eight of the 20 patients. Emerging RAS, BRAF, and EGFR mutations occurred in patients with primary and secondary resistance to EGFR blockade.

Free Research Field

消化器外科

Academic Significance and Societal Importance of the Research Achievements

Liquid biopsyを用いて、抗EGFR抗体はEGFRのみならず、その下流にあるRASやBRAFに変異を誘導することにより耐性化することを明らかにした。がん遺伝子パネル検査が保険適応となり、分子標的薬がより多くの患者に用いられるようになることが予測されるが、これに伴い、耐性化メカニズムの解明、耐性化の早期予知、耐性化後の治療開発、等の重要性が増す。今後Liquid biopsyを用いた様々な分子治療薬に関する研究が進むと考えられる。