Detection of acquired resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer using circulating tumor DNA

• Project/Area Number: 17K10625
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kanazawa University
• Principal Investigator: Nakamura Keishi 金沢大学, 附属病院, 講師 (30608691)
• Co-Investigator(Kenkyū-buntansha): 高橋 直樹 地方独立行政法人埼玉県立病院機構埼玉県立がんセンター(臨床腫瘍研究所), 病院 消化器内科, 医長 (20744204) ; 澤田 武 金沢大学, 附属病院, 医員 (60345626)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 循環腫瘍DNA / 大腸癌 / 上皮成長因子受容体 / 遺伝子変異 / 個別化治療 / 個別化医療 / 抗上皮成長因子受容体抗体

Outline of Final Research Achievements

Circulating tumor DNA (ctDNA) has been attracting attention for its ability to provide comprehensive, minimally invasive tissue profiling. To assess clinical usefulness of ctDNA as prognostic and predictive marker for the treatment of metastatic colorectal cancer (mCRC), we explored genetic alterations in ctDNA in 50 patients with RAS wildtype mCRC treated with anti-EGFR antibodies. Blood samples were collected before initiation and during administration of anti-EGFR antibodies as well as after disease progression (PD). Extraction of ctDNA from plasma and detection of genetic changes associated with resistance to anti-EGFR antibodies were performed by digital PCR. For patients with genetic alteration identified before chemotherapy or after PD, we also performed analysis of ctDNA during the course of the disease. Analyses are ongoing to determine if ctDNA can be used to predict response to EGFR blockade before treatment, as well as to monitor disease response during EGFR blockade.

Academic Significance and Societal Importance of the Research Achievements

今後解析を進めることにより、切除不能進行再発大腸癌に対する抗EGFR抗体薬投与前に、RAS以外の遺伝子異常が予後不良因子となり得るか、またどの程度の変異アレルで治療無効と予測可能かの知見を蓄積できる。それにより、抗EGFR抗体薬の適応判定および治療効果予測をより精密に行うことが可能となる。また、抗EGFR抗体投与後に、耐性因子と想定される（複数の）遺伝子異常がどのタイミングで検出されるかの新たな知見を得ることができる。それをもとに、ctDNAによる治療標的の同定と治療効果のモニタリングを目的とした繰り返し実施可能な低侵襲検査が提案できる。

Research Products

• [Presentation] RAS野生型転移性大腸癌患者における循環腫瘍DNA中のRAS, BRAF, PIK3CA変異の同定と腫瘍組織の変異との比較 (2021)
  • Author(s): 澤田 武, 久保田英嗣, 中村慶史, 高橋直樹, 太田亮介, 井戸川雅史, 佐々木泰史, 時野隆至, 源 利成, 片岡洋望
  • Organizer: 第80回日本癌学会学術総会