Matsuda Akihisa, Yamada Takeshi, Takahashi Takao, Hirata Keiji, Nagasaka Takeshi, Ishimaru Kei, Sakamoto Kazuhiro, Koda Keiji, Ishikawa Toshiaki, Ishida Hideyuki, Matsuda Kenji, Kuramochi Hidekazu, Yoshida Yoichiro, Sonoda Hiromichi, Yoshida Hiroshi
Department of Gastrointestinal Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan.
Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan.
J Anus Rectum Colon. 2022 Jan 28;6(1):52-57. doi: 10.23922/jarc.2021-042. eCollection 2022.
Anti-epidermal growth factor receptor (EGFR) therapy has been identified to prolong the survival of metastatic colorectal cancer (mCRC) patients without mutations. However, its efficacy is not always consistent for these patients. Genomic profiles of primary tumors and metastases are not always concordant; thus, chemotherapeutic agents can alter the tumor molecular profile. This molecular heterogeneity may explain resistance to anti-EGFR therapy. Liquid biopsy using circulating tumor DNA (ctDNA) is a novel, non-invasive diagnostic tool that can accommodate this molecular heterogeneity, providing a comprehensive, real-time view of the molecular landscape. In this study, we evaluated the predictive value of genomic mutations in ctDNA for primary and acquired resistance to anti-EGFR therapy.
METHODS/DESIGN: This study is a prospective, multicenter, observational study of mCRC patients with wild-type tissue treated with cytotoxic agents and anti-EGFR antibodies as first-line therapy. Genomic mutations, including , , , and in ctDNA, are assessed via Droplet Digital PCR before starting chemotherapy and every 3 months thereafter until disease progression. The target sample size is estimated to be 100. The primary endpoint is the response rate in patients without mutation in their blood sample before starting chemotherapy.
This study will clarify the predictive value of baseline mutation in ctDNA for responses to anti-EGFR therapy; the frequency of emerging , , , and mutations in ctDNA; and the association with secondary resistance to anti-EGFR therapy in first-line therapy for wild-type tissue mCRC patients.
抗表皮生长因子受体（EGFR）疗法已被证实可延长无突变的转移性结直肠癌（mCRC）患者的生存期。然而，其对这些患者的疗效并不总是一致的。原发性肿瘤和转移灶的基因组特征并不总是一致的；因此，化疗药物可改变肿瘤分子特征。这种分子异质性可能解释了对抗EGFR治疗的耐药性。使用循环肿瘤DNA（ctDNA）进行液体活检是一种新型的非侵入性诊断工具，它可以适应这种分子异质性，提供分子格局的全面、实时视图。在本研究中，我们评估了ctDNA中基因组突变对于抗EGFR治疗原发性和获得性耐药的预测价值。
方法/设计：本研究是一项对野生型组织的mCRC患者进行的前瞻性、多中心观察性研究，这些患者接受细胞毒性药物和抗EGFR抗体作为一线治疗。在开始化疗前以及此后每3个月直至疾病进展，通过液滴数字PCR评估ctDNA中的基因组突变，包括 、 、 和 。目标样本量估计为100。主要终点是开始化疗前血样中无 突变的患者的缓解率。
本研究将阐明ctDNA中基线 突变对抗EGFR治疗反应的预测价值；ctDNA中出现 、 、 和 突变的频率；以及野生型组织mCRC患者一线治疗中与抗EGFR治疗继发性耐药的关联。
