循环肿瘤DNA在HER2阳性晚期胃癌中的临床意义：一项HER2和PD-1双重靶向治疗Ib期试验（Ni-High）的合作研究
Clinical relevance of circulating tumor DNA in HER2-positive advanced gastric cancer: a collaborative study of a phase Ib trial of dual HER2 and PD-1 targeted therapy (Ni-High).
作者信息
Osumi Hiroki, Wakatsuki Takeru, Ooki Akira, Chin Keisho, Shoji Hirokazu, Ogura Mariko, Nakayama Izuma, Yamamoto Noriko, Hirano Hidekazu, Hara Hiroki, Minashi Keiko, Shinozaki Eiji, Kato Ken, Ishizuka Naoki, Kitano Shigehisa, Takeuchi Kengo, Boku Narikazu, Yamaguchi Kensei, Takahari Daisuke
机构信息
Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.
Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
出版信息
Ther Adv Med Oncol. 2025 Sep 12;17:17588359251367344. doi: 10.1177/17588359251367344. eCollection 2025.
BACKGROUND
The combination of anti-programmed cell death-1 antibody with human epidermal growth factor receptor 2 (HER2)-targeted therapy and chemotherapy is widely used in the United States and Europe for HER2-positive advanced gastric cancer (AGC). Molecular profiles that predict the efficacy of this dual-target therapy are unclear.
OBJECTIVES
To explore the clinical utility of circulating tumor DNA (ctDNA) as a predictive marker of the efficacy of standard chemotherapy plus HER2 and programmed death-ligand 1 dual-targeted therapy in patients with HER2-positive AGC.
DESIGN
Collaborative study of the Ni-High phase Ib clinical trial.
METHODS
A total of 21 patients with tissue-confirmed HER2-positive AGC who received chemotherapy with dual-targeted therapy (capecitabine/S-1, oxaliplatin, trastuzumab, and nivolumab) in a phase Ib clinical trial (UMIN000034222) were enrolled. The association of genomic profiles in plasma ctDNA with tissue HER2 amplification status and their correlation with clinical outcomes was investigated.
RESULTS
Among the 21 patients studied, 20 (95.2%) showed somatic alterations in ctDNA. amplifications and single-nucleotide variants (SNVs)/indels were found in 12 (57.1%) and 3 (14.3%) patients, respectively. Significant associations between maximum mutant allele frequency (mMAF) and tumor size and between ctDNA and tissue copy numbers were found. Patients without SNV/indels showed longer median progression-free survival (PFS) and overall survival (OS) than those with these alterations. Patients with focal amplification in ctDNA showed better outcomes than those with aneuploidy (median PFS: 20.8 vs 8.4 months, hazard ratio (HR) = 0.08; median OS: NA vs 14.8 months, HR = 0.077). Lower mMAF at cycle 2 was associated with a better response to chemotherapy with dual-targeted therapy.
CONCLUSION
genetic status and mMAF changes in ctDNA may, respectively, predict and reflect the efficacy of chemotherapy with dual-targeted therapy in HER2-positive AGC.
TRIAL REGISTRATION
UMIN000034222.
背景
在美国和欧洲，抗程序性细胞死亡蛋白1抗体与人表皮生长因子受体2（HER2）靶向治疗及化疗联合应用于HER2阳性晚期胃癌（AGC）的治疗较为广泛。预测这种双靶点治疗疗效的分子特征尚不清楚。
目的
探讨循环肿瘤DNA（ctDNA）作为HER2阳性AGC患者标准化疗联合HER2及程序性死亡配体1双靶点治疗疗效预测标志物的临床应用价值。
设计
Ni-High Ib期临床试验的协作研究。
方法
纳入21例经组织学确诊为HER2阳性AGC且在Ib期临床试验（UMIN000034222）中接受双靶点化疗（卡培他滨/S-1、奥沙利铂、曲妥珠单抗和纳武单抗）的患者。研究血浆ctDNA中的基因组特征与组织HER2扩增状态的相关性及其与临床结局的关系。
结果
在研究的21例患者中，20例（95.2%）ctDNA存在体细胞改变。分别在12例（57.1%）和3例（14.3%）患者中发现扩增和单核苷酸变异（SNV）/插入缺失。发现最大突变等位基因频率（mMAF）与肿瘤大小之间以及ctDNA与组织拷贝数之间存在显著相关性。无SNV/插入缺失的患者中位无进展生存期（PFS）和总生存期（OS）长于有这些改变的患者。ctDNA中存在局灶性扩增的患者比非整倍体患者预后更好（中位PFS：20.8个月对8.4个月，风险比（HR）=0.08；中位OS：不可评估对14.8个月，HR=0.077）。第2周期较低的mMAF与双靶点化疗的更好反应相关。
结论
ctDNA中的基因状态和mMAF变化可能分别预测和反映HER2阳性AGC患者双靶点化疗的疗效。
试验注册号
UMIN000034222。
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