精准医学中，探索和监测分子生物标志物是必不可少的。然而，在存在内脏损害的晚期胃癌（GC）患者中，常规的侵入性检查不能重复进行分子生物标志物的随访。为了验证循环肿瘤DNA（ctDNA）作为液体活检的临床意义，我们对15例HER2阳性转移性GC患者进行了 ctDNA 的靶向深度测序，这些患者接受了抗PD-1抑制剂与标准系统治疗的联合治疗。在基线 ctDNA 中，14例患者（93%）携带了一个以上的遗传改变。发现了许多已知癌症相关基因，如KRAS和PIK3CA的突变。在8例GC中发现了拷贝数改变（53.3%），而ERBB2基因的扩增（6/15, 40.0%）最为频繁。当我们将每个ctDNA中的突变的平均等位基因频率（VAF）作为分子肿瘤负担指数（mTBI）进行计算时，mTBI趋势在反应组和非反应组的VAF谱中基本一致。值得注意的是，在ctDNA的纵向分析中，相比于常规CT成像随访，mTBI在疾病进展的检测方面提供了2-42周（平均13.4周）的提前量。我们的数据表明，在HER2阳性GC患者中，通过序列基因突变分析 ctDNA 是一种可行的、微创的预测治疗反应的方法。在实际应用中，ctDNA档案不仅对GC的分子诊断有用，还对选择预后不良的GC患者进行系统治疗也有指导意义（ClinicalTrials.gov标识符：NCT02901301）。© 版权所有：延世大学医学院2023年。

For precision medicine, exploration and monitoring of molecular biomarkers are essential. However, in advanced gastric cancer (GC) with visceral lesions, an invasive procedure cannot be performed repeatedly for the follow-up of molecular biomarkers.To verify the clinical implication of serial liquid biopsies targeting circulating tumor DNA (ctDNA) on treatment response, we conducted targeted deep sequencing for serially collected ctDNA of 15 HER2-positive metastatic GC patients treated with anti-PD-1 inhibitor in combination with standard systemic treatment.In the baseline ctDNAs, 14 patients (93%) harbored more than one genetic alteration. A number of mutations in well-known cancer-related genes, such as KRAS and PIK3CA, were identified. Copy number alterations were identified in eight GCs (53.3%), and amplification of the ERBB2 gene (6/15, 40.0%) was the most recurrent. When we calculated the mean variant allele frequency (VAF) of mutations in each ctDNA as the molecular tumor burden index (mTBI), the mTBI trend was largely consistent with the VAF profiles in both responder and non-responder groups. Notably, in the longitudinal analysis of ctDNA, mTBI provided 2-42 weeks (mean 13.4 weeks) lead time in the detection of disease progression compared to conventional follow-up with CT imaging.Our data indicate that the serial genetic alteration profiling of ctDNA is feasible to predict treatment response in HER2-positive GC patients in a minimally invasive manner. Practically, ctDNA profiles are useful not only for the molecular diagnosis of GC but also for the selection of GC patients with poor prognosis for systemic treatment (ClinicalTrials.gov identifier: NCT02901301).© Copyright: Yonsei University College of Medicine 2023.