The progress and future prospects of the application of circulating tumor DNA in the diagnosis and treatment of gastric cancer

Chongyuan SUN; Dongbing ZHAO

doi:10.19401/j.cnki.1007-3639.2023.08.007

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The progress and future prospects of the application of circulating tumor DNA in the diagnosis and treatment of gastric cancer

Review | 更新时间：2025-12-31

- The progress and future prospects of the application of circulating tumor DNA in the diagnosis and treatment of gastric cancer
- China Oncology Vol. 33, Issue 8, Pages: 782-789(2023)
- 作者机构：
  
  国家癌症中心，国家肿瘤临床医学研究中心，中国医学科学院北京协和医学院肿瘤医院胰胃外科，北京 100021
- 作者简介：
  
  ZHAO Dongbing.
- 基金信息：
- DOI：10.19401/j.cnki.1007-3639.2023.08.007
  CLC： R735.2
- Received：26 April 2023，
  
  Revised：2023-07-06，
  
  Published：30 August 2023
- 稿件说明：
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Chongyuan SUN, Dongbing ZHAO. The progress and future prospects of the application of circulating tumor DNA in the diagnosis and treatment of gastric cancer[J]. China Oncology, 2023, 33(8): 782-789.
DOI：

Chongyuan SUN, Dongbing ZHAO. The progress and future prospects of the application of circulating tumor DNA in the diagnosis and treatment of gastric cancer[J]. China Oncology, 2023, 33(8): 782-789. DOI： 10.19401/j.cnki.1007-3639.2023.08.007.

摘要

胃癌是全球范围内常见的恶性肿瘤之一，因起病隐匿、缺乏特异性临床表现，多数患者就诊时已处于晚期，预后较差。因此，寻找具有特异性和敏感性的生物标志物以协助诊断、指导治疗和预判预后具有重要意义。循环肿瘤DNA（circulating tumor DNA，ctDNA）是肿瘤细胞释放到血浆中的游离DNA片段，携带肿瘤相关的特异性基因特征和表观遗传学改变。与传统的组织活检相比，ctDNA具有许多优势，它可以利用微创获取的血液样本捕获肿瘤基因组图谱、克服肿瘤异质性并动态监测治疗反应、预测复发风险。在早期诊断方面，研究者将外周血ctDNA突变与蛋白质标志物相结合研发出名为CancerSEEK的检测方法，在胃癌、食管癌及胰腺癌早期诊断的敏感度超过69%。另一项研究则利用153个游离DNA甲基化位点进行联合检测，对Ⅰ、Ⅱ、Ⅲ期胃癌的诊断灵敏度分别为44%、59%和78%，特异度为92%。在指导治疗方面，ctDNA检测有助于筛选可能从人表皮生长因子受体2（human epidermal growth factor receptor 2，HER2）、成纤维细胞生长因子受体2（fibroblast growth factor receptor 2，FGFR2）和表皮生长因子受体（epidermal growth factor receptor，EGFR）靶向治疗中获益的胃癌患者。此外，免疫治疗联合化疗已成为晚期胃癌患者的标准治疗方案，ctDNA检测能够对微卫星状态、肿瘤突变负荷和EB病毒相关胃癌进行评估，从而预测免疫治疗的效果，而特定基因如

TGFBR

2、

RHOA

和

PREX

2突变则提示免疫治疗效果不佳。对接受新辅助化疗或姑息性化疗的胃癌患者，化疗期间ctDNA拷贝数不稳定性、拷贝数变异和突变等位基因频率负荷的动态变化与疗效显著相关，动态监测有利于在出现影像学改变前及时调整治疗方案。在预测复发和预后方面，已有研究发现微小残留病变（minimal residual dis

ease，MRD）可能是局部晚期癌症患者成功治疗后复发的主要原因，这在乳腺癌、肺癌和结直肠癌的随访复查中得到证实。利用ctDNA检测胃癌术后MRD表明，在随访过程中任何时间节点的ctDNA阳性都与复发风险增加相关，无病生存期和总生存期也较短，与影像学复发相比其中位提前时间为4.5 ~ 6.0个月。此外，ctDNA检测中的

53突变、

MET

扩增、

THBS

1与

TIMP

-3甲基化和肿瘤进展或腹膜转移相关，预后同样较差。尽管 ctDNA 作为一种微创肿瘤筛查和监测生物标志物具有巨大的潜力，其在胃癌的应用中仍面临一些限制和挑战。本文就ctDNA在胃癌中的应用现状和前景进行综述。

Abstract

Gastric cancer is a prevalent malignant neoplasm globally

characterized by insidious onset

lack of specific clinical manifestations

and a tendency for patients to present at advanced stages with poor prognosis. Therefore

the quest for highly specific and sensitive biomarkers to assist in diagnosis

guide treatment

and predict prognosis holds paramount significance. Circulating tumor DNA (ctDNA)

consisting of cell-free DNA fragments released by tumor cells into the plasma

carries tumor-specific genetic features and epigenetic alterations. In comparison to conventional tissue biopsies

ctDNA offers numerous advantages. It enables the capture of tumor genomic profiles from minimally invasive blood samples

overcomes tumor heterogeneity

and allows for dynamic monitoring of treatment response and prediction of recurrence risk. In the realm of early diagnosis

researchers have developed a detection method called CancerSEEK by combining peripheral blood ctDNA mutations with protein markers

achieving a sensitivity of over 69% in the early detection of gastric

esophageal and pancreatic cancers. Another study utilized a combined detection of 153 methylated DNA sites to diagnose stage Ⅰ

Ⅱ

and Ⅲ gastric cancer with sensitivities of 44%

59% and 78%

respectively

and a specificity of 92%. Regarding treatment guidance

ctDNA testing facilitates the selection of gastric cancer patients who may benefit from targeted therapies against human epidermal growth factor receptor 2 (HER2)

fibroblast growth factor receptor 2 (FGFR 2) and epidermal growth factor receptor (EGFR). Furthermo

immunotherapy in combination with chemotherapy has become the standard treatment regimen for advanced gastric cancer. Evaluating microsatellite status

tumor mutation burden and EB virus-associated gastric cancer through ctDNA analysis can predict the efficacy of immunotherapy. However

specific gene mutations such as

TGFBR

RHOA

and

PREX

2 indicate a poor response to immunotherapy. For gastric cancer patients undergoing neoadjuvant or palliative chemotherapy

the dynamic changes in ctDNA copy number instability

copy number variation and mutation allele frequency load during chemotherapy significantly correlate with treatment efficacy. Dynamic monitoring through ctDNA analysis is beneficial for timely adjustment of treatment strategies before imaging changes occur. In the realm of predicting recurrence and prognosis

research has shown that minimal residual disease (MRD) may be the primary cause of post-treatment relapse in patients with locally advanced cancer

which has been confirmed through follow-up studies in breast

lung and colorectal cancers. The utilization of ctDNA testing to detect postoperative MRD in gastric cancer has revealed that ctDNA positivity at any time point during follow-up is associated with an increased risk of recurrence. Furthermore

patients with ctDNA-positive results experience shorter disease-free survival and overall survival

with a median lead time of 4.5 to 6.0 months compared to radiographic recurrence. Additionally

ctDNA analysis has shown correlations between

53 mutations

MET

amplification

THBS

1 and

TIMP

-3 methylation

and tumor progression or peritoneal metastasis

indicating similarly poor prognosis. Despite the tremendous potential of ctDNA as a minimally invasive biomarker for tumor screening and monitoring

its application in gastric cancer still faces certain limitations and challenges. This article provided a comprehensive review of the curr

ent status and prospects of ctDNA in the field of gastric cancer..

关键词

Keywords

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