循环肿瘤DNA甲基化检测在乳腺癌早期筛查中的进展与展望

Progress and Prospects of Circulating Tumor DNA Methylation Detection in Early Breast Cancer Screening

摘要: 乳腺癌位居全球女性恶性肿瘤发病与死亡首位，传统筛查手段存在有创操作、致密乳腺漏诊、假阳性率偏高等缺陷。循环肿瘤DNA (ctDNA)甲基化检测是液体活检领域的早筛热点技术。本文系统检索2013年1月~2026年4月PubMed、Embase、中国知网、万方数据库收录的相关文献，纳入17项高质量病例对照研究、队列研究及专家共识，从技术原理、标志物诊断效能、临床应用短板与未来发展方向开展定性系统分析，并对比ctDNA甲基化检测与乳腺钼靶、超声、MRI及穿刺活检等传统筛查手段的优劣。纳入研究包含单基因甲基化标志物、多基因检测Panel、前瞻性队列研究三类。结果显示，ctDNA甲基化检测具备无创采样、特异性高、可溯源肿瘤原发灶等优势，多基因检测Panel诊断乳腺癌的受试者工作特征曲线下面积(AUC)为0.80~0.89，特异性均超过90%；但该技术对I期乳腺癌的检测灵敏度仅为40%~60%。目前该技术临床转化仍面临多项瓶颈：大样本前瞻性研究证据不足、全流程检测标准缺失、人群筛查阳性预测值偏低。综上，ctDNA甲基化检测暂无法替代常规筛查方案，更适用于乳腺癌高危人群的分层筛查。未来需建立全流程标准化体系，开展多中心前瞻性队列研究，推进多组学联合检测技术研发，助力该技术落地临床。

Abstract: Breast cancer ranks among the leading causes of morbidity and mortality in women worldwide. Conventional breast cancer screening methods are limited by invasiveness, missed diagnoses in dense breasts, and high false-positive rates. Circulating tumor DNA (ctDNA) methylation detection is a cutting-edge liquid biopsy technology for early cancer screening. Relevant literature published from January 2013 to April 2026 was retrieved from PubMed, Embase, CNKI and Wanfang databases. A total of 17 high-quality case-control studies, cohort studies and expert consensuses were included. A qualitative systematic analysis was conducted from four dimensions: technical principles, diagnostic performance of biomarkers, clinical challenges and future development directions. Meanwhile, we made a head-to-head comparison between ctDNA methylation detection and traditional screening methods including mammography, ultrasound, MRI and needle biopsy. The included studies were divided into three categories: single-gene methylation biomarkers, multi-gene detection panels and prospective cohort studies. The results indicated that ctDNA methylation detection has the advantages of non-invasive sampling, high specificity and tumor origin tracing. The area under the receiver operating characteristic curve (AUC) of multi-gene panels for breast cancer diagnosis ranged from 0.80 to 0.89, with the specificity higher than 90%. However, its sensitivity for stage I breast cancer was only 40% to 60%. Multiple translational bottlenecks remain, such as insufficient evidence from large-sample prospective studies, lack of unified detection standards and low positive predictive value in population screening. In conclusion, ctDNA methylation detection cannot replace conventional screening methods at present, and it is recommended for risk-stratified screening of high-risk breast cancer populations. Further studies should focus on establishing a full-process standardization system, conducting multicenter prospective cohort studies and developing multi-omics combined detection technologies to promote the clinical application of this technique.