Martella Serafina, Cusumano Giacomo, Senevirathne Thilini Hemali, Stylianakis Dimitrios, Palmas Enrico, Denaro Nerina, Tommasi Chiara, Scartozzi Mario, Gerratana Lorenzo, Solinas Cinzia
Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
Thoracic Surgery Unit, Policlinico-San Marco Hospital, University of Catania, 95124, Catania, Italy.
Mol Diagn Ther. 2025 Aug 30. doi: 10.1007/s40291-025-00811-8.
ESR1 gene mutations represent one of the main mechanisms of acquired resistance to endocrine therapy (ET) in estrogen receptor-positive (ER+) breast cancer. The introduction of liquid biopsy as a minimally invasive technique for analyzing circulating tumor DNA (ctDNA) has opened new avenues for real-time mutation monitoring and personalized treatment strategies. This review explores the clinical relevance of ESR1 mutations in endocrine resistance, the potential of liquid biopsy for early detection and monitoring, and the integration of advanced sequencing technologies and artificial intelligence to improve diagnostic accuracy. Preclinical and clinical studies on key mutations (D538G, Y537S) were analyzed, emerging technologies [(next-generation sequencing (NGS), digital droplet PCR (ddPCR), Cancer Personalized Profiling by deep Sequencing (CAPP-Seq), Targeted Digital Sequencing (TARDIS)] were compared, and survival data from seven major studies were summarized to assess the impact of ESR1 mutations on progression-free survival (PFS) and overall survival (OS). The results show that these mutations, particularly those affecting the ligand-binding domain, are associated with reduced efficacy of aromatase inhibitors and increased tumor aggressiveness. Liquid biopsy proves useful for early detection of resistance mutations and dynamic disease monitoring, but its clinical implementation is limited by low ctDNA levels, technological variability, and the lack of standardized clinical cut-offs. Integration with tissue biopsy, radiomics, and artificial intelligence (AI)-based platforms enhances its clinical utility and prognostic value. In conclusion, liquid biopsy, when combined with advanced technologies and predictive tools, represents an innovative resource for the personalized management of ER+ breast cancer, with the potential to guide timely therapeutic interventions and improve long-term survival.
ESR1基因突变是雌激素受体阳性（ER+）乳腺癌获得性内分泌治疗（ET）耐药的主要机制之一。液体活检作为一种用于分析循环肿瘤DNA（ctDNA）的微创技术，为实时突变监测和个性化治疗策略开辟了新途径。本综述探讨了ESR1突变在内分泌耐药中的临床相关性、液体活检用于早期检测和监测的潜力，以及先进测序技术与人工智能的整合以提高诊断准确性。分析了关键突变（D538G、Y537S）的临床前和临床研究，比较了新兴技术[下一代测序（NGS）、数字液滴PCR（ddPCR）、深度测序癌症个性化分析（CAPP-Seq）、靶向数字测序（TARDIS）]，并总结了七项主要研究的生存数据，以评估ESR1突变对无进展生存期（PFS）和总生存期（OS）的影响。结果表明，这些突变，尤其是那些影响配体结合域的突变，与芳香化酶抑制剂疗效降低和肿瘤侵袭性增加有关。液体活检被证明对耐药突变的早期检测和疾病动态监测有用，但其临床应用受到ctDNA水平低、技术变异性和缺乏标准化临床临界值的限制。与组织活检、放射组学和基于人工智能（AI）的平台相结合可提高其临床效用和预后价值。总之，液体活检与先进技术和预测工具相结合，是ER+乳腺癌个性化管理的创新资源，有可能指导及时的治疗干预并改善长期生存。
