HER2在尿路上皮癌中的分子异质性、 检测标准化与靶向治疗进展

Molecular Heterogeneity, Standardized Assessment, and Therapeutic Advances of HER2 in Urothelial Carcinoma

摘要: 目的：综述HER2 (ERBB2)在尿路上皮癌中的分子异常特征及其临床病理意义，阐明HER2检测与判读的规范化要点，系统总结抗HER2治疗证据链，重点评述抗体偶联药物(ADC)在晚期、一线及围手术期/膀胱保留治疗中的最新进展，并提出适用于ADC时代的临床分层与精准治疗框架。资料来源：检索PubMed及主要学术期刊近年发表的UC-HER2相关基础与临床研究，并结合近年国内外关于UC HER2检测与质控的共识性观点进行归纳。综述重点：UC中HER2异常可由蛋白过表达、ERBB2扩增及激活突变共同驱动，且呈现显著肿瘤内/灶间异质性与原发–转移不一致。ADC时代的核心矛盾已从“是否扩增”转向“是否具备足够的膜表达与内吞递送能力”，并进一步升级为“肿瘤对不同细胞毒载荷是否敏感”。以维迪西妥单抗(Disitamab Vedotin, DV)等HER2-ADC为代表的证据显示：在HER2表达(IHC 1+/2+/3+)晚期UC一线，DV联合PD-1抑制剂较化疗显著延长无进展生存与总生存；在MIBC新辅助与高危NMIBC膀胱保留策略中亦出现较高病理缓解/无病生存信号。结论：HER2在尿路上皮癌中并非失效靶点，但其临床价值受限于显著的表达异质性、肿瘤生物学背景差异及载荷敏感性不匹配。面向ADC时代，HER2靶向治疗亟需从单一表达分层升级为整合靶点可及性、载荷敏感性与分子背景的精准分层体系，并以标准化检测与动态监测为基础，实现治疗策略的合理选择与排序。

Abstract: Objective: To review the molecular alterations and clinicopathological significance of human epidermal growth factor receptor 2 (HER2, ERBB2) in urothelial carcinoma (UC), to clarify key issues in the standardization of HER2 testing and interpretation, and to systematically summarize the evidence base for anti-HER2 therapies. Particular emphasis is placed on recent advances in antibody-drug conjugates (ADCs) across advanced, first-line, and perioperative or bladder-preserving treatment settings, and on proposing a precision stratification framework tailored to the ADC era. Data Sources: Relevant basic and clinical studies on HER2 in urothelial carcinoma published in recent years were retrieved from PubMed and major academic journals. These data were integrated with recent national and international consensus opinions on HER2 testing and quality control in UC. Review Highlights: HER2 alterations in urothelial carcinoma may be driven by protein overexpression, ERBB2 amplification, and activating mutations, and are characterized by marked intratumoral and interlesional heterogeneity as well as discordance between primary and metastatic lesions. In the ADC era, the central clinical question has shifted from “whether ERBB2 is amplified” to “whether sufficient membranous expression and internalization capacity are present”, and has further evolved toward “whether the tumor is intrinsically sensitive to specific cytotoxic payloads”. Evidence from HER2-ADC agents, exemplified by disitamab vedotin (DV), demonstrates that in first-line treatment of advanced UC with HER2 expression (IHC 1+/2+/3+), DV combined with PD-1 inhibitors significantly prolongs progression-free and overall survival compared with chemotherapy. Promising signals of pathological response and disease-free survival have also been observed in neoadjuvant settings for muscle-invasive bladder cancer (MIBC) and in bladder-preserving strategies for high-risk non-muscle-invasive bladder cancer (NMIBC). Conclusions: HER2 is not an invalid therapeutic target in urothelial carcinoma; however, its clinical utility is constrained by pronounced expression heterogeneity, tumor-specific biological context, and mismatches between target expression and payload sensitivity. In the ADC era, HER2-directed therapy in UC must evolve from single-parameter expression stratification toward an integrated precision framework that incorporates target accessibility, payload sensitivity, and molecular background. Such an approach, grounded in standardized testing and dynamic monitoring, is essential for rational treatment selection and sequencing.