Raggi Daniele, Crupi Emanuele, Pederzoli Filippo, Martini Alberto, Briganti Alberto, Alhalabi Omar, O'Donnell Peter H, Ross Jeffrey, Gupta Shilpa, Kamat Ashish M, Faltas Bishoy M, Black Peter C, Spiess Phillip E, Grivas Petros, Gao Jianjun, Apolo Andrea B, Huddart Robert A, Necchi Andrea, Galsky Matthew D
Genitourinary Oncology; The Royal Marsden Hospital NHS Foundation Trust, London, UK.
Vita-Salute "San Raffaele" University Hospital, Milan, Italy.
Nat Rev Urol. 2025 Aug 15. doi: 10.1038/s41585-025-01075-x.
Human epidermal growth factor receptor 2 (HER2) has emerged as a crucial biomarker across various cancers, shaping therapeutic strategies and prognostic evaluations. In urothelial carcinoma, HER2 positivity rates can reach up to 68% when HER2-low tumours (immunohistochemistry 1+) are included in the analysis. HER2 overexpression and ERBB2 genomic alterations have been linked to advanced disease stages and poor outcomes in urothelial carcinoma. Emerging evidence suggests that HER2-low tumours might be a distinct and actionable subgroup. Accurate and consistent assessment of HER2 status is increasingly vital to identify patients likely to benefit from HER2-targeted therapies, raising interest in refining thresholds for HER2 expression, aiming to predict treatment response. HER2 heterogeneity across stages and histological subtypes complicates its evaluation, with definitions of HER2 positivity differing between clinical trials and treatments. In urothelial carcinoma, HER2-targeted therapies, such as tyrosine kinase inhibitors, monoclonal antibodies and antibody-drug conjugate (ADCs) have been explored. Unlike tyrosine kinase inhibitors and monoclonal antibodies, which act through HER2-related pathways, ADCs use HER2 as a target but achieve efficacy through additional mechanisms, enabling their activity even at low HER2 expression levels. Trastuzumab deruxtecan, a novel anti-HER2 ADC, has received FDA tumour-agnostic approval for unresectable or metastatic HER2+ solid tumours, including urothelial carcinoma, after prior therapies. Interactions between HER2 protein and putative biomarkers such as EGFR, NECTIN4, PDL1 and FGFR3 genomic alterations might influence therapeutic outcomes, offering opportunities for improved patient selection and innovative combination strategies.
人表皮生长因子受体2（HER2）已成为各类癌症中的关键生物标志物，影响着治疗策略和预后评估。在尿路上皮癌中，若将HER2低表达肿瘤（免疫组织化学1+）纳入分析，HER2阳性率可达68%。HER2过表达和ERBB2基因改变与尿路上皮癌的晚期疾病阶段及不良预后相关。新证据表明，HER2低表达肿瘤可能是一个独特且可采取行动的亚组。准确且一致地评估HER2状态对于识别可能从HER2靶向治疗中获益的患者愈发重要，这引发了人们对完善HER2表达阈值的兴趣，旨在预测治疗反应。HER2在不同阶段和组织学亚型中的异质性使其评估变得复杂，HER2阳性的定义在临床试验和治疗之间存在差异。在尿路上皮癌中，已对HER2靶向治疗进行了探索，如酪氨酸激酶抑制剂、单克隆抗体和抗体药物偶联物（ADC）。与通过HER2相关途径发挥作用的酪氨酸激酶抑制剂和单克隆抗体不同，ADC以HER2为靶点，但通过其他机制实现疗效，即使在HER2低表达水平时也能发挥活性。曲妥珠单抗德鲁替康是一种新型抗HER2 ADC，在先前治疗后，已获得美国食品药品监督管理局（FDA）针对不可切除或转移性HER2阳性实体瘤（包括尿路上皮癌）的肿瘤不依赖型批准。HER2蛋白与诸如表皮生长因子受体（EGFR）、NECTIN4、程序性死亡受体配体1（PDL1）和FGFR3基因改变等假定生物标志物之间的相互作用可能会影响治疗结果，为改善患者选择和创新联合策略提供了机会。
