HER2 expression in cervical squamous cell carcinoma: high prevalence of HER2-low/ultralow and spatiotemporal heterogeneity across tumor evolution

Human epidermal growth factor receptor 2 (HER2) overexpression and gene amplification are established biomarkers in breast and gastric cancers. However, their role in cervical squamous cell carcinoma (CSCC) remains unclear. We evaluated 548 untreated primary CSCC lesions (313 biopsies and 235 hysterectomies). Initial immunohistochemistry (IHC) results were: 0 (56.9%), 1+ (26.3%), 2+ (equivocal, 14.1%), and 3+ (positive, 2.7%). Fluorescence in situ hybridization confirmed HER2 gene amplification in all 3+ cases and 5.2% of 2+ cases. Based on reclassification, HER2 status was categorized as HER2-null (24.4%), HER2-ultralow (32.5%), HER2-low (39.6%), and HER2-positive (3.5%). HER2 discordance rates were observed in 48.3% of paired biopsies and hysterectomy specimens, 52.2% of post-neoadjuvant residual lesions, and 50.8% of metastatic sites. Temporal analysis showed conversion rates of 50.0% for synchronous metastases, 30.8% within 12 months, and 63.6% beyond 12 months. We identified a high prevalence of HER2-low and HER2-ultralow subtypes, suggesting potential eligibility for ADC therapies.