HER-2 underexpression

P2, N=120, Not yet recruiting, Sichuan Baili Pharmaceutical Co., Ltd.

P=N/A, N=100, Not yet recruiting, Tianjin Medical University Cancer Institute and Hospital

P2, N=70, Recruiting, Peking Union Medical College Hospital

P1, N=150, Recruiting, Chia Tai Tianqing Pharmaceutical Group Nanjing Shunxin Pharmaceutical Co., Ltd. | -> Recruiting | Phase classification: PN/A --> P1

Recent advances in molecular profiling and the development of HER2-directed ADCs have fundamentally reshaped the therapeutic relevance of HER2 in UC, enabling activity even in tumors with heterogeneous or low expression of HER2. This comprehensive narrative review synthesizes current knowledge on HER2 biology in UC, addresses challenges in biomarker assessment, critically appraises the evolving clinical trial landscape of HER2-directed ADCs, explores the interaction between HER2 and other oncogenic alterations and discusses mechanisms of resistance with future directions for HER2-targeted strategies in UC.

The incidence of brain metastases in each group were 0 (0/3), 33.33% (39/117), 74.55% (82/110) and 100.00% (17/17), respectively. The risk stratification of brain metastasis based on clinicopathological characteristics and levels of related tumor markers are helpful to predict the risk of brain metastasis in non-stage Ⅳ breast cancer patients with HER-2 low expression after systematic treatment, so as to accurately identify patients with high recurrence risk and formulate targeted follow-up strategies for them.

Antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) offer new and potent options for curing for curing hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-low advanced breast cancer; however, comparisons in terms of their relative effectiveness and safety concerns are lacking. Compared with other ADC drugs, T-DXd showed relatively better treatment characteristics, better PFS benefit, and relatively low incidence of serious AEs (SAEs). Combined with RCTs and real-world data, T-DXd has potential advantages in this population.

Collectively, these findings establish HER2‑low expression as a negative predictor of immunotherapy response, shaped by a less immunogenic tumor microenvironment. These results provide important insights into the distinct immunological features of HER2‑low triple‑negative breast cancer and warrant further mechanistic and clinical investigations.

Whole-exome sequencing revealed low tumor mutational burden (median 1.28 Muts/Mb), recurrent mutations in AK1, ARHGAP39, KRT24, MICAL3, SLC6A9 (27.3%), KRAS, and KMT2C (18.2%), alongside MUC2 copy gain (63.6%) and bidirectional Y_RNA alterations (gain 54.5%/loss 45.5%). Collectively, HPV-associated CPCC represents a distinct and aggressive subtype characterized by distinctive histopathological features, a predominant association with HPV18, frequent presentation at advanced stages, and marked molecular and biomarker heterogeneity.

A cross-tumor perspective contrasts GC/GEJ testing and biology with the breast cancer paradigm and summarizes the importance of HER2-low expression in non-gastric malignancies. Finally, we discuss the therapeutic strategies in HER2-low GC/GEJ and highlight key safety and monitoring considerations for HER2-directed ADCs.

HER2-low GC helps refine GC classification and is associated with higher PD-L1 expression, supporting immunotherapy strategies. Further research is needed to explore its clinical and therapeutic value in personalized precision treatment.

P1/2, N=178, Recruiting, Chia Tai Tianqing Pharmaceutical Group Nanjing Shunxin Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting