HER-2 amplification

ADCs against TROP2 (Sacituzumab govitecan) or HER2 (T-DXd) have demonstrated efficacy in metastatic breast cancer, yet paradoxically, outside of HER2-amplified breast cancers, expression levels of these breast cancer-enriched epitopes in tumor biopsies have not been strongly correlated with clinical response. Thus, while CTC burden is correlated with response to these ADCs, the level of TROP2 or HER2 expression is poorly predictive. These findings point to sensitivity to the drug payload as a potential driver of clinical response to currently approved ADCs in breast cancer.

P2, N=63, Completed, City of Hope Medical Center | Active, not recruiting --> Completed

P2, N=124, Recruiting, The First Affiliated Hospital of Soochow University

Complex relationships between ERBB2 alterations and HER2 IHC expression exist, including increased expression in non-ERBB2-amplified tumors with pathogenic mutations. Importantly, ERBB2/HER2 amplification and/or mutation rates as well as transcript and protein expression varied between cancers and within cancer types, emphasizing the need for individual assessment.

P2, N=8, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Active, not recruiting | N=36 --> 8

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.

However, clinical implementation requires greater methodological standardization, validated predictive biomarkers, accessible diagnostic platforms, and dynamic monitoring strategies capable of capturing subtype evolution under therapeutic pressure. TNBC should therefore not be regarded as a single disease, but as a spectrum of biologically distinct and clinically evolving entities whose integrated characterization may be essential to improving outcomes in this historically poor-prognosis population.

P1/2, N=30, Recruiting, Beijing Biotech

Multimodal HER2 testing is needed to accurately identify candidates for HER2-targeted treatment, as NGS alone misses a significant proportion of cases. Patients who develop resistance to one anti-HER2 agent may still achieve benefit from subsequent HER2-directed regimens. Early and serial treatment with HER2-directed agents should be considered for patients with HER2 + GI cancers.

HER2 DISH advantages included the ability of pathologists to directly score slides in correlation with morphology and immunohistochemistry, improved turnaround time, and greater automation for high-volume HER2 testing, as compared with FISH. In summary, we found HER2 DISH to be an accurate and practical alternative.

P1, N=16, Recruiting, Memorial Sloan Kettering Cancer Center

Awareness of definitional sensitivity at receptor cut-off margins is essential for accurate reporting, avoidance of misclassification and informed multidisciplinary decision-making. Recognition of TNBC as a biologically heterogeneous spectrum has implications for therapeutic selection, trial eligibility and future refinement of classification systems.