HER-2 underexpression

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

Evaluation of cell death using the WST-8 assay also demonstrated a significantly higher cytotoxic effect of G-Ce6-trastuzumab in HER2-high-expression cells compared with conventional PS G-Ce6. Thereby, G-Ce6-trastuzumab may be an excellent novel PS for PDT because of its strong selectivity for HER2-high-expression cells.

A retrospective analysis was conducted on 104 patients diagnosed with advanced breast cancer who received trastuzumab deruxtecan treatment at the Affiliated Hospital of Xuzhou Medical University, with the study period spanning from January 2023 to September 2025. Earlier initiation of trastuzumab deruxtecan may maximize survival benefits. These findings help bridge the gap between clinical trial evidence and routine clinical practice.

This multicenter retrospective cohort study included patients with HR+/HER2- metastatic breast cancer who received first-line endocrine therapy combined with palbociclib or ribociclib between January 2018 and May 2025. In patients with HR+/HER2- metastatic breast cancer treated with first-line endocrine therapy plus CDK4/6 inhibitors, HER2-low expression was not associated with differences in treatment response or survival outcomes. These findings suggest that HER2-low status does not have prognostic or predictive relevance in this endocrine-sensitive population.

Planned enrollment is 62 patients.ConclusionThe PRaG3.0 protocol represents an innovative approach combining ADC therapy with radioimmunotherapy to address HER2-expressing cancers, including those with HER2-low expression. If successful, this regimen could establish a highly effective combination strategy.

This review systematically outlines the evolution of HER2 expression profiles, the mechanism of action and limitations of trastuzumab, and focuses on analyzing the breakthrough role of ADCs centered on trastuzumab emtansine (T-DM1) and T-DXd in HER2-low tumors, key clinical evidence, and adverse reaction management. Additionally, it explores the application prospects of combination strategies involving ADCs with chemotherapy and immunotherapy. Finally, the article summarizes challenges facing the current treatment paradigm and outlines future directions for standardized testing and novel therapeutic development.

High expression of STAT6 is significantly correlated with HER2-low expression. STAT6-high/HER2-low may predict a good prognosis.

High FGFR1 mRNA expression is observed across different molecular subtypes of breast cancer. High-level FGFR1 gene amplification is uncommonly detected; therefore, further studies with large amount samples are required.

In cell lines sensitive to the combination, combining T-DXd with capivasertib targeted complimentary pathways which resulted in disruption of the cell cycle and increased cell death. These results suggest that T-DXd combined with capivasertib has the potential to be active in HER2-positive as well as HER2-low tumours independent of PI3K pathway alteration status.

P3, N=541, Active, not recruiting, DualityBio Inc. | Recruiting --> Active, not recruiting

The tumor progressed after two cycles of first-line induction chemotherapy with paclitaxel plus cisplatin. The response to disitamab vedotin, despite prior taxane progression, suggests the potential critical role of HER2-mediated drug delivery and indicates that low antigen density may be sufficient for ADC efficacy. This case indicates the importance of routine HER2 testing with explicit HER2-low categorization in advanced SGCs and offers preliminary evidence that may help expand therapeutic options for this treatment-refractory population.

Overall, we analyzed the cross-talk signaling pathways between RKIP and HER2, established a novel dysregulated axis in HER2+ BC, and delineated the various mechanisms involved in the regulation of immune evasion by RKIP and HER2. Hence, we present various therapeutic strategies aimed at targeting the RKIP-HER2 axis in HER2+ BC to circumvent unresponsiveness to therapeutics and immune evasion.