HER-2 underexpression

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

HER2-low early breast cancer shows lower pCR after neoadjuvant therapy but better long-term survival. These findings support the clinical relevance of HER2-low as a biologically meaningful subgroup within HER2-negative disease, while its status as a stable and independent subtype still requires further validation through prospective studies, standardized testing, and multi-omics investigation.

P2/3, N=574, Recruiting, SUNHO（China）BioPharmaceutical CO., Ltd. | N=90 --> 574 | Trial completion date: Jul 2028 --> Jul 2029 | Trial primary completion date: Jul 2026 --> Jul 2028

HER2-low breast cancer is distinct from HER2-0 and HER2-high breast cancer with respect to clinicopathological characteristics. HER2-low breast cancer is highly unstable during chemotherapy; therefore, reevaluating HER2 expression may provide new treatment strategies for some patients after neoadjuvant therapy.

HER2-low and HER2-zero TNBC are biologically distinct subgroups. HER2-low tumors are enriched in luminal AR-like characteristics, whereas HER2-zero tumors exhibit basal-like, highly proliferative, and immunogenic features. Although the treatment outcomes did not differ significantly, these findings suggest that HER2-low and HER2-zero TNBC may require different therapeutic approaches. Prospective studies are warranted to validate these findings and further explore tailored treatment strategies.

This review highlights the importance of radiotherapy in the management of BCBM and provides evidence-based recommendations. Future research should focus on optimizing treatment protocols and investigating the optimal timing of radiotherapy across different subtypes.

HER2-low G/GEJ cancer represents a distinct biological subtype with intermediate survival outcomes and specific angiogenesis-related molecular features. These findings support the need for dedicated therapeutic strategies and further clinical research in HER2-low G/GEJ cancer.