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Updated: Jul 18, 2025
Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
Published on: December 5, 2017
Molecular features and clinical implications of the heterogeneity in Chinese patients with HER2-low breast cancer
Lei-Jie Dai1,2,3, Ding Ma4,5,6, Yu-Zheng Xu1,2,3
1Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Abstract:
The molecular heterogeneity and distinct features of HER2-low breast cancers, particularly in the Chinese population, are not well understood, limiting its precise management in the era of antibody‒drug conjugates. To address this issue, we established a cohort of 434 Chinese patients with HER2-low breast cancer (433 female and one male) and integrated genomic, transcriptomic, proteomic, and metabolomic profiling data. In this cohort, HER2-low tumors are more distinguished from HER2-0 tumors in the hormone receptor-negative subgroup. Within HER2-low tumors, significant interpatient heterogeneity also exists in the hormone receptor-negative subgroup: basal-like tumors resemble HER2-0 disease, and non-basal-like HER2-low tumors mimic HER2-positive disease. These non-basal-like HER2-low tumors are enriched in the HER2-enriched subtype and the luminal androgen receptor subtype and feature PIK3CA mutation, FGFR4/PTK6/ERBB4 overexpression and lipid metabolism activation. Among hormone receptor-positive tumors, HER2-low tumors show less loss/deletion in 17q peaks than HER2-0 tumors. In this work, we reveal the heterogeneity of HER2-low breast cancers and emphasize the need for more precise stratification regarding hormone receptor status and molecular subtype.
Insights
This study reveals significant molecular differences in HER2-low breast cancers within the Chinese population. Understanding this heterogeneity is crucial for personalized treatment strategies, especially with antibody-drug conjugates.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- HER2-low breast cancer presents unique challenges in diagnosis and treatment.
- Limited understanding of its molecular landscape, particularly in diverse populations like the Chinese, hinders precise management.
Purpose of the Study:
- To investigate the molecular heterogeneity of HER2-low breast cancer in a Chinese cohort.
- To identify distinct molecular features and subtypes within HER2-low breast cancer.
- To inform personalized treatment strategies in the era of antibody-drug conjugates.
Main Methods:
- Integrated analysis of genomic, transcriptomic, proteomic, and metabolomic data.
- Establishment of a cohort of 434 Chinese patients with HER2-low breast cancer.
- Comparative analysis of HER2-low tumors with HER2-0 and HER2-positive disease.
Main Results:
- HER2-low tumors are more distinct from HER2-0 tumors in the hormone receptor-negative subgroup.
- Significant heterogeneity exists within HER2-low tumors, with basal-like resembling HER2-0 and non-basal-like mimicking HER2-positive disease.
- Non-basal-like HER2-low tumors show PIK3CA mutations, specific gene overexpression (FGFR4/PTK6/ERBB4), and activated lipid metabolism.
Conclusions:
- HER2-low breast cancer exhibits substantial molecular heterogeneity, influenced by hormone receptor status and molecular subtype.
- Precise stratification based on these factors is essential for optimizing treatment selection.
- Further research is needed to fully elucidate the therapeutic implications of these findings.
