Molecular features and clinical implications of the heterogeneity in Chinese patients with HER2-low breast cancer

Sep 24, 2026

Molecular heterogeneity of HER2-low breast cancer in Chinese patients remains insufficiently characterized, limiting precise treatment decisions in the antibody–drug conjugate era. A cohort of 434 Chinese HER2-low cases was profiled using integrated genomic, transcriptomic, proteomic, and metabolomic analyses. HER2-low tumors show distinct separation from HER2-0 in hormone receptor–negative disease, with basallike-like versus non-basal-like patterns linked to subtype enrichment and pathway features. Findings also highlight altered 17q loss/deletion in hormone receptor–positive tumors and support refined stratification by hormone receptor status and molecular subtype.

LanguageEnglish

CategoryHealthcare

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Study design and cohort information

Article [https://doi.org/10.1038/s41467-023-40715-x](https://doi.org/10.1038/s41467-023-40715-x) Molecular features and clinical implications of the heterogeneity in Chinese patients with HER2-low breast cancer Received: 15 August 2022 | Accepted: 4 August 2023 | | --- | | | | Check for updates | Lei-Jie Dai 1,2,3,5, Ding Ma 1,2,3,5 , Yu-Zheng Xu1,2,3,5, Ming Li 4,5, Yu-Wei Li1,2,3, Yi Xiao1,2,3, Xi Jin1,2,3, Song-Yang Wu1,2,3, Ya-Xin Zhao1,2,3, Han Wang1,2,3, Wen-Tao Yang 4 , Yi-Zhou Jiang1,2,3 & Zhi-Ming Shao 1,2,3 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: basallike 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. Breast cancer is the most common malignancy in women worldwide and in China1,2. Breast cancers can be subdivided into several subtypes according to hormone receptors(HRs, includingthe estrogen receptor and the progesterone receptor) and human epidermal growth factor receptor 2 (HER2, or ERBB2) status. HER2 is a major driving molecule and a therapeutic target of breast cancer, and HER2 status is determined by immunohistochemistry (IHC) and in situ hybridization (ISH) methods in the clinic3,4. Although HER2-positive diseases (deﬁned as IHC 3+ or 2+ with ISH+) can beneﬁt from anti-HER2 targeted therapies, they account for only 15–20% of all breast cancers5. On the other hand, many more patients bearing tumors with low to moderate levels of HER2, which are called HER2-low breast cancers (IHC 1+ or 2+ with ISH–), have not been considered candidates for conventional antiHER2 therapies during the past two decades. Intriguingly, recent advances regarding anti-HER2 antibody‒drug conjugates (ADCs) have shown promising effects in HER2-low breast cancers6–8. The results from the DESTINY-Breast04 trial proved the efﬁcacy and safety of trastuzumab deruxtecan (T-DXd) in HER2-low breast cancers, where heavily pretreated advanced HER2-low breast cancer patients achieved signiﬁcantly improved survival compared 1Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. 2Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai 200032, China. 3Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. 4Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China. 5These authors contributed equally: Lei-Jie Dai, Ding Ma, Yu-Zheng Xu, Ming Li. e-mail: [dma09@fudan.edu.cn](dma09@fudan.edu.cn); [yangwt2000@163.com](yangwt2000@163.com); [yizhoujiang@fudan.edu.cn](yizhoujiang@fudan.edu.cn); [zhimingshao@fudan.edu.cn](zhimingshao@fudan.edu.cn) with chemotherapy-treated patients8. These results expand our knowledge on the subtyping and treatment of breast cancer, which also emphasizes the importance of this subgroup of patients in future

FAQs

How was the HER2-low patient cohort established and what data types were used?

The study constructed a cohort of 434 Chinese patients with HER2-low breast cancer and integrated genomic, transcriptomic, proteomic, and metabolomic profiling to characterize the disease clinically and molecularly.

How do HER2-low tumors differ from HER2-0 tumors in hormone receptor–negative cases?

HER2-low tumors are more distinguishable from HER2-0 tumors in the hormone receptor–negative subgroup, with HER2-low interpatient heterogeneity separating basallike-like and non-basal-like patterns.

What molecular characteristics are enriched in non-basal-like HER2-low tumors?

Non-basal-like HER2-low tumors are enriched in HER2-enriched and luminal androgen receptor subtypes, featuring PIK3CA mutation, FGFR4/PTK6/ERBB4 overexpression, and activation of lipid metabolism.

Sep 24, 2026

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