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

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.

Prognostic value and relapse pattern of HER2‐low in hormone receptor‐positive breast cancer

“…In addition, compared with the hormone receptor‐negative subgroup, the molecular characteristics of breast cancer with HER2‐low and HER2‐zero were more similar in the hormone receptor‐positive subgroup. 12 This may explain why there was no significant difference in prognosis between the HER2‐low and HER2‐zero groups in our study.…”

“…However, in another study, no significant differences in luminal‐associated gene expression or higher endocrine sensitivity scores were observed in hormone receptor‐positive HER2‐low breast cancer. 12 Lower levels of 17q21.31 and 17q11.2 loss/deletion were also observed in HER2‐low breast cancer than in HER2‐zero breast cancer, which was correlated with a better prognosis in hormone receptor‐positive patients. 12 Different studies have reached different conclusions as to whether there is a prognostic difference between the HER2‐low group and the HER2‐zero group in breast cancer.…”

“… 12 Lower levels of 17q21.31 and 17q11.2 loss/deletion were also observed in HER2‐low breast cancer than in HER2‐zero breast cancer, which was correlated with a better prognosis in hormone receptor‐positive patients. 12 Different studies have reached different conclusions as to whether there is a prognostic difference between the HER2‐low group and the HER2‐zero group in breast cancer. A previous meta‐analysis of 14 studies found that among patients with early‐stage hormone receptor‐positive BC, compared to the HER2‐zero BC, the HER2‐low BC had significantly favorable OS, DFS, and relapse‐free survival (RFS).…”

“…This may be related to the fact that all of the breast cancers in our study were hormone receptor‐positive. Recently, a large‐scale multiomics study 12 has shown that the difference between HER2 IHC 1+ and IHC 2+ breast cancer in the hormone receptor‐negative subgroup was more significant than in the hormone receptor‐positive subgroup at the levels of the transcriptome, proteome, and metabolome. In addition, compared with the hormone receptor‐negative subgroup, the molecular characteristics of breast cancer with HER2‐low and HER2‐zero were more similar in the hormone receptor‐positive subgroup.…”

“… 3 Also, there is heterogeneity in the HER2‐low breast cancer. A cohort 12 of 434 Chinese patients with HER2‐low breast cancer with multiomics data has shown that HER2‐low is more distinct from HER2‐zero in triple negative breast cancer (TNBC) compared with hormone receptor‐positive breast cancer. Basal‐like breast cancer is like HER2‐zero breast cancer, and non‐basal‐like HER2‐low breast cancer is like HER2‐positive breast cancer in molecular characteristics.…”