Analysis of clinical features, genomic landscapes and survival outcomes in HER2-low breast cancer

Abstract

Background Novel human epidermal growth factor receptor 2 (HER2)-directed antibody–drug conjugates prompt the identification of the HER2-low subtype. However, the biological significance of HER2-low expression in breast cancer is unclear. Methods Clinical and genomic data of 579 metastatic breast cancer patients were reviewed from our next-generation sequencing (NGS) database and genomic analysis of early breast cancer patients from TCGA was also analyzed. Findings First, the clinicopathological characteristics of HER2-low patients were profoundly influenced by HR status and no difference of prognosis was observed between HER2-low and HER2-zero patients when paired by HR status, but notably HER2-low patients showed similar metastatic patterns to HER2-positive patients in the HR-positive (HR+ ) subgroup, with more brain and initial lung metastases and more cases of de novo stage IV breast cancer than HER2-zero patients. Second, among patients with primary HER2-low or HER2-zero tumors, the discordance of HER2 status between primary and metastatic tumors was significant, with 48.4% of patients with HER2-zero primary tumors exhibiting HER2-low phenotype in metastatic tumors in the HR+ subgroup. Third, within HR+ and HR-negative subtypes, HER2-low and HER2-zero tumors showed no substantial differences in mutation alterations and copy number variations. Forth, germline BRCA2 mutations were observed only in HER2-low patients in our NGS database, especially in HR+ HER2-low tumors. Finally, three molecular subtypes based on genomic alterations in HER2-low breast cancer were identified, which provided novel insights into heterogeneity in HER2-low breast cancer. Conclusions After correcting for HR expression, only marginal differences in clinical and molecular phenotypes were determined between HER2-low and HER2-zero breast cancer. Therefore, HER2-low breast cancer is insufficient to be defined as a distinct molecular entity, but rather a heterogenous disease.

HER2-Low Breast Cancer: Now and in the Future

“…Jin et al [ 15 ] conducted next-generation sequencing on their metastatic breast cancer (mBC) cohort (n=445) and the TCGA dataset. They found no significant differences in common gene mutations and copy number variations between HER2- low and HER2-zero tumors after correcting for HR status.…”

New insights into HER2-low breast cancer brain metastasis: A retrospective analysis

“…Recent studies suggest that HER2-low breast cancer may have different clinicopathological characteristics and outcomes compared to HER2-positive or HER2-negative breast cancers [ [5] , [6] , [7] ]. Two recent studies conducted by Guven et al [ 8 ] and Jin et al [ 9 ] have both demonstrated a correlation between HER2-low disease and an elevated risk of brain metastasis compared with HER2-zero breast cancer, particularly within the HR-positive subgroup.…”