Evolving Perspectives in Clinical Landscape and Molecular Characteristics of HER2-Low Breast Cancer and Beyond

Background: The novel HER2-directed antibody-drug conjugates prompt the identification of the HER2-low subtype in breast cancer, defined as HER2 immunohistochemical (IHC) 1+, or 2-positive without ERBB2 amplification.Methods: Our retrospective study reviewed clinical and biological data from 579 metastatic breast cancer patients undergoing Next Generation Sequencing (NGS) testing.Results: First, HER2-low tumors were more frequently HR (hormone receptor)-positive and the clinicopathological characteristics of HER2-low patients were associated with HR status. Second, quite a number of HER2-zero (HER2 IHC-0) primary tumors would translate to HER2-low ones in the metastatic sites, even up to 48.4% in HR-positive tumors, highlighting the importance of revaluation of metastatic lesions. Third, the metastatic traits of HER2-low tumors were more like to HER2-positive ones in HR-positive subtype with more brain and lung metastasis and de novo stage IV breast cancer. Fourth, although mutation, copy number variation and mRNA profiles were similar between HER2-low and HER2-zero tumors, different to HER2-positive ones, some differences still were observed between HER2-low and HER2-zero tumors, including rates of BRCA2 germline mutations and PIK3CA and TP53 somatic mutations. Fifth, HER2-low tumors had a longer overall survival (OS) and disease-free survival (DFS) versus HER2-zero tumors, but no difference was observed when paired by HR status. Finally, three molecular subtypes based on genomic alterations in HER2-low breast cancer were identified and Cluster 2 enriched of TP53 mutations was significantly associated worse clinical outcomes, which provided novel insights into heterogeneity in HER2-low breast cancer.Conclusions: Although the clinical and molecular significance of HER2-low status was influenced by HR status, HER2-low tumors indeed had some distinct features in subtype analysis based on HR status. Our results of molecular subtypes in HER2-low tumors encouraged clinicians to concern the heterogeneity in HER2-low breast cancer.