HER2-low and ultra-low breast cancer: expanding the therapeutic spectrum in precision oncology

The classification of breast cancer has undergone a paradigm shift with the identification of HER2-low and HER2-ultra-low subtypes, representing a continuum of HER2 protein expression. These categories challenge the traditional binary system of HER2-positive and HER2-negative cancers, offering new insights into tumor biology and therapeutic opportunities. This review was done to look into the emerging concepts of HER2-low and ultra-low breast cancers, their molecular characteristics, diagnostic challenges, and evolving therapeutic landscape. A comprehensive review of recent literature was conducted, focusing on definitions, diagnostic criteria, and clinical implications of HER2-low (immunohistochemistry (IHC) 1 + or 2+, FISH-negative) and HER2-ultra-low (IHC 0 with faint staining) breast cancers. Emphasis was placed on assay standardisation, emerging diagnostic modalities, and ongoing clinical trials evaluating targeted therapies. HER2-low and ultra-low tumors demonstrate distinct molecular signatures and clinical behaviours compared with both HER2-positive and completely HER2-negative counterparts. Conventional immunohistochemistry often fails to accurately distinguish these subgroups due to limited sensitivity. Novel, standardised, and more sensitive assays are essential to reliably identify these categories. Several ongoing trials are exploring the efficacy of novel anti-HER2 agents and antibody-drug conjugates in these subtypes, indicating promising therapeutic potential. Recognition of HER2-low and HER2-ultra-low breast cancers marks a critical evolution in breast cancer pathology and precision oncology. Improved diagnostic tools and targeted therapies may enable more personalised treatment approaches, refining prognostic assessment and improving patient outcomes.