HER2 Low and Ultralow Breast Cancer: A Narrative Review of Evolving Classification, Diagnostic Challenges, and Antibody–Drug Conjugate Therapy

The advent of next-generation antibody-drug conjugates (ADCs), notably trastuzumab deruxtecan (T-DXd), has fundamentally reshaped the classification of human epidermal growth factor receptor 2 (HER2) in breast cancer, moving beyond a traditional binary paradigm. This review synthesizes the evolution towards a graded HER2 spectrum encompassing HER2-low (IHC 1+ or 2+/ISH-negative) and HER2-ultralow categories, which now carry direct therapeutic implications. While these categories define actionable populations for ADC therapy, they expose significant diagnostic challenges, including substantial interobserver variability, pre-analytical fragility, and biological heterogeneity at low expression levels. Molecular analyses indicate that HER2-low does not constitute a distinct intrinsic subtype but is primarily a theranostic label on the ERBB2 expression continuum, with clinical behavior largely governed by hormone receptor status. Clinically, T-DXd has demonstrated significant survival benefit in metastatic HER2-low breast cancer, establishing a new standard of care and altering treatment algorithms. However, its integration necessitates optimized, reproducible HER2 testing protocols and vigilant management of toxicities, particularly interstitial lung disease. Future directions require refined diagnostic standardization, biological stratification within HER2-low/ultralow cohorts, and strategies to navigate an increasingly complex therapeutic landscape involving sequencing and combination therapies.