HER2 ultralow in metastatic breast cancer: Diagnostic boundaries in the era of antibody-drug conjugates.

The introduction of antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan (T-DXd) has challenged the traditional binary classification of HER2 in breast cancer. Evidence from the DESTINY-Breast04/06 and DAISY trials demonstrates clinically meaningful antitumour activity across a continuum of HER2 expression, including HER2-low and HER2-ultralow categories, while efficacy in HER2-null tumours remains uncertain. Despite this graded biological response, regulatory criteria remain categorical, requiring detectable membrane staining for treatment eligibility and excluding IHC 0 tumours. Pathologists face diagnostic challenges at the null-ultralow boundary, where conventional immunohistochemistry (IHC) assays operate near their analytical limits, reproducibility is constrained, and inter-observer variability is high. Pathologists should exercise caution when assigning IHC 0, and practical measures such as reflexive re-evaluation, re-staining of alternative blocks, and referral to high-sensitivity laboratories are recommended. Transparent communication of analytical uncertainty is essential to optimise patient access to ADC therapy.