Triple-negative breast cancer: a threshold-defined diagnostic category within a biological continuum

Triple-negative breast cancer (TNBC) is defined in routine practice by the absence of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expression using fixed immunohistochemical and in situ hybridisation cut-offs. Although this framework ensures reproducibility and regulatory consistency, it does not equate to biological uniformity. TNBC is an operational clinicopathological category defined by reproducible biomarker thresholds applied to continuous gradients of receptor expression. This review examines the evolution of hormone receptor assessment from semiquantitative composite scoring systems to the current ≥1% ER positivity threshold, and analyses the diagnostic and clinical implications of ER-low-positive (1%-10%) tumours. We discuss the rarity and interpretative challenges of ER-/PR+ phenotypes, the impact of evolving HER2 testing criteria, including borderline amplification and HER2-low categories, and the consequences of guideline variation on TNBC classification. We also address histological heterogeneity within TNBC and propose a pragmatic three-tier framework that distinguishes definite TNBC, context-dependent/borderline TNBC and non-TNBC categories. Collectively, these considerations highlight that TNBC is a regulatory definition anchored to diagnostic thresholds rather than a discrete molecular entity. Awareness of definitional sensitivity at receptor cut-off margins is essential for accurate reporting, avoidance of misclassification and informed multidisciplinary decision-making. Recognition of TNBC as a biologically heterogeneous spectrum has implications for therapeutic selection, trial eligibility and future refinement of classification systems.