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

Area of Science:

• Oncology
• Pathology
• Biomarker Analysis

Background:

• Triple-negative breast cancer (TNBC) is operationally defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and HER2 expression.
• Current diagnostic criteria ensure reproducibility but overlook the biological heterogeneity within TNBC.
• TNBC is a clinicopathological category based on fixed biomarker thresholds applied to continuous receptor expression levels.

Purpose of the Study:

• To review the evolution of hormone receptor assessment in breast cancer diagnosis.
• To analyze the diagnostic and clinical implications of ER-low-positive tumors and evolving HER2 testing criteria.
• To propose a framework for classifying TNBC considering its biological heterogeneity and diagnostic nuances.

Main Methods:

• Review of diagnostic criteria evolution for ER, PR, and HER2 expression.
• Analysis of implications of current and evolving testing guidelines on TNBC classification.
• Examination of histological heterogeneity within TNBC.
• Proposal of a pragmatic three-tier classification framework.

Main Results:

• The definition of TNBC relies on diagnostic thresholds (e.g., ≥1% ER positivity) rather than a discrete molecular entity.
• ER-low-positive tumors (1-10% ER) and evolving HER2 testing criteria (including HER2-low) challenge traditional TNBC classification.
• Guideline variations and histological heterogeneity contribute to classification complexities.

Conclusions:

• TNBC is a regulatory definition characterized by diagnostic thresholds, encompassing a biologically heterogeneous spectrum.
• Accurate reporting and multidisciplinary decision-making require awareness of definitional sensitivity at receptor cut-off margins.
• Recognizing TNBC heterogeneity impacts therapeutic selection, clinical trial eligibility, and future classification refinement.