Emerging Breast Cancer Subpopulations: Functional Heterogeneity Beyond the Classical Subtypes

Abstract

Breast cancer (BC) is increasingly recognized as a heterogeneous disease, with complexity that extends beyond the classical luminal A/B, HER2-enriched, and triple-negative framework. Advances in molecular and functional profiling have uncovered emerging subpopulations, including HER2-low, claudin-low, BRCA-deficient (“BRCAness”), and refined TNBC subsets, such as luminal AR (LAR) and basal-like immune variants, that extend beyond traditional taxonomies. These novel classifications provide additional resolutions, offering both prognostic insight and therapeutic opportunities. In this comprehensive review, we integrate evidence from genomic, epigenetic, proteomic, immune-related, and liquid biopsy biomarkers, underscoring how they define the biology of these subgroups and predict responses to targeted therapies, such as antibody–drug conjugates, PARP inhibitors, and immune checkpoint blockade. We further highlight the role of the tumor microenvironment (TME) and intratumoral heterogeneity in shaping these entities. Collectively, recognition of emerging subtypes as clinically actionable groups represents a paradigm shift from static receptor-based models to dynamic, biomarker-driven frameworks that refine prognosis, enable patient stratification, and support precision oncology in aggressive BC.