Molecular Classification of Breast Cancer and Its Implications for Contemporary Management: A PRISMA-Guided Narrative Review

Background: Breast cancer is biologically heterogeneous, and gene-expression studies have demonstrated clinically relevant intrinsic subtypes with differing patterns of prognosis and treatment response. Contemporary management, however, does not rely on intrinsic subtype alone; clinicopathological factors, immunohistochemistry (IHC), in situ hybridization, validated genomic assays, germline alterations, and treatment-specific biomarkers are integrated to guide therapy. Objective: This paper aims to review the evolution of molecular classification of breast cancer and critically summarize how molecular and biomarker information informs contemporary diagnosis, prognostication, systemic treatment, and precision-oncology strategies. Methods: A PRISMA-guided narrative review was conducted using PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library, and Google Scholar, with reference-list screening of landmark molecular studies, clinical trials, and major guidelines. Searches covered database inception through June 2025. Titles and abstracts were screened, followed by full-text assessment; two reviewers independently screened and extracted data, with disagreements resolved by discussion and, when necessary, a third reviewer. Evidence was synthesized narratively, with explicit separation of intrinsic molecular subtypes, prognostic assays, predictive biomarkers, and treatment-eligibility biomarkers. Results: The reviewed evidence supports a layered model of classification. Intrinsic subtypes are transcriptomic constructs and are not interchangeable with routine IHC-defined clinical categories; in particular, HER2-enriched is not defined by ERBB2 amplification. Validated genomic assays have assay- and population-specific roles in HR-positive/HER2-negative early breast cancer, ranging from recurrence-risk estimation to chemotherapy-benefit assessment in defined populations. In TNBC, treatment selection is driven primarily by disease setting and validated biomarkers such as germline BRCA1/2 and PD-L1 in specific metastatic contexts, whereas proposed transcriptomic subclasses remain investigational. HER2-low is a treatment-relevant IHC expression category rather than an intrinsic molecular subtype. Overall, molecular information is most useful when integrated with stage, pathology, receptor status, and patient factors. Conclusion: Molecular classification has moved breast oncology from morphology-based categorization toward biologically informed treatment selection. Its greatest clinical value arises when molecular