Breast Cancer Care Is Shifting From Subtypes to Precision Molecular Medicine

Why it matters: Breast cancer is the most common cancer and the leading cause of cancer death in women worldwide. In 2022 there were roughly 2.3 million new cases and 670,000 deaths, about 25% of new cancer diagnoses and 15.5% of cancer deaths in women. Projections suggest incidence will rise 38% and mortality 68% by 2050, with the heaviest burden in countries with low human development index scores. Screening access is uneven, and women in low- and middle-income countries tend to be diagnosed later and die more often.

What the review covers: This is a narrative review of four linked areas: molecular pathogenesis, targeted therapy, screening, and prevention. Standard classification uses immunohistochemistry for ER, PR, HER2, and Ki-67 to define Luminal A, Luminal B, HER2-enriched, and triple-negative disease. The authors describe a move toward omics-driven classification, including single-cell and spatial transcriptomics and circulating cell-free DNA sequencing, which reveal intratumoral heterogeneity and rare cell populations tied to resistance and metastasis.

Key points from the portions available: Germline BRCA1/2 variants are the most common hereditary risk factor, and PALB2, BARD1, PTEN, TP53, ATM, and CHEK2 also raise risk. Somatic TP53 mutations occur in over 30% of tumors and are especially common in TNBC. PIK3CA mutations reach up to 40% of ER-positive disease. ESR1 mutations arise after endocrine therapy and drive ligand-independent resistance. Several of these are actionable: alpelisib for PIK3CA, PARP inhibitors (olaparib, talazoparib) for germline BRCA1/2, and fulvestrant or CDK4/6 inhibitor combinations for ESR1-related resistance. The introduction cites trastuzumab deruxtecan extending HER2-directed therapy to HER2-low disease, capivasertib plus fulvestrant improving progression-free survival in tumors with PIK3CA, AKT1, or PTEN alterations (CAPItello-291), and pembrolizumab plus chemotherapy extending survival in PD-L1-high TNBC (KEYNOTE-355). The epigenetics section describes reversible DNA methylation, histone modification, chromatin remodeling, and noncoding RNA networks, with unbalanced methylation especially pronounced in TNBC.

Implications: On the screening and prevention side, the authors highlight digital breast tomosynthesis, MRI, contrast-enhanced mammography, and AI-assisted interpretation, with AI reported to raise cancer detection by 13–18%. Polygenic risk scores may allow finer lifetime risk estimates than the Gail model, guiding enhanced screening or preventive therapy. The authors expect comprehensive molecular profiling to become routine, much like ER/PR/HER2 testing today.

Caveats: The authors note unresolved problems: drug resistance, toxicity, global inequity, suboptimal risk stratification, and inconsistent screening guidelines, such as the starting age for average-risk women. Noncoding variants are poorly annotated, and multiomics integration lacks standardization. The text supplied for this summary ended partway through the epigenetics section, so the therapy-resistance, screening-trial, and prevention sections were not reviewed in detail.