Early detection remains the single strongest predictor of breast cancer survival, yet current screening tools carry well-documented blind spots—particularly in women with dense breast tissue and in tracking disease trajectory over time. A comprehensive review published in Cancers maps the evolving landscape of blood-based tumor signals that may eventually close this diagnostic gap without repeated needle biopsies.
The review systematically evaluates six distinct biomarker classes extracted from peripheral blood: circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), extracellular vesicles (EVs), circulating RNAs (including microRNAs and long non-coding RNAs), proteins, and composite multi-marker panels. Each captures a different biological dimension of early malignancy. ctDNA analysis goes beyond simple mutation detection—methylation patterns and nucleosome-level fragmentation profiles ('fragmentomics') can distinguish tumor-derived DNA from normal cell-free DNA even when variant allele fractions are vanishingly small. CTCs offer a cellular window into metastatic potential, while EVs carry a cargo of proteins and nucleic acids reflective of the tumor microenvironment. The central challenge highlighted throughout is signal-to-noise: early-stage tumors shed biomarkers at levels that currently push or exceed the sensitivity thresholds of most detection platforms.
This review arrives at a pivotal moment in oncology diagnostics. Multi-cancer early detection (MCED) blood tests are already in late-stage clinical trials, yet breast cancer—the most common female malignancy—has proven particularly difficult to isolate via ctDNA alone at stage I. The field's response has been combinatorial: stacking ctDNA with protein markers (e.g., CA 15-3, HER2 extracellular domain) or EV-derived signatures appears to meaningfully boost sensitivity without sacrificing specificity. The most significant limitation flagged across most included studies is cohort size and the absence of prospective, population-level validation; most evidence comes from small case-control designs that may overestimate real-world performance. Clinically, this review is best categorized as a rigorous synthesis rather than a breakthrough finding—it consolidates scattered evidence and identifies where the evidentiary gaps are largest, making it a useful roadmap for researchers and clinicians tracking when liquid biopsy may enter routine screening workflows.