Plasma Circular RNAs in Breast Cancer: From Biomarker Potential to Functional Significance

Breast cancer remains life-threatening, but mortality declines with earlier diagnosis. Conventional work-ups rely on invasive tissue biopsy of imaging-detected masses. Liquid biopsy offers a minimally invasive alternative by assessing circulating biomarkers. Among these, circular RNAs (circRNAs) are compelling because their covalently closed structure confers high stability in blood. Recent studies connected circRNAs to malignancy process in breast and proposed their diagnostic potential. This review has collected relevant evidence on circRNA biogenesis, functions and their dysregulated plasma signatures in breast cancer.

Multiple plasma circRNAs showed diagnostic and prognostic signal in breast cancer. Upregulated hsa_circ_0001785 outperformed traditional plasma tumor markers (CEA and CA15-3) for detection of breast cancer; higher plasma levels associated with distant metastasis, advanced TNM stage, and higher grade. Elevated hsa circ_0108942 in plasma correlated with larger tumors, lymph node involvement, and advanced stage. Hsa circ 0042881 was increased in tumors and plasma and correlated with higher TNM stage and larger tumor size. Conversely, downregulated plasma circRNAs, included hsa circ 0068033 with inverse links to stage and tumor size, and hsa_circ_0104824, both are promising for non-invasive diagnosis of breast cancer and prognostication of breast cancer. Subtype-specific circRNAs are also noted: circEGFR was upregulated in triple-negative subtype and aligned with aggressive clinical features and reduced chemotherapy sensitivity, whereas circ-FOXO3 was downregulated and associated with lymph-node metastasis, consistent with a tumor-suppressive role.

Plasma circRNAs represent a biologically grounded class of minimally invasive biomarkers with promise for early detection, risk stratification, and real-time monitoring in breast cancer. To progress toward clinical utility, priorities are larger multi-center cohorts, harmonized reporting standards, head-to-head comparisons with established markers, transparent cut-offs and prospective evaluation of multi-marker panels integrated with imaging and clinicopathologic variables.