Nipple aspirate fluid as a proximal breast liquid biopsy platform: advancing precision risk management in breast...

Current breast cancer (BC) risk management relies primarily on imaging and blood‑based liquid biopsies. However, these approaches are constrained by morphological blind spots, limited sensitivity for early lesions, and an inability to directly capture the biology of the ductal microenvironment where most tumors originate. There is a pressing need for novel strategies that provide direct, local insight into breast tissue risk.

This review repositions nipple aspirate fluid (NAF) as a proximal, breast-specific liquid biopsy platform. Emerging evidence demonstrates that NAF, obtained by nipple aspiration from non-lactating breasts and not limited to cases of spontaneous nipple discharge, originates from a functionally autonomous ductal microenvironment and provides rich multi-omics information, including proteins, metabolites, epigenetic alterations, extracellular vesicles, inflammatory/oxidative mediators, microbiome-associated signals, and other local regulatory readouts, rather than simply representing a filtrate of blood. We summarize the biological foundations of NAF and its multi-omics landscape, highlighting its potential in three key clinical scenarios: (1) molecular risk stratification for pathologic nipple discharge, (2) individualized biological risk profiling in women with high-risk or dense breasts, and (3) proximal monitoring of treatment response and microenvironmental dynamics in patients with diagnosed BC.

Although standardization and prospective validation remain essential challenges, the development of robust collection protocols, integration of multi‑omics data, and execution of well‑designed clinical trials could enable NAF to shift BC management from a paradigm of "early detection" toward one of "precision risk insight and intervention," ultimately aiming to improve patient outcomes and net benefit.