DCIS Redefined: Circulating Tumor Cells Prove Early Dissemination and Challenge the 'Preinvasive' Label

There is a widespread overtreatment of ductal carcinoma in situ (DCIS), a "stage 0" breast cancer, due to the lack of reliable biomarkers to predict which cases will progress to invasive disease.

A recent study published last month in Science Advances suggests that cancer cells can disseminate from the primary tumor before any clinical evidence of invasion, entering the bloodstream as circulating tumor cells (CTCs). By isolating and analyzing these CTCs, the researchers provided compelling evidence for this "early dissemination" hypothesis.

DCIS represents a non-obligate precursor to invasive breast cancer. While many cases remain indolent, up to half may progress to invasive disease if untreated. The clinical predicament lies in the absence of reliable prognostic biomarkers to distinguish low-risk from high-risk patients. As a result, overtreatment is common: women undergo surgery, radiation, and endocrine therapy despite uncertain survival benefit.

The central question addressed by Sunitha Nagrath, Ph.D., a professor from the department of chemical engineering at the University of Michigan, and her team is whether CTCs can serve as predictive biomarkers of biological aggressiveness and early dissemination in DCIS, thereby improving risk stratification and reducing unnecessary interventions.

Current management of DCIS is largely preventive and aggressive. Approximately 50% of patients undergo lumpectomy with radiation, 20% receive mastectomy or lumpectomy alone, and hormone receptor–positive cases are often prescribed adjuvant endocrine therapy. While these approaches reduce local recurrence, they have not demonstrated a survival advantage.

The five-year survival rate for DCIS is already high (≈98%), yet once progression to invasive or metastatic disease occurs, survival drops precipitously. Thus, the standard of care errs on the side of overtreatment, exposing patients to the morbidity of surgery, radiation, and endocrine therapy without clear evidence of improved long-term outcomes.

Nagpal and team enrolled 34 patients with DCIS and applied a multi-pronged approach. CTC enrichment and enumeration were obtained using the microfluidic Labyrinth device after researchers isolated CTCs from patient blood samples. CTCs were identified via immunofluorescence. Comparative analysis of CTCs was profiled alongside matched DCIS tissue using single-cell RNA sequencing. Copy number variation analysis and gene expression profiling were performed to assess clonal relationships.

The Mouse-INtraDuctal (MIND) model was used to provide functional evidence of early dissemination. Human-derived DCIS cells were injected into the mammary ducts of immunocompromised mice, and blood samples were longitudinally monitored for the appearance of CTCs before the development of invasive tumors.

Nagrath and team demonstrated that 76% of the 34 DCIS patients studied had significantly higher concentrations of CTCs compared to healthy controls. Patients with DCIS had a median of 6.1 CTCs per mL of blood, significantly higher than the median of 0.92 CTCs per mL in healthy controls (P < 0.0001). CTC concentration demonstrated high sensitivity and specificity in differentiating patients with DCIS from healthy controls, with an area under the curve (AUC) of 0.9097.

The study uncovered a stark difference in CTC concentrations based on race, suggesting a biological basis for known disparities in breast cancer outcomes. Black patients (n=6) had a median of 16 CTCs per mL of blood, a count significantly higher than that of white patients (n=28), who had a median of 5 CTCs per mL (P = 0.0263). Single-cell analysis revealed that CTCs from Black patients exhibited notable suppression of immune regulation pathways (specifically natural killer cell-mediated cytotoxicity). This suppression was not observed in the CTCs of white patients, potentially explaining the higher CTC survival and concentration in Black patients.

A single-cell molecular study of CTCs and corresponding original tumor tissues substantiates an "evolutionary bottleneck model," wherein only specific, aggressive cell clones enter circulation, gaining distinct genetic modifications associated with metastasis and chemoresistance.

Additional confirmation in a preclinical MIND model substantiates that CTCs manifest when the disease remains in a preinvasive phase. These results confirm that CTCs are a potent, minimally invasive liquid biopsy biomarker with the capacity to transform the management of DCIS by pinpointing high-risk patients necessitating intensive treatment, thus protecting low-risk patients from superfluous and frequently debilitating medicines.

From a managed care point of view, the present "one-size-fits-all" approach to DCIS results in overtreatment, extra expenses, and avoidable patient morbidity. Using CTC tests in clinical practice could help figure out who is at risk. Patients with a large CTC load or aggressive molecular markers could be directed toward systemic medicines or more intensive monitoring, whereas low-risk patients might safely forgo radiation or endocrine therapy.

As payers focus more on results than volume, a validated CTC assay could help doctors make decisions by matching therapy intensity to disease biology and making treatments more cost-effective. Healthcare organizations might advance toward precision risk categorization by adding CTC analysis to clinical workflows. This would improve patient outcomes while lowering overtreatment and the expenses that come with it. CTCs have the potential to not only improve precision oncology but also change how DCIS is treated into a more efficient, fair, and value-driven paradigm.