# Circulating cell-free DNA as an integrative biomarker in breast cancer: correlation with molecular subtypes, mutation status, and treatment response

## TL;DR

This study shows that cell-free DNA (cfDNA) levels in blood can help track breast cancer progression, treatment response, and genetic mutations, especially in underrepresented populations.

## Contribution

The study explores cfDNA dynamics in relation to breast cancer subtypes and mutations in underrepresented populations, offering new insights into its clinical utility.

## Key findings

- Baseline cfDNA levels were significantly higher in breast cancer patients compared to healthy controls.
- TNBC and HER2-enriched subtypes had the highest cfDNA levels, while Luminal A had the lowest.
- TP53-mutated TNBC showed the highest cfDNA increases, suggesting molecular residual disease.

## Abstract

Cell-free DNA (cfDNA) is an emerging non-invasive biomarker in oncology. While its diagnostic and prognostic roles in breast cancer are established, limited studies have examined cfDNA dynamics in relation to molecular subtypes and mutation profiles, particularly in underrepresented populations.

To assess the diagnostic and predictive utility of cfDNA in breast cancer by analyzing its association with molecular subtypes, TP53 and PIK3CA mutations, and treatment response across dual timepoints.

Fifty histologically confirmed breast cancer patients and 20 age-matched healthy controls were enrolled. Baseline and follow-up cfDNA levels were quantified in 32 paired cases. cfDNA dynamics (ΔcfDNA) were analyzed by subtype and mutation status. Diagnostic and predictive performance was evaluated using ROC (Receiver operating characteristic) and Precision–Recall (PR) curve analyses. Mutation distribution and subtype frequencies were compared with global and regional datasets.

Baseline cfDNA levels were significantly elevated in breast cancer patients compared to controls (p < 0.001), with highest levels in TNBC (Triple-negative breast cancer) and HER2-enriched subtypes and lowest in Luminal A. Follow-up cfDNA remained persistently elevated in aggressive subtypes and TP53-mutated cases, suggesting molecular residual disease. ΔcfDNA trends varied, with TP53-mutated TNBC showing the highest increases. PIK3CA mutations were observed in 36% of cases, predominantly E545K (28%), while H1047R was rare (2%). TP53 mutations were detected in 10%. PR analysis showed moderate predictive value for TP53 (Average Precision = 0.72) and PIK3CA (Average Precision = 0.71). A cfDNA threshold of 137 ng/mL achieved 91% sensitivity and 92% specificity (Area Under the Curve = 0.97).

cfDNA levels reflect tumor burden, subtype biology, and mutation status, offering real-time, non-invasive insight into disease dynamics. The high E545K and rare H1047R frequencies suggest underexplored, population-specific genomic patterns. cfDNA trends across subtypes range from persistent elevation in TNBC to decline in Luminal A, suggesting its potential role in treatment monitoring. These findings underscore cfDNA’s relevance to evolving precision oncology frameworks, particularly in biopsy-limited and resource-constrained settings.

Graphical summary illustrating the study workflow and key findings, highlighting cfDNA dynamics across breast cancer molecular subtypes, mutation status (TP53 and PIK3CA), and treatment response.Infographic summarizing a breast cancer study using cell-free DNA as a biomarker, detailing study cohorts, diagnostic power with ROC curve, impact of specific gene mutations, treatment monitoring, and key conclusions about cfDNA’s clinical utility.

Graphical summary illustrating the study workflow and key findings, highlighting cfDNA dynamics across breast cancer molecular subtypes, mutation status (TP53 and PIK3CA), and treatment response.