Impact of Early Changes in Circulating Cell-Free DNA Load on Outcome in Metastatic Luminal Breast Cancer Patients

Abstract

Abstract

Background: Circulating cell-free DNA (cfDNA) is a promising non-invasive biomarker that reflects tumor burden and treatment dynamics in metastatic breast cancer (MBC). However, the prognostic significance of early cfDNA changes in hormone receptor–positive, HER2-negative (luminal) subtypes remains insufficiently defined.

Methods: This prospective study included 50 patients with metastatic HR+/HER2– breast cancer treated at Alexandria University between January 2022 and December 2023. Plasma cfDNA levels were quantified at baseline and after 3–4 weeks of therapy using real-time PCR targeting the β-actin gene. Patients were classified based on early cfDNA kinetics (≥10% decrease vs. no decrease/increase). Progression-free survival (PFS), overall survival (OS), and objective response rates (ORR) were analyzed using Kaplan–Meier and Cox regression models.

Results: Median baseline cfDNA was 86.4 ng/mL (range 12–410). Early cfDNA decline occurred in 62% of patients and was associated with higher ORR (52% vs. 18%, p=0.021). Patients with early cfDNA decrease had significantly longer median PFS (14.2 vs. 6.3 months; HR 0.48, 95% CI 0.26–0.88, p=0.016). Multivariate analysis identified early cfDNA decrease (HR 0.42, p=0.009) and endocrine-based therapy (HR 0.55, p=0.041) as independent predictors of prolonged PFS. Median OS was not reached in patients with cfDNA decrease versus 16.5 months in those without (p=0.044).

Conclusions: Early reduction in cfDNA load within the first month of systemic therapy predicts improved outcomes in metastatic HR+/HER2– breast cancer. cfDNA dynamics represent a minimally invasive and practical biomarker that may complement radiologic assessment and support earlier treatment decision-making. Larger studies integrating molecular profiling are warranted to validate the clinical utility of cfDNA kinetics.