Methylation-based ctDNA monitoring in metastatic breast cancer during CDK4/6 inhibitor therapy.
prospective_cohort · Level II
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- Record sourced from PubMed, PMID 42243127.
- Also identified by DOI 10.1038/s41467-026-73126-9.
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Abstract
Circulating tumor DNA (ctDNA) enables minimally invasive treatment monitoring, yet the clinical validity of longitudinal ctDNA surveillance in metastatic breast cancer remains incompletely defined. Here we show that methylation-based tumor fraction (mTF), a tissue-agnostic epigenomic measure of ctDNA, closely mirrors radiographic response and clinical outcomes in 57 patients with estrogen receptor-positive, HER2-negative metastatic breast cancer receiving endocrine therapy with a CDK4/6 inhibitor across 350 serial plasma timepoints. Baseline ctDNA is detectable in 94.7% of patients. Clearance of mTF on treatment is associated with prolonged time to treatment discontinuation (HR = 0.17, 95% CI: 0.07-0.41; p < 0.0001). A rise in mTF (molecular progression) precedes treatment discontinuation by a median of 5.8 months and outperforms mutation-based tracking, with resistance-associated alterations in ESR1 and RB1 frequently emerging at molecular progression. These findings support prospective evaluation of mTF-guided treatment strategies.