Circulating tumor DNA (ctDNA) monitoring before and after surgery predicted relapse and survival outcomes in patients with early breast cancer more accurately than standard measures of treatment response, according to a prospective study published in EMBO Molecular Medicine.
Researchers followed 136 patients undergoing neoadjuvant treatment for early breast cancer and monitored ctDNA levels across nearly 1,500 plasma samples collected over a median follow-up of 6.5 years. The study evaluated a personalized assay that tracks structural variants, large-scale genomic alterations unique to each patient’s tumor, using multiplex digital PCR.
The investigators found that persistence of ctDNA after neoadjuvant therapy was strongly associated with recurrence and death. Patients whose ctDNA cleared during treatment had substantially better outcomes, while those with ongoing ctDNA detection faced markedly higher relapse risk. Importantly, ctDNA dynamics appeared more prognostic than pathologic complete response, which is currently widely used to assess treatment effectiveness after neoadjuvant therapy.
The assay also identified molecular residual disease after surgery, often long before recurrence became clinically apparent. Among patients who later developed distant metastases, ctDNA detection preceded clinical relapse by a median of 13.8 months and, in some cases, by almost four years.
The study highlights the growing clinical relevance of ultrasensitive liquid biopsy testing in routine cancer management. Unlike many existing ctDNA approaches that focus on single nucleotide mutations, the assay targets tumor-specific structural variants identified through low-coverage whole-genome sequencing. The authors argue that these structural changes may provide greater specificity and stability for longitudinal monitoring because they are less likely to arise from technical artifacts or age-related clonal hematopoiesis.
The workflow was designed with scalability in mind. After tumor sequencing establishes a personalized “fingerprint,” follow-up testing can be performed using digital PCR, a platform that offers relatively rapid turnaround times and lower analytical complexity than next-generation sequencing-based monitoring.
The findings support broader integration of ctDNA testing into breast cancer surveillance and treatment stratification, particularly for identifying patients at high risk of relapse despite apparently successful therapy.
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