Circulating tumor DNA in early-stage triple-negative breast cancer: clinical landscape and key open challenges

Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for noninvasive detection of minimal residual disease (MRD), prognosis, and treatment monitoring in early-stage triple-negative breast cancer (eTNBC), an aggressive subtype with high relapse risk. This review synthesizes the state-of-the-art and the advances in ctDNA technologies and evaluates their clinical relevance across the neoadjuvant, postneoadjuvant, and adjuvant settings.

We highlight the most recent (last 18-24 months) key prospective studies demonstrating ctDNA's potential to predict pathological response and recurrence, emphasizing the prognostic value of the ctDNA dynamics and the implications of persistent positivity. We discuss tumor-informed versus tumor-agnostic assays, address challenges in detecting MRD, and explore future directions, including ultrasensitive detection strategies, novel methylation and machine learning-based approaches, and ctDNA-guided therapeutic interventions.

Despite encouraging results, the clinical utility of ctDNA remains unproven due to technical limitations, especially in assay sensitivity, timing of testing, and low ctDNA shedding/high relapse rate in early-stage disease. Randomized trials are essential to confirm the role of ctDNA in guiding treatment de-escalation or escalation, ultimately aiming to personalize care and improve outcomes in patients with eTNBC.