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Liquid biopsies are emerging as promising approaches to capture minimal residual disease (MRD) and interpret the heterogeneity of pathological responses after neoadjuvant therapy for patients with early stage cancers. Minimally invasive analyses of circulating cell-free tumor DNA (ctDNA) are enabled by advances in next generation sequencing and bioinformatic methodologies, resulting in sensitive and specific ctDNA detection. Emerging data supports the clinical utility of ctDNA status at different timepoints during the treatment trajectory and ctDNA MRD has been shown to predict clinical outcomes. Herein, we critically review ctDNA technologies and their analytical performance together with an assessment of the clinical sensitivity of these approaches to predict disease recurrence.