Detection of Solid Tumor Molecular Residual Disease (MRD) UsingCirculating Tumor DNA (ctDNA)

摘要

Circulating tumor DNA (ctDNA) is a component of cell-free DNA that is shed by malignant tumors into the bloodstream and other bodily fluids. Levels of ctDNA are typically low, particularly in patients with localized disease, requiring highly sophisticated methods for detection and quantification. Multiple liquid biopsy methods have been developed for ctDNA analysis in solid tumor malignancies and are now enabling detection and assessment of earlier stages of disease, post-treatment molecular residual disease (MRD), resistance to targeted systemic therapy, and tumor mutational burden. Understanding ctDNA biology, mechanisms of release, and clearance and size characteristics, in conjunction with the application of molecular barcoding and targeted error correction, have increased the sensitivity and specificity of ctDNA detection techniques. Combinatorial approaches including integration of ctDNA data with circulating protein biomarkers may further improve assay sensitivity and broaden the scope of ctDNA applications. Circulating viral DNA may be utilized to monitor disease in some virally induced malignancies. In spite of increasingly accurate methods of ctDNA detection, results need to be interpreted with caution given that somatic mosaicisms such as clonal hematopoiesis of indeterminatepotential (CHIP) may give rise to genetic variants in the bloodstream unrelatedto solid tumors, and the limited concordance observed between differentcommercial platforms. Overall, highly precise ctDNA detection and quantificationmethods have the potential to transform clinical practice via non-invasivemonitoring of solid tumor malignancies, residual disease detection at earliertimepoints than standard clinical and/or imaging surveillance, and treatmentpersonalization based on real-time assessment of the tumor genomiclandscape.