Utilizing Plasma Circulating Tumor DNA Sequencing for Precision Medicine in the Management of Solid Cancers

Abstract

Plasma circulating tumor DNA (ctDNA) sequencing has demonstrated clinical utility for tumor molecular profiling at initial diagnosis or tumor progression in advanced solid cancers and is being rapidly incorporated into the clinical practice guidelines, including non-small cell lung and breast cancer. Despite relatively low sensitivity, plasma ctDNA sequencing has several advantages over tissue-based assays, including ease of sampling, rapid turnaround time, repeatability, and the ability to overcome spatial heterogeneity, which makes it ideal for investigating acquired resistance and monitoring tumor evolution and dynamics. With technological advancement and declining costs, the clinical application of plasma ctDNA is expanding, and numerous ongoing clinical trials are examining its potential to guide the management of advanced, localized, and even preclinical cancers of various tumor types. The ability of plasma ctDNA analysis to detect minimal residual disease following curative treatment in the absence of clinical disease is among its most promising attributes. Plasma ctDNA sequencing can also facilitate the conduct of clinical trials and drug development, particularly in immunotherapy. In order to incorporate plasma ctDNA sequencing for clinical decision-making, it is important to understand the preanalytical and analytical factors that may affect its sensitivity and reliability.

Keywords: Circulating tumor DNA; High-throughput nucleotide sequencing; Minimal residual disease; Molecular profiling; Mutation.

Fig. 1

The clinical utility of plasma circulating tumor DNA (ctDNA) sequencing for the management of solid tumors in various clinical scenarios. At each time point, the brown circles represent a major clone within the tumor. Yellow and burgundy ellipses within brown circles represent the development of subclones in tumors at disease progression (PD) following first- and second-line therapy. The limit of detection (LOD) for clinical modalities and plasma ctDNA sequencing is represented by the red and blue dashed lines, respectively.