Owing to its advantages over prior relevant technologies, massive parallel or next-generation sequencing (NGS) is rapidly evolving, with growing applications in a wide range of human diseases. The burst in actionable molecular alterations in many cancer types advocates for the practicality of using NGS in the clinical setting, as it permits the parallel characterization of multiple genes in a cost- and time-effective way, starting from low-input DNA. In advanced clinical practice, the oncological management of colorectal cancer requires prior knowledge of KRAS, NRAS, and BRAF status, for the design of appropriate therapeutic strategies, with more gene mutations still surfacing as potential biomarkers. Tumor heterogeneity, as well as the need for serial gene profiling due to tumor evolution and the emergence of novel genetic alterations, have promoted the use of liquid biopsies—especially in the form of circulating tumor DNA (ctDNA)—as a promising alternative to tissue molecular analysis. This review discusses recent studies that have used plasma NGS in advanced colorectal cancer and summarizes the clinical applications, as well as the technical challenges involved in adopting this technique in a clinically beneficial oncological practice.
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