Capturing Tumor Heterogeneity and Clonal Evolution by Circulating Tumor DNA Profiling

Abstract

Most malignancies are characterized by remarkable molecular heterogeneity. The understanding of genetic and epigenetic processes underlying tumor heterogeneity has become increasingly important for the clinical management of cancer patients. This includes the identification of patients who likely benefit from conventional or targeted therapies, classification of patients into risk groups based on their mutational landscape, and the detection of molecular mechanisms that drive treatment resistance and cancer progression. Detection of tumor heterogeneity by tumor tissue genotyping is hampered by the fact that tissue sampling is often insufficient for comprehensive genetic assessment and is associated with a higher risk of surgical complications. Detection and profiling of circulating tumor DNA (ctDNA) have emerged as a promising alternative to direct tumor genotyping. It potentially enables noninvasive and quantitative characterization of the full genetic landscape and identification of clonal evolution during treatment and towards disease progression in cancer patients. In the present chapter, we explore the role of noninvasive genotyping and ctDNA profiling for accurate and robust characterization of various types of tumor heterogeneity and its relevance for management of patients with hematologic and solid cancers.