Utility of circulating tumor DNA in cancer diagnostics with emphasis on early detection

Abstract

Various recent studies have focused on analyzing tumor genetic material released into the blood stream, known as circulating tumor DNA (ctDNA). Herein, we describe current research on the application of ctDNA to cancer management, including prognosis determination, monitoring for treatment efficacy/relapse, treatment selection, and quantification of tumor size and disease burden. Specifically, we examine the utility of ctDNA for early cancer diagnostics focusing on the development of a blood test to detect cancer in asymptomatic individuals by sequencing and analyzing mutations in ctDNA. Next, we discuss the prospect of using ctDNA to test for cancer, and present our calculations based on previously published empirical findings in cancer and prenatal diagnostics. We show that very early stage (asymptomatic) tumors are not likely to release enough ctDNA to be detectable in a typical blood draw of 10 mL. Data are also presented showing that mutations in circulating free DNA can be found in healthy individuals and will likely be very difficult to distinguish from those associated with cancer.We conclude that the ctDNA test, in addition to its high cost and complexity, will likely suffer from the same issues of low sensitivity and specificity as traditional biomarkers when applied to population screening and early (asymptomatic) cancer diagnosis.

Keywords: Biomarker; Blood test; Cancer diagnosis; Cancer mutations; Circulating tumor DNA; Early cancer detection; Translational omics.

Fig. 1

Outcomes and consequences for an asymptomatic individual undergoing a blood serum test for cancer detection

Fig. 2

Each patient depicted in this figure has a fetus (far left patient) or a tumor (rest of the patients) of a different mass, decreasing from left to right. Data from Table 4 was plotted and sizes are not to scale. The fetus/tumors secrete DNA into the blood stream in quantities proportional to their masses; the ratio of tumor/fetal DNA (in italics) to total DNA secreted from healthy cells (in bold) is shown underneath a dividing line for each patient. As tumor size decreases, the ratio of circulating tumor DNA to total circulating DNA decreases proportionally. Thus, it becomes increasingly difficult for a test to extract these miniscule amounts of tumor DNA from the rest of the circulating DNA, compromising its effectiveness in detecting small, early stage tumors. For more details see text and Table 4