Circulating Tumor DNA Analysis: Clinical Implications for Colorectal Cancer Patients. A Systematic Review

Abstract

Background: Liquid biopsies could improve diagnosis, prognostication, and monitoring of colorectal cancer (CRC). Mutation, chromosomal copy number alteration, and methylation analysis in circulating tumor DNA (ctDNA) from plasma or serum has gained great interest. However, the literature is inconsistent on preferred candidate markers, hampering a clear direction for further studies and clinical translation. This review assessed the potential of ctDNA analysis for clinical utility.

Methods: A systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines was conducted up to December 3, 2018, followed by methodological quality assessment. Primary endpoints were accuracy for detection, prognostication, and monitoring.

Results: Eighty-four studies were included. For CRC detection, sensitivity was 75% using ctDNA mutation analysis and up to 96% using copy number analysis. Septin 9 (SEPT9) hypermethylation analysis showed sensitivities of 100% and specificities of 97%. Regarding prognostication, ctDNA KRAS mutations were associated with oncological outcome and could predict response to anti-epidermal growth factor receptor therapy. For monitoring, sequential ctDNA KRAS mutation analysis showed promise for detection of relapses or therapy resistance.

Conclusions: This comprehensive overview of ctDNA candidate markers demonstrates SEPT9 methylation analysis to be promising for CRC detection, and KRAS mutation analysis could assist in prognostication and monitoring. Prospective evaluation of marker panels in clinical decision making should bring ctDNA analysis into practice.

Figure 1.

The three types of circulating tumor DNA aberrations covered in this review. For every DNA aberration, commonly used techniques to determine its presence in plasma or serum are depicted. PCR = polymerase chain reaction.

Figure 2.

The Preferred Reporting Items for Systematic Reviews and Meta-analyses flowchart for inclusion of the studies. The risk of bias assessment using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) was incorporated in the flowchart. CNA = copy number alteration; CRC = colorectal cancer; ctDNA = circulating tumor DNA.

Figure 3.

A graphical overview of the evidence for circulating tumor DNA (ctDNA) use in clinical practice. The most promising markers are presented for each clinical implication. Markers considered to be of special interest are underlined. Other markers depicted in the figure are promising but require further research. CNA = copy number alteration.

Figure 4.

Associations between the presence of preoperative circulating tumor DNA and clinicopathological variables and oncologic outcomes. The percentage of patients with a positive marker is represented for the categories of the variables. Green: all studies reporting on the specific marker found statistically significant associations; orange: part of the studies found statistically significant and part found statistically nonsignificant (NS) associations; pink: all studies found statistically NS associations. The overall (OS) and disease-free survival (DFS) is presented for patients with a positive (+) and a negative (−) marker. # = no percentage of patients or median or mean OS or DFS provided, * = median, ** = mean. TNM = tumor (T), nodes (N), and metastases (M).