Circulating tumor DNA: current challenges for clinical utility
Donna K. Dang, Ben H. Park
Donna K. Dang, Ben H. Park
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Review Series

Circulating tumor DNA: current challenges for clinical utility

Abstract

Cancer cells shed naked DNA molecules into the circulation. This circulating tumor DNA (ctDNA) has become the predominant analyte for liquid biopsies to understand the mutational landscape of cancer. Coupled with next-generation sequencing, ctDNA can serve as an alternative substrate to tumor tissues for mutation detection and companion diagnostic purposes. In fact, recent advances in precision medicine have rapidly enabled the use of ctDNA to guide treatment decisions for predicting response and resistance to targeted therapies and immunotherapies. An advantage of using ctDNA over conventional tissue biopsies is the relatively noninvasive approach of obtaining peripheral blood, allowing for simple repeated and serial assessments. Most current clinical practice using ctDNA has endeavored to identify druggable and resistance mutations for guiding systemic therapy decisions, albeit mostly in metastatic disease. However, newer research is evaluating potential for ctDNA as a marker of minimal residual disease in the curative setting and as a useful screening tool to detect cancer in the general population. Here we review the history of ctDNA and liquid biopsies, technologies to detect ctDNA, and some of the current challenges and limitations in using ctDNA as a marker of minimal residual disease and as a general blood-based cancer screening tool. We also discuss the need to develop rigorous clinical studies to prove the clinical utility of ctDNA for future applications in oncology.

Authors

Donna K. Dang, Ben H. Park

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Figure 3

Rationale for increasing genome equivalents versus increasing the number of tracking mutations to identify ctDNA.

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Rationale for increasing genome equivalents versus increasing the number...
In this example, the tumor/cancer cells have six distinct mutations (colored stars) that are being shed into the circulation along with normal DNA from normal cells (in blue). If an assay only queries for a single mutation, then a large amount of DNA is required to ensure a high likelihood that the mutation will be in the sample (bottom left). On the other hand, if plasma DNA is limited, then there may be only a single mutation in the sample (green star), and therefore querying for all DNA mutations is needed such that there is high likelihood that any mutation will be identified (bottom right).