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Review
. 2022 Jan 28;8(4):eabi8618.
doi: 10.1126/sciadv.abi8618. Epub 2022 Jan 26.

Monitoring and adapting cancer treatment using circulating tumor DNA kinetics: Current research, opportunities, and challenges

Enrique Sanz-Garcia  1 , Eric Zhao  2 , Scott V Bratman  2   3 , Lillian L Siu  1
Affiliations
Review

Monitoring and adapting cancer treatment using circulating tumor DNA kinetics: Current research, opportunities, and challenges

Enrique Sanz-Garcia et al. Sci Adv. .

Abstract

Circulating tumor DNA (ctDNA) has emerged as a biomarker with wide-ranging applications in cancer management. While its role in guiding precision medicine in certain tumors via noninvasive detection of susceptibility and resistance alterations is now well established, recent evidence has pointed to more generalizable use in treatment monitoring. Quantitative changes in ctDNA levels over time (i.e., ctDNA kinetics) have shown potential as an early indicator of therapeutic efficacy and could enable treatment adaptation. However, ctDNA kinetics are complex and heterogeneous, affected by tumor biology, host physiology, and treatment factors. This review outlines the current preclinical and clinical knowledge of ctDNA kinetics in cancer and how early on-treatment changes in ctDNA levels could be applied in clinical research to collect evidence to support implementation in daily practice.

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Figures

Fig. 1.
Fig. 1.. ctDNA kinetics vary with kinetics of release and degradation/clearance and interact closely with treatment effects.
The interplay of these factors governs the various potential applications of ctDNA along the cancer treatment timeline. Both early transient changes in ctDNA and gradual decay kinetics may be informative of response to treatment. Understanding the implications of these kinetics may inform treatment decisions, allowing for early adjustments. Studies examining ctDNA kinetics vary by how they quantify ctDNA, which time points they sample, what metrics are used to summarize ctDNA kinetics, and which clinical outcomes they collect. WES, whole exome sequencing.
Fig. 2.
Fig. 2.. Adaptive clinical trials are a potential strategy for evaluating treatment optimizations guided by early ctDNA kinetics.
In an escalation trial, patients with below threshold ctDNA levels (suggesting poor biochemical response) could be randomized to a predetermined treatment escalation with the goal of improved disease control over continuing standard management. Conversely, in a de-escalation trial, patients whose ctDNA levels exceed threshold (excellent biochemical response) could be randomized to a predetermined treatment de-escalation with hope of sparing toxicity while achieving a noninferior outcome.
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