Blood, toil, and taxoteres: Biological determinants of treatment-induced ctDNA dynamics for interpreting tumor response

Abstract

Collection and analysis of circulating tumor DNA (ctDNA) is one of the few methods of liquid biopsy that measures generalizable and tumor specific molecules, and is one of the most promising approaches in assessing the effectiveness of cancer care. Clinical assays that utilize ctDNA are commercially available for the identification of actionable mutations prior to treatment and to assess minimal residual disease after treatment. There is currently no clinical ctDNA assay specifically intended to monitor disease response during treatment, partially due to the complex challenge of understanding the biological sources of ctDNA and the underlying principles that govern its release. Although studies have shown pre- and post-treatment ctDNA levels can be prognostic, there is evidence that early, on-treatment changes in ctDNA levels are more accurate in predicting response. Yet, these results also vary widely among cohorts, cancer type, and treatment, likely due to the driving biology of tumor cell proliferation, cell death, and ctDNA clearance kinetics. To realize the full potential of ctDNA monitoring in cancer care, we may need to reorient our thinking toward the fundamental biological underpinnings of ctDNA release and dissemination from merely seeking convenient clinical correlates.

Keywords: biomarkers; circulating tumor DNA; ctDNA; liquid biopsy; treatment response; tumor growth.

FIGURE 1

The relationships between treatment, biological factors, clinical indicators and outcomes, and potential insights with regard to serial ctDNA monitoring during treatment. MOA, mechanism of action; Tx, treatment.

FIGURE 2

Hypothetical ctDNA dynamics from blood sampled frequently before, during, and after treatment. Characteristic ctDNA dynamics are depicted as observed in various studies throughout the text or otherwise hypothesized. The speculated driving tumor biology is described for each plot and example outcomes are stated. Response patterns defined by Xi et al. (14) for metastatic melanoma patients undergoing tumor infiltrating lymphocyte (TIL) immunotherapy are indicated when relevant. Tx, treatment; TKI, tyrosine kinase inhibitors; ICI, immune checkpoint inhibitors; MRD, molecular/minimal residual disease; ChemoRT, chemoradiation therapy.