Longitudinal Monitoring of Circulating Tumor DNA to Predict Treatment Outcomes in Advanced Cancers

Abstract

Purpose: The response to cancer therapies is typically assessed with radiologic imaging 6-10 weeks after treatment initiation. Circulating tumor DNA (ctDNA), however, has a short half-life, and dynamic changes in ctDNA quantity may allow for earlier assessment of the therapeutic response.

Methods: Patients with advanced solid tumors referred to the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center were invited to participate in a liquid biopsy protocol for which serial blood samples were collected before, during, and after systemic therapy. We isolated ctDNA from serially collected plasma samples at baseline, mid-treatment, and first restaging. Genomically informed droplet digital polymerase chain reaction (ddPCR) was performed, and ctDNA quantities were reported as aggregate variant allele frequencies for all detected molecular aberrations.

Results: We included 204 patients receiving 260 systemic therapies. The ctDNA detection rate was higher in progressors (patients with progressive disease) compared with nonprogressors (patients with stable disease, partial responses, or complete responses) at all time points (P < .009). Moreover, ctDNA detection was associated with a shorter median time-to-treatment failure (P ≤ .001). Positive delta and slope values for changes in ctDNA quantity were more frequent in progressors (P ≤ .03 and P < .001, respectively) and were associated with a shorter median time-to-treatment failure (P ≤ .014 and P < .001, respectively). Increasing ctDNA quantity was predictive of clinical and/or radiologic progressive disease in 73% of patients (median lead time, 23 days).

Conclusion: Detection of ctDNA and early dynamic changes in its quantity can predict the clinical outcomes of systemic therapies in patients with advanced solid tumors.

FIG 1.

Kaplan-Meier curves for the differences in median TTF between patients with detectable and undetectable ctDNA at (A) baseline, (B) mid-treatment, and (C) first restaging. Detectable ctDNA was associated with a shorter median TTF than undetectable ctDNA at baseline (11 weeks; 95% CI, 9.1 to 12.9 v 16 weeks; 95% CI, 12.3 to 19.7, respectively; P = .001), mid-treatment (10 weeks; 95% CI, 7.9 to 12.1 v 18 weeks; 95% CI, 10.5 to 25.5, respectively; P < .001), and first restaging (10 weeks; 95% CI, 8.5 to 11.5 v 24 weeks; 95% CI, 17.3 to 30.7, respectively; P < .001). ctDNA, circulating tumor DNA; TTF, time-to-treatment failure.

FIG 2.

Studied variables and treatment response as assessed with the RECIST, version 1.1. Positive delta and slope values are highlighted in blue. Color gradients in the middle of the figure show the VAF changes at different time points. BL, baseline; FR, first restaging; MT, mid-treatment; PD, progressive disease; PR, partial response; SD, stable disease; VAF, variant allele frequency.

FIG 3.

Kaplan-Meier curves demonstrate the differences in TTF between patients with positive and nonpositive delta values at (A) MT and (B) FR and the differences in TTF between patients with positive and nonpositive slope values at (C) MT and (D) FR. FR, first restaging; MT, mid-treatment; TTF, time-to-treatment failure.