Preclinical circulating tumor DNA shedding duration and prognostic implications of modeling 3669 patients with cancer in the American Cancer Society Cancer Prevention Study-3 and Circulating Cell-Free Genome Atlas Substudy 3.

Abstract

Previous studies have estimated the mean sojourn and dwell times within stages for commonly screened cancer types. However, little is known about the preclinical detection window of circulating tumor DNA (ctDNA) (ie, ctDNA positivity), which is important for understanding multicancer early detection. The duration of preclinical detectability and prognostic value of ctDNA detection was estimated from patients with cancer in two biobank studies: CPS-3, where cancer was diagnosed (n = 1064) within 3 years of a prior blood draw (2006-2013), and CCGA3 (NCT02889978), with a blood draw (2016-2019) concurrent with clinical diagnosis (n = 2604). To infer these quantities, Bayesian models were used for detection rates as a function of time, as well as to infer prognostic effects. Median [credible interval] sojourn times were 0.75 [0.47, 1.30], 0.89 [0.61, 1.33], 1.2 [0.84, 1.67] years for cancers diagnosed at local, regional, and distant stage, respectively, and ranged by type from pancreas, 0.49 [0.26, 0.88] to lymphoma, 2.45 [1.14, 4.87]. The extrapolated effect of ctDNA positivity at clinical diagnosis versus negative in CPS-3 cancer cases was a relative hazard ratio of 1.98 [1.08-4.22] for mortality. These results provide estimates for average ctDNA detectable sojourn time in tumors across multiple cancer sites and stages and can inform the design of future screening studies for multicancer early detection.