A mathematical model of ctDNA shedding predicts tumor detection size

Abstract

Early cancer detection aims to find tumors before they progress to an uncurable stage. Prospective studies with tens of thousands of healthy participants are ongoing to determine whether asymptomatic cancers can be accurately detected by analyzing circulating tumor DNA (ctDNA) from blood samples. We developed a stochastic mathematical model of tumor evolution and ctDNA shedding to investigate the potential and the limitations of ctDNA-based cancer early detection tests. We inferred ctDNA shedding rates of early stage lung cancers and calculated that a 15 mL blood sample contains on average only 1.5 genome equivalents of ctDNA for lung tumors with 1 billion cells (size of ~1 cm 3 ). We considered two clinically different scenarios: cancer screening and cancer relapse detection. For monthly relapse testing with a sequencing panel covering 20 tumor-specific mutations, we found a median detection size of 0.24 cm 3 corresponding to a lead time of 160 days compared to imaging-based relapse detection. For annual screening, we found a median detection size of 2.8-4.8 cm 3 depending on the sequencing panel size and on the mutation frequency. The expected detection sizes correspond to lead times of 390-520 days compared to current median lung tumor sizes at diagnosis. This quantitative framework provides a mechanistic interpretation of ctDNA-based cancer detection approaches and helps to optimize cancer early detection strategies.

Prognostic significance of postsurgery circulating tumor DNA in nonmetastatic colorectal cancer: Individual patient pooled analysis of three cohort studies

“…ctDNA is not a conventional prognostic marker such as CEA, in which measurable levels are found in normal individuals. The presence of ctDNA, in theory, is a binary metric indicating that a large number of residual metastatic cancer cells exist in the patient's body 22 . There are at least two potential explanations for this unexpected result.…”

Clonal Hematopoiesis in Liquid Biopsy: From Biological Noise to Valuable Clinical Implications

“…Smaller tumor burdens usually shed less ctDNA into the bloodstream than larger tumor burdens [ 40 ]. A recent study developed a mathematical model to predict the shedding rate of early-stage non-small cell lung cancer (NSCLC) [ 41 ]. From this study, it has been estimated that there would be an average of only 1.7 genome copies of ctDNA in 15 mL of blood for lung tumors with a volume of 1 cm 3 .…”

Current Advances in Clinical Application of Liquid Biopsy

“…As any cancer grows, it sheds more DNA, more cellular debris and more cancer cells into the bloodstream which eventually leads to the cancer spreading to distant organs. Although the ctDNA shedding rate can vary among patients, a mathematical model can predict tumour size by assessing haploid genome equivalents per plasma volume (correlation: R 2 = 0.32; P = 2.6x10- 16 ) [87]. The smaller the tumour, the higher the probability of a false negative result for a particular actionable mutation.…”