Mathematical Model Identifies Blood Biomarker–Based Early Cancer Detection Strategies and Limitations

Abstract

Most clinical blood biomarkers lack the necessary sensitivity and specificity to reliably detect cancer at an early stage, when it is best treatable. It is not yet clear how early a clinical blood assay can be used to detect cancer, or how biomarker-based strategies can be improved to enable earlier detection of smaller tumors. To address these issues, we developed a mathematical model describing dynamic plasma biomarker kinetics in relation to the growth of a tumor, beginning with a single cancer cell. To exemplify a realistic scenario in which biomarker is shed by both cancerous and non-cancerous cells, we primed the model on ovarian tumor growth and CA125 shedding data, for which tumor growth parameters and shedding rates are readily available in published literature. We found that a tumor could grow unnoticed for over 10.1 years and reach a volume of (20.44 mm)3 before becoming detectable by current clinical blood assays. Model parameters were perturbed over log-orders of magnitude to quantify ideal shedding rates and identify other blood-based strategies required for early sub-millimeter tumor detectability. Detection times we estimated are consistent with recently published tumor progression timelines based on clinical genomic sequencing data for several cancers. In this study, we rigorously showed that shedding rates of current clinical blood biomarkers are likely 104-fold too low to enable detection of a developing tumor within the first decade of tumor growth. The model presented here can be extended to virtually any solid cancer and associated biomarkers.

Point-of-care diagnostics for noncommunicable diseases using synthetic urinary biomarkers and paper microfluidics

“…Endogenous biomarkers are often limited by fundamental biological constraints, making detection challenging, especially at the earliest stages of disease when treatments are more likely curative (36,37). By contrast, small inert analytes in plasma such as our ligand-encoded reporters are concentrated into the urine: in our animal models, reporters were enriched to levels that required the urine samples to be diluted (fourfold to fivefold for LFA; 10 2 -to 10 4 -fold for ELISA) to prevent signal saturation when NPs were administered at a dose typical of nanomedicines (∼1 mg/kg) (30,31).…”

Physiopathological factors affecting the diagnostic value of serum HE4-test for gynecologic malignancies

“…Candidate factors may include age, infection/inflammation, renal function, menopause, hormonal levels, and menstrual cycle. The amount of HE4 shed into the circulation may be related to HE4 expression and secretion by tumor and normal cells, the volume of tumor and the structural heterogeneity of cancer, tumor vasculature, vascular permeability, and HE4 clearance by degradation or excretion [98]. Much remains unknown regarding to what extents and by what mechanisms these factors may affect the level of circulatory HE4.…”

Detecting cancers through tumor-activatable minicircles that lead to a detectable blood biomarker

“…First is the opportunity to optimize our system iteratively to improve the stringency of tumor-activatable gene expression, to generate more potent vectors, and to enhance vector delivery to the tumor. Although ways to augment endogenous tumor biomarker secretion rates exogenously are being developed (53), sensitivity using endogenous biomarkers will be inherently limited by the amount of biomarker produced by the tumor (6). In contrast, we can tune our MC system's sensitivity.…”

“…However, it also is quite possible that scaling across species will be nonlinear. For example, we have developed a mathematical model for relating tumor volume and endogenous blood biomarkers (6), and a biomarker detectable in the blood of a mouse bearing a~5-mm 3 tumor can still be detectable in the blood of a human even if their tumors are not 3,500-fold larger. Another potential issue to consider for translation is whether the production of enough MC for a human dose is feasible.…”

“…This is highly attractive because it facilitates affordable cancerscreening programs but often suffers from sensitivity and specificity issues resulting from low blood biomarker concentrations (3), rapid in vivo and ex vivo biomarker degradation (4), tumor heterogeneity, and highly variable background expression in nonmalignant tissues (5). Using current clinical biomarker assays, we have computationally estimated that a tumor can grow for 10-12 y and reach a spherical diameter >2.5 cm before endogenous blood biomarkers reach sufficient levels to indicate disease (6). Of the thousands of potential blood biomarkers reported, only a small percentage (<1%) are used in the clinic (7), and the implementation of new blood biomarkers in the clinical setting is decreasing because of their lack of validated specificity and diagnostic value (4, 7).…”