Opportunities for Early Cancer Detection: The Rise of ctDNA Methylation-Based Pan-Cancer Screening Technologies

Abstract

The efficiency of conventional screening programs to identify early-stage malignancies can be limited by the low number of cancers recommended for screening as well as the high cumulative false-positive rate, and associated iatrogenic burden, resulting from repeated multimodal testing. The opportunity to use minimally invasive liquid biopsy testing to screen asymptomatic individuals at-risk for multiple cancers simultaneously could benefit from the aggregated diseases prevalence and a fixed specificity. Increasing both latter parameters is paramount to mediate high positive predictive value—a useful metric to evaluate a screening test accuracy and its potential harm-benefit. Thus, the use of a single test for multi-cancer early detection (stMCED) has emerged as an appealing strategy for increasing early cancer detection rate efficiency and benefit population health. A recent flurry of these stMCED technologies have been reported for clinical potential; however, their development is facing unique challenges to effectively improve clinical cost–benefit. One promising avenue is the analysis of circulating tumour DNA (ctDNA) for detecting DNA methylation biomarker fingerprints of malignancies—a hallmark of disease aetiology and progression holding the potential to be tissue- and cancer-type specific. Utilizing panels of epigenetic biomarkers could potentially help to detect earlier stages of malignancies as well as identify a tumour of origin from blood testing, useful information for follow-up clinical decision making and subsequent patient care improvement. Overall, this review collates the latest and most promising stMCED methodologies, summarizes their clinical performances, and discusses the specific requirements multi-cancer tests should meet to be successfully implemented into screening guidelines.

Evaluation of the Multi-Cancer Early Detection (MCED) value of YiDiXie™-HS and YiDiXie™-SS

“…Compared to the SCED model, the MCED model has the following advantages: (1) Having a broader cancer screening spectrum and aggregated prevalence 20 . (2) Significant improving mental health and decrease subsequent medical costs with reduction in false-positive results 20 . (3) Having a higher early cancer detection rate 50,51 .…”

“…However, the screening model of existing cancer screening tests does not fulfill the need for "Universal cancer screening". This screening model 20 can be referred to as the model of "Single-Cancer Early Detection (SCED)" , which refers to the application of existing cancer screening tests (e.g., CT, ultrasound, gastroscopy, colonoscopy, blood TPSA, etc.) to screen for one site-specific cancer at a time (e.g., CT scan for lung cancer, mammogram for breast cancer, TPSA for blood, etc.…”

The Role of Cell-Free DNA in Cancer Treatment Decision Making

“…The cfDNA methylation analysis in cancer has the potential of clinical applications, e.g., investigating single-gene methylation profiles in different cancer types [ 168 ]. Recently emerged the possibility to develop a single test for early cancer detection (stMCED) by using ctDNA methylation fingerprints as a biomarker of malignancies [ 169 ]. The “methylome” leads to a better understanding of the onset and the phenotype evolution of a cancer.…”

Multimodal analysis of methylomics and fragmentomics in plasma cell-free DNA for multi-cancer early detection and localization

“…In recent years, there has been considerable interest in exploring the potential of ctDNA alterations for early detection of cancer and localization of the tissue of origin (TOO) (11,12). One such approach is the PanSeer test, which uses 477 differentially methylated regions (DMRs) in ctDNA to detect five different types of cancer up to four years prior to conventional diagnosis (13).…”