Novel Multi-Dimensional Liquid Biopsy Paradigms: Harnessing ctDNA Fragmentomics and AI-Enhanced Detection for Next-Generation Cancer Screening

Abstract

Liquid biopsy is a disruptive approach to cancer diagnostics, which examines cell-free RNA, extracellular vesicles, circulating tumour DNA, and circulating tumour cells in bodily fluids. In contrast to invasive tissue biopsy, it can monitor tumor dynamics in real time and in a noninvasive manner allowing early detection and signaling the personalized therapy. The enhancement of sensitivity of next generation sequencing, fragmentomics, and integration of multi-omics has allowed a lesser emphasis on allele fractions in detection of mutation, epigenomic, and proteomic changes. Integration with machine learning and AI takes it a step further by examining multi-modal data and stratifying patient risk. Clinical validation, regulatory approvals, marketing authorizations, and FDA Breakthrough Device Designation of multi-cancer early detection (MCED) tests such as the GRAIL Galleri test illustrate the plausibility of early detection, but limitations in cancer detection in early stages persist, coupled with limitations in addressing tumor heterogeneity. Economic models indicate that liquid biopsy lowers costs of treatments at the final stages and increases the quality-adjusted life years, which validates its clinical meaningfulness. However, there are ongoing issues of global access, equity and population specific validation. Vigorous academic-industry collaborations, convergence of international standards and AI-enabled large data platforms will open up new directions. Liquid biopsy is placed as scalable and minimally invasive, thus has the potential of revolutionizing precision oncology in the global arena.