Challenges in Using ctDNA to Achieve Early Detection of Cancer

Early detection of cancer is a significant unmet clinical need. Improved technical ability to detect circulating tumor-derived DNA (ctDNA) in the cell-free DNA (cfDNA) component of blood plasma via next-generation sequencing and established correlations between ctDNA load and tumor burden in cancer patients have spurred excitement about the possibilities of detecting cancer early by performing ctDNA mutation detection.\n\nWe reanalyze published data on the expected ctDNA allele fraction in early-stage cancer and the population statistics of cfDNA concentration to show that under conservative technical assumptions, high-sensitivity cancer detection by ctDNA mutation detection will require either more blood volume (150-300mL) than practical for a routine screen or variant filtering that may be impossible given our knowledge of cancer evolution, and will likely remain out of economic reach for routine population screening without multiple-order-of-magnitude decreases in sequencing cost. Instead, new approaches that integrate ctDNA mutations with multiple other blood-based analytes (such as exosomes, circulating tumor cells, ctDNA epigenetics, metabolites) as well as integration of these signals over time for each individual may be needed.