Background: There are two distinct ‘liquid biopsy’ cancer screening approaches. Focused testing for selected cancers where screening is recommended but not being received, in which test sensitivity can be prioritized as false positives reflex to standard of care screening. Broad testing for many cancers where false-positives necessitate high test specificity, typically at the expense of sensitivity. The public health impact and testing burden of these approaches has not been explored. Methods: Projected cancer deaths averted and annual number of tests performed based on published performance and target populations for liquid biopsy tests with published data. Focused screening modeled for patients who are not receiving guideline-recommended screening for lung, liver and colorectal cancer. Broad screening modeled for all individuals aged 50-80 and assumed to detect all cancer types. Averted deaths determined by combining the mortality reduction associated with screening (published literature, 20% if no literature); adjusted for reported prospective test sensitivities: focused (85%), broad (28%). Only individuals not receiving a particular cancer screening could have liquid biopsy avert a death for that cancer. Results: Focused and broad screening strategies each prevented approximately 20,000 cancer deaths annually. Focused screening required testing one-fifth as many people annually as the broad testing approach (30MM vs.150MM). All of the projected reduction in mortality associated with focused testing was based on randomized studies; for the broad strategy the equivalent statistic was 53%. Conclusions: Cancer deaths can be reduced equivalently through focused cancer screening at high sensitivity and broad cancer screening at high specificity at one-fifth the testing burden. The impact of false positives in the focused testing approach and false reassurance in the broad testing approach might alter these findings, which could also be affected by the cost of testing and follow-up.

*Prostate, breast, cervical.