Background: Multi-cancer tests offer screening for multiple cancers with one blood draw, but the potential population impact is poorly understood.

Methods: We formulate mathematical expressions for expected numbers of: (i) individuals exposed to unnecessary confirmation tests (EUC), (ii) cancers detected (CD), and (iii) lives saved (LS) given test performance, disease incidence and mortality, and mortality reduction. We add colorectal, liver, lung, ovary, and pancreatic cancer to a test for breast cancer, approximating prevalence at ages 50, 60, or 70 using incidence over the next 5 years and mortality using corresponding probabilities of cancer death over 15 years in the Surveillance, Epidemiology, and End Results registry.

Results: EUC is overwhelmingly determined by specificity. For a given specificity, EUC/CD is most favorable for higher prevalence cancers. Under 99% specificity and sensitivities as published for a 50-cancer test, EUC/CD is 1.1 for breast + lung versus 1.3 for breast + liver at age 50. Under a common mortality reduction associated with screening, EUC/LS> is most favorable when the test includes higher mortality cancers (e.g., 19.9 for breast + lung vs. 30.4 for breast + liver at age 50 assuming a common 10% mortality reduction).

Conclusions: Published multi-cancer test performance suggests a favorable tradeoff of EUC to CD, yet the full burden of unnecessary confirmations will depend on the posttest work-up protocol. Harm–benefit tradeoffs will be improved if tests prioritize more prevalent and/or lethal cancers for which curative treatments exist.

Impact: The population impact of multi-cancer testing will depend not only on test performance but also on disease characteristics and efficacy of early treatment.

See related commentary by Duffy and Sasieni, p. 3