Modeled sojourn time and sensitivity for detecting preclinical cancers retrospectively by a multi-cancer early detection test

BACKGROUND: Blood-based multi-cancer early detection tests have potential for clinical benefit, but key performance metrics for cancer screening, such as sojourn time and sensitivity of these tests for detecting pre-clinical disease, are not yet known. METHODS: In a retrospective analysis of stored plasma samples in the American Cancer Society Cancer Prevention Study-3 (CPS-3), GRAIL's MCED test was evaluated for detectability prior to cancer diagnosis. Classical state-transition models for cancer screening were modified to characterize the natural history of ctDNA-shedding cancers. The sensitivity estimand for detecting preclinical cancers by the MCED test was proposed in the context of retrospective testing, and a Bayesian likelihood method was developed to estimate preclinical detectable duration and sensitivity. RESULTS: Analysis of CPS-3 data showed that for the twelve prespecified cancers that represent two-thirds of cancer deaths in the United States, the test had 64% estimated overall sensitivity across all stages, 43% sensitivity during an average 1.36-years preclinical detectable window before metastasis. Untestable assumptions on state transition and sensitivity are discussed, along with limitations related to using stored plasma samples. CONCLUSIONS: State-transition models were developed for retrospective analysis of plasma samples from the CPS-3 study. Estimates for the length of the preclinical detectable window and the sensitivity at screening support annual MCED screening to intercept late-stage cancers. IMPACT: Retrospective analysis of plasma samples from the CPS-3 study supports the potential of GRAIL's MCED test to detect cancers early in the preclinical state.