Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set

TLDR

A multi‑cancer early detection (MCED) test could increase cancer detection in population screening, as demonstrated by the CCGA study, which showed that cfDNA sequencing combined with machine learning can identify signals across many cancer types. The study aimed to validate a refined MCED test for screening in a large independent cohort. Using cfDNA sequencing and machine learning, the substudy evaluated specificity, sensitivity, and cancer‑signal‑origin prediction accuracy in 4077 participants (2823 cancer, 1254 non‑cancer confirmed at year‑one follow‑up). The test achieved 99.5% specificity, 51.5% overall sensitivity that rose to 90.1% at stage IV, 67.6% sensitivity in the 12 most common cancers, detected signals in over 50 cancer types, and 88.7% accuracy in predicting cancer origin.

Abstract

A multi-cancer early detection (MCED) test used to complement existing screening could increase the number of cancers detected through population screening, potentially improving clinical outcomes. The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) was a prospective, case-controlled, observational study and demonstrated that a blood-based MCED test utilizing cell-free DNA (cfDNA) sequencing in combination with machine learning could detect cancer signals across multiple cancer types and predict cancer signal origin (CSO) with high accuracy. The objective of this third and final CCGA substudy was to validate an MCED test version further refined for use as a screening tool.This pre-specified substudy included 4077 participants in an independent validation set (cancer: n = 2823; non-cancer: n = 1254, non-cancer status confirmed at year-one follow-up). Specificity, sensitivity, and CSO prediction accuracy were measured.Specificity for cancer signal detection was 99.5% [95% confidence interval (CI): 99.0% to 99.8%]. Overall sensitivity for cancer signal detection was 51.5% (49.6% to 53.3%); sensitivity increased with stage [stage I: 16.8% (14.5% to 19.5%), stage II: 40.4% (36.8% to 44.1%), stage III: 77.0% (73.4% to 80.3%), stage IV: 90.1% (87.5% to 92.2%)]. Stage I-III sensitivity was 67.6% (64.4% to 70.6%) in 12 pre-specified cancers that account for approximately two-thirds of annual USA cancer deaths and was 40.7% (38.7% to 42.9%) in all cancers. Cancer signals were detected across >50 cancer types. Overall accuracy of CSO prediction in true positives was 88.7% (87.0% to 90.2%).In this pre-specified, large-scale, clinical validation substudy, the MCED test demonstrated high specificity and accuracy of CSO prediction and detected cancer signals across a wide diversity of cancers. These results support the feasibility of this blood-based MCED test as a complement to existing single-cancer screening tests.NCT02889978.