Development of a comprehensive cell-free DNA (cfDNA) assay for early detection of multiple tumor types: The Circulating Cell-free Genome Atlas (CCGA) study.

12021 Background: Globally most cancers are detected at advanced stages with high treatment burden and low cure rates. A noninvasive cfDNA blood test detecting multiple cancers at early stages when curative treatment is more likely to succeed is desirable. CCGA (NCT02889978) is a prospective multi-center observational study for development of a noninvasive cfDNA-based multi-cancer detection assay. Methods: Prospectively collected samples (N = 1627) from 749 controls (no cancer diagnosis, C) and 878 participants (pts) with newly diagnosed untreated cancer (20 tumor types, all stages) were analyzed in a preplanned substudy. 3 prototype sequencing assays were performed: paired cfDNA and white blood cell (WBC, 60,000X) targeted sequencing (507 genes) for single nucleotide variants/indels; paired cfDNA and WBC whole genome sequencing (WGS, 30X) for copy number variation; cfDNA whole genome bisulfite sequencing (WGBS, 30X) for methylation. For each assay a detection model was developed for all cancer pts; sensitivity was estimated at 95% specificity. Results: Pts w/cancer and C had similar age, smoking status and gender. WGBS had the highest sensitivity and is reported here; results were consistent across assays. Detected (sensitivity [95% CI]) cancers (stage I-III) included 28 colorectal (66% [48-84]), 19 esophageal (63% [38-84]), 5 head and neck (56% [21-86]), 5 hepatobiliary (80% [28-99]), 73 lung (59% [47-70]), 17 lymphoma (77% [50-93]), 11 multiple myeloma (73% [39-94]), 10 ovarian (90% [56-99]), and 10 pancreatic (80% [44-98]). Breast cancer-specific assay results are reported separately. Cancers with low signal ( < 10% sensitivity) include low gleason score prostate cancer, thyroid, uterine, melanoma, and renal. Comparison to tumor WGS and multi-assay classification will be reported. Conclusions: A cfDNA-based blood test detected multiple cancers at various stages with high specificity, indicating this approach is promising as a multi-cancer screening test, including for lethal unscreened cancers where stage shift can impact mortality. Further assay and clinical development of a multi-cancer cfDNA test in an asymptomatic population is ongoing. Clinical trial information: NCT02889978.