1704 - Plasma cell-free DNA (cfDNA) assays for early multi-cancer detection: the Circulating Cell-Free Genome Atlas (CCGA) study

Background

A noninvasive cfDNA blood test detecting multiple high-mortality cancers at early stages when treatment is more likely effective could decrease cancer mortality. CCGA (NCT02889978) is a prospective multi-center observational study to develop a plasma cfDNA-based multi-cancer detection assay.

Methods

Prospectively collected clinically evaluable samples (N = 2402) from non-cancer controls (C) and participants with newly diagnosed untreated cancer (pts; 20 tumor types, all stages) were divided into training (n = 1458; 580 C, 878 pts) and test (n = 944; 368 C, 576 pts) sets and analyzed as a preplanned substudy. Prototype sequencing assays included paired cfDNA/white blood cell (WBC, 60000X) targeted sequencing, paired cfDNA/WBC whole genome sequencing (30X), cfDNA whole genome bisulfite sequencing (WGBS, 30X). Sensitivity was estimated at 98% specificity. Cancers with >5 pts in training and test are reported.

Results

Overall, pts (all stages) and C had similar age, smoking status, and gender. WGBS returned the highest sensitivity and is included here; results were consistent across the targeted, WGS, and WGBS assays, and will be reported in full. WBC signal was used to correct for clonal hematopoiesis. Stage I-IV cancer detection was consistent in training and test sets. In training, cancer-specific sensitivities (high-signal cancers) ranged from 54-92% and will be reported in detail. In individual cancers in the test set, numbers and sensitivity (95% CI) were: 22 hormone receptor negative breast (36%, 17-59), 45 colorectal (60%, 44-74), 7 esophageal (43%, 10-82), 12 head & neck (50%, 21-79), 15 hepatobiliary (73%, 45-92), 47 lung (70%, 55-83), 22 lymphoma (64%, 41-83), 7 ovarian (71%, 29-96) and 23 pancreatic (74%, 52-90). Results were also consistent between training and test sets in stage I-III and stage IV cancers.

Conclusions

A cfDNA-based blood test detected multiple cancers at various stages consistently in training and test sets. This approach is promising as a multi-cancer early detection test, including for high mortality unscreened cancers where stage shift can impact mortality. Further assay and clinical development of a multi-cancer cfDNA test in large-scale clinical studies, including CCGA, is ongoing.

Clinical trial identification

NCT02889978.

Legal entity responsible for the study

GRAIL, Inc.

Funding

GRAIL, Inc.

Editorial Acknowledgement

Writing support provided by Megan P. Hall, PhD (GRAIL, Inc., Menlo Park, CA).

Disclosure

M.C. Liu: Advisory board member: GRAIL, Inc. E. Klein: Consultant: GRAIL Inc., GenomicHealth, GenomeDx. E. Hubbell: Employee: GRAIL, Inc. with options to hold stock; Stock: ThermoFisher. T. Maddala, A.M. Aravanis, J.F. Beausang, D. Filippova, S. Gross, L. Shen, N. Zhang, O. Venn, J. Yecies, S. Patel, A-R. Hartman: Employee: GRAIL, Inc. with options to hold stock in the company. A. Jamshidi, K. Kurtzman: Employee: GRAIL, Inc. with options to hold stock in the company; Stock: Illumina. M. Seiden: Employee and stocks: McKesson. G.Oxnard: Advisory board member, consultant: Inivata; Honorarium: Guardant Health, Sysmex, BioRad; Consultant: DropWorks, AstraZeneca, GRAIL, Inc. All other authors have declared no conflicts of interest.