Geoffrey R. Oxnard, MD
A study by Geoffrey R. Oxnard, MD, and colleagues using bisulfite sequencing of plasma cell-free DNA to identify methylomic signatures for multicancer detection and tissue-of-origin determination found the assay achieved accurate detection of multiple cancers across stages and tissue-of-origin localization. The targeted methylation assay is now undergoing validation in preparation for prospective clinical investigation as a cancer detection diagnostic tool.
Dr. Oxnard is Associate Professor of Medicine at Harvard Medical School and a medical oncologist at the Thoracic Cancer Treatment Center at Dana-Farber Cancer Institute in Boston. He was the first author of this report presented at ASCO Breakthrough: A Global Summit for Oncology Innovators, held recently in Bangkok, Thailand.1
Study Background and Methodology
Previous research has shown whole-genome bisulfite sequencing outperformed whole-genome and targeted sequencing approaches for multicancer detection at all cancer stages with high specificity. The current researchers analyzed data from 2,301 participants (1,422 with cancer, including more than 20 tumor types and all stages, and 879 without cancer) in a prespecified substudy from the Circulating Cell-Free Genome Atlas Study (ClinicalTrials.gov identifier NCT02889978), a prospective, multicenter, observational, case-control study with longitudinal follow-up.
Plasma cell-free DNA was subjected to a targeted methylation sequencing assay using high-efficiency methylation chemistry to enrich for methylation targets, and a machine learning classifier determined cancer status and tissue of origin. Observed methylation fragments characteristic of cancer and tissue of origin were combined across targeted regions and assigned a relative probability of cancer and a specific tissue of origin.
Performance was reported at > 99% specificity (ie, a combined false-positive rate across all cancer types of < 1%), a level required for population-level screening. Across cancer types, sensitivity ranged from 59% to 86%.
Combined cancer detection sensitivity was 34% (95% confidence interval [CI] = 27%–43%) in stage I disease (n = 151); 77% (95% CI = 70%–83%) in stage II (n = 171); 84% (95% CI = 79%–89%) in stage III (n = 204); and 92% (95% CI = 88%–95%) in stage IV (n = 281). Tissue of origin was provided for 94% of all cancers detected; of these cases, the tissue of origin was correct in more than 90%.
“Detection of multiple deadly cancers across stages using methylation signatures in plasma cell-free DNA was achieved with a single, fixed, low false-positive rate and simultaneously provided accurate tissue-of-origin localization. This targeted methylation assay is undergoing validation in preparation for prospective clinical investigation as a cancer detection diagnostic,” said Dr. Oxnard and his coauthors.■
DISCLOSURE: The research sponsor for this study is GRAIL, Inc. Dr. Oxnard has received honoraria from Foundation Medicine, Guardant Health, and Sysmex; has served as consultant or advisor for AstraZeneca, DropWorks, GRAIL, Ignyta, Inivata, Janssen, LOXO, Sysmex, and Takeda; and is a coauthor of a pending patent with Dana-Farber Cancer Institute titled “Non-invasive blood-based monitoring of genomic alterations in cancer.” For disclosures of all study authors, visit coi.asco.org.
1. Oxnard G, Klein E, Seiden E, et al: Simultaneous multi-cancer detection and tissue of origin localization using targeted bisulfite sequencing of plasma cell-free DNA. ASCO Breakthrough. Abstract 47. Presented October 11, 2019.