A noninvasive, blood-based, cell-free DNA test focused on the presence of DNA methylation appears to be highly sensitive in detecting gastrointestinal cancers and may pinpoint the tissue of origin in the vast majority of these cancers.1 The assay was developed based on findings from the multicenter, prospective Circulating Cell-Free Genome Atlas (CCGA) study. Once optimized, the test may provide a simple, practical method of screening for gastrointestinal cancers and other malignancies with a single blood draw, study investigators maintained.
Brian M. Wolpin, MD, MPH
The assay relies on targeted methylation sequencing of select CpG sites found in cell-free DNA. In addition to its high sensitivity at a high specificity threshold, “highly accurate tissue of origin localization was achieved in gastrointestinal cancer,” said Brian M. Wolpin, MD, MPH, Director of the Gastrointestinal Cancer Center at Dana-Farber Cancer Institute, Boston.
Key Findings
The findings came from 447 individuals diagnosed with gastrointestinal cancers who were divided into training and validation sets to test the assay. A specificity of more than 99% was maintained in the independent validation set. Based on this preset specificity, across all disease stages, the assay had a sensitivity of 82% in the training set and 81% in the validation set. Moreover, some 97% of detected gastrointestinal cancers were assigned a tissue of origin. Overall, the predicted accuracy of the tissue of origin for patients with gastrointestinal cancers (pinpointing locations in the esophagus, stomach, pancreas, gallbladder, liver/intrahepatic bile duct, or colon/rectum) was 91% for the training set and 89% for the validation set, Dr. Wolpin reported.
False-positive results were recorded for just 3 of 1,521 patients (0.2%) in the training set and 4 of 610 patients (0.7%) of the validation set, he added. The sensitivity of the test, however, varied considerably by stage. Dr. Wolpin noted that it performed well in stage IV disease, where it detected 96% of gastrointestinal cancers, and in stage III disease, where its sensitivity was 85%. In stages where there is curative potential, however, there was some room for improvement, with a sensitivity rate of 69% for stage II gastrointestinal cancer and 48% for stage I disease, Dr. Wolpin reported.
Part of a Larger Study
Minetta C. Liu, MD
Similar results from the larger CCGA study were reported at the 2019 ASCO Annual Meeting by Minetta C. Liu, MD, Research Chair and Professor in the Department of Oncology at the Mayo Clinic, Rochester.2 “We see 90% accuracy overall for identifying the tissue of origin, which is critical for guiding the efficient downstream workup for a positive signal,” she told The ASCO Post at that time.
The aim of the manufacturer is to develop a noninvasive cancer detection assay to be used to screen for a variety of cancer types. The CCGA study involved more than 15,000 individuals (56% with cancer, 44% without) and is evaluating the test in 20 different cancer types.
In the initial CCGA discovery substudy, researchers evaluated several approaches to cancer detection, ultimately identifying whole-genome bisulfite sequencing for DNA methylation as the most effective approach, and the one that is being developed further. DNA methylation helps regulate gene expression, with some regions of hypermethylation and some regions of hypomethylation. Methylation patterns are unique to the tumor DNA.
The current substudy of the CCGA included 4,500 people, with and without cancer, who were divided into a training cohort and a validation cohort. Of the 2,185 patients with newly diagnosed cancer, 447 were diagnosed with a cancer in the gastrointestinal tract. They included 174 with colorectal tumors, 25 with stomach tumors, 71 with esophageal tumors, 123 with pancreatic tumors, 14 with gallbladder tumors, and 40 with tumors of the liver or biliary duct.
KEY POINTS
- Substudies of the Circulating Cell-Free Genome Atlas study are showing that a noninvasive blood test may not only detect the presence of cancer, but also detect the tissue of origin.
- The test looks at patterns of DNA methylation.
- For cancers in the gastrointestinal tract, the test detected 82% of cancers across various stages and 96% of stage IV cancers.
- The test had a 90% accuracy for identifying the tissue of origin.
“This investigational, multicancer, early detection test evaluating cell-free DNA methylation may be a practical method for detecting and localizing gastrointestinal and numerous other cancers, thus directing downstream diagnostic evaluation,” Dr. Wolpin said, emphasizing the potential of the test to save lives. “Gastrointestinal cancers cause substantial cancer-related mortality, and that is in large part because patients present with advanced disease.”
Dr. Wolpin sees a more far-reaching potential for cell-free DNA methylation testing: “At the moment, the focus has been in the setting of early detection, but there are other ways this type of approach could be applied in the future that would be beneficial to patients, beyond just trying to diagnose cancer early,” he said.
DISCLOSURE: Dr. Wolpin has received honoraria from, or consulted for, Celgene, G1 Therapeutics, BioLineRx, Genentech, and GRAIL (the manufacturer of the study test) and has received research funding from Celgene and Eli Lilly. Dr. Liu has received institutional research funding from Eisai, GRAIL, Janssen Diagnostics, Merck, Novartis, Roche/Genentech, Seattle Genetics, and Tesaro and has also been reimbursed for travel, accommodations, or other expenses by Agena Bioscience, Celgene, Cynvenio Biosystems, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, and Pfizer.
REFERENCES
1. Wolpin BM, Richards DA, Cohn AL, et al: Performance of a blood-based test for the detection of multiple cancer types. 2020 Gastrointestinal Cancers Symposium. Abstract 283. Presented January 23, 2020.
2. Liu MC, Jamshidi A, Venn O, et al: Genome-wide cell-free DNA methylation signatures and effect on tissue of origin performance. 2019 ASCO Annual Meeting. Abstract 3049. Presented June 1, 2019.
