1. Fuerst, Mark L.

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SAN FRANCISCO-A blood-based screening test using cell-free DNA to identify methylation signals of hard-to-detect gastrointestinal (GI) cancers could potentially help detect cancer at earlier stages, according to a new study presented at the 2020 ASCO Gastrointestinal Cancers Symposium.

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"The potential of this test is to diagnose cancer earlier, when it is more treatable. The ability to do that across cancer types could be quite valuable. Many of the cancer types that this test detects do not currently have screening tests that allow earlier cancer detection before the cancers cause symptoms," said lead investigator Brian M. Wolpin, MD, MPH, Director of the Gastrointestinal Cancer Center and Director of the Hale Family Research Center for Pancreatic Cancer at Dana-Farber Cancer Institute in Boston.


In general, GI cancers are difficult to identify early. The GI organs are deep inside the body, so small tumors cannot easily be seen or felt during routine physical examination. No screening tests are available for GI cancers such as gallbladder, bile duct, and pancreatic cancer. Screening exams do exist for other types of GI cancers, including colorectal and stomach cancer, but many of these tests are invasive. When GI cancers are diagnosed, they are often at advanced stages that are more difficult to treat. An accurate test based on a simple blood sample could lead to earlier diagnosis for GI cancers.


Cancers of the esophagus, stomach, pancreas, gallbladder, liver, bile duct, colon, and rectum accounted for 17 percent of incident cancer diagnoses and 26 percent of cancer-related deaths in the U.S. in 2019, noted Wolpin.


The test uses cell-free DNA-degraded DNA fragments circulating through the bloodstream, which can come from a number of sources, including tumor cells that have died and released DNA fragments. The test is based on DNA methylation, a chemical process that can change how a gene's function is carried out by the body without changing the order of the DNA bases. Methylation plays a role in many processes in the body, including the development of cancer. The researchers used a technique called bisulfite sequencing, which allows them to identify a pattern of methylation in the cell-free DNA (Abstract 283).


Key Findings

In the Circulating Cell-free Genome Atlas (CCGA) Study, a prospective, multi-center, observational, case-control study with longitudinal follow-up, the researchers included patients with more than 20 tumor types at all disease stages and non-cancer controls. In a second sub-study of CCGA, plasma DNA underwent targeted methylation analysis to develop an algorithm that could identify whether the patient had cancer and the tissue of origin of the cancer-the presence or absence of cancer and its location in the body.


"Methylation fragments were combined across targeted genomic regions and assigned a probability of cancer and a predicted tissue of origin," said Wolpin.


The cancers included were of the esophagus/stomach (67 patients), pancreas/gallbladder/extrahepatic bile duct (95 patients), liver/intrahepatic bile duct (29 patients), and colon/rectum (121 patients). Data included training and validation sets.


The technology had an overall sensitivity of 82 percent for cancer detection for the training set and 81 percent for the validation set, with a specificity of more than 99 percent. Overall accuracy for defining the GI tissue of origin among the samples for which tissue of origin was assigned was 91 percent and 89 percent for the training and validation sets, respectively.


"The data show that evaluating methylation of cell-free DNA within a blood sample may detect a variety of GI cancers with good sensitivity and with a low rate of false positives. If further validated with additional testing, this approach has the potential to allow us to diagnose GI cancers earlier, when they are more treatable," said Wolpin.


Next Steps

The test's developers are also conducting two large population-based studies to further validate the screening potential of the test. The STRIVE study has enrolled nearly 100,000 women undergoing screening mammograms, and the SUMMIT study is enrolling 50,000 men and women without a known cancer diagnosis.


In conclusion, Wolpin and colleagues stated: "Simultaneous detection at high specificity (more than 99%) of multiple cancer types, including GI cancers across stages at high sensitivity (82%), was shown using targeted methylation analysis of cell-free DNA. Accurate (92%) localization of cancers to specific regions of the GI tract was also achieved. Detection of multiple GI cancers from a single noninvasive blood test could be a practical method for detecting GI and other cancers, and may facilitate diagnostic workups."


ASCO Expert Muhammad Shaalan Beg, MD, Associate Professor at the UT Southwestern Medical Center, commented: "Blood tests that can identify cancer in asymptomatic individuals, particularly GI cancers that can be difficult to detect in early stages, could change cancer diagnostics by making it easier to accurately screen for and identify these cancers earlier. The preliminary results seen in this study, however, will need to be validated by screening large populations of asymptomatic individuals."


Mark L. Fuerst is a contributing writer.