Myriad Cancers Found with One Blood Draw

Multicancer early detection (MCED) by dint of a simple blood assay is still in its infancy and not yet ready for broad deployment. However, data from a prospective study of one such test, Galleri (GRAIL), show glimpses of potential and suggest that MCED may one day fundamentally change cancer screening as we know it.

Through next-generation sequencing and machine learning, Galleri “looks at methylation patterns on cell-free DNA in the blood, then returns a binary result,” explained Deborah Schrag, MD, of Memorial Sloan Kettering Cancer Center in New York, NY. “Either no cancer is found, or if there is a signal, the assay goes on to predict the most likely tumor type.”

During the ESMO 2022 Congress in Paris, France, September 9–13, Schrag presented final results from the PATHFINDER study, which enrolled 6,621 participants age 50 or older to be tested with Galleri. “Our motivation was to understand the clinical experience of MCED,” she said. “What diagnostic evaluations are precipitated by the receipt of a ‘signal detected’ result? What are [Galleri's] performance characteristics?”

The vast majority of PATHFINDER's participants received negative results, Schrag said. In all, 92 tested positive, “amounting to a signal detection rate of 1.4%.” After undergoing CT, MRI, or PET, 57 turned out to be false positives. Of the remaining 35, Galleri definitively predicted the origin of malignancy in 34, with an overall accuracy rate of 97.1%. “This helps guide diagnostic workups,” Schrag added. “If the prediction is head and neck, for instance, physicians could start with an oropharyngeal exam and perhaps an ENT referral.”

Among these 35 participants, 18 were diagnosed with solid tumors and 17 with blood malignancies. One was found to have both breast and uterine cancers. Roughly 40% had early-stage disease, and nearly 75% of the diagnoses “were cancers such as pancreatic and ovarian for which there is no standard screening,” Schrag said.

To discussant Federica Di Nicolantonio, PhD, of the University of Turin in Italy, although the number of false positives with PATHFINDER was not unreasonable, more work is needed to figure out why this happens and to reduce its occurrence. The same is true with false negatives—there were 86 in the study—and she wondered “if it might be due to nonshedding tumors or fast-growing disease that wasn't even present at the time of testing.”

“We're still far from perfect in this setting [MCED],” Di Nicolantonio remarked, “but taking a long-term view, the future seems bright. As blood-based assays are further refined, perhaps fragmentomics should also be incorporated”—whereby analyses of cell-free DNA fragment sizes could complement epigenetic (methylation patterns) knowledge, potentially improving predictive power.

An updated version of Galleri is already being used in PATHFINDER 2, which aims to screen 20,000 individuals, Schrag said. As well, several other large studies, including NHS-Galleri, STRIVE, and REFLECTION, should help optimize this test's real-world performance.

Meanwhile, the NCI is also going all out on investigating MCED's future promise. With a plethora of biotechs developing various assays, there is a pressing need to examine their actual utility. To that end, as part of the reignited Cancer Moonshot, the agency plans to launch a feasibility study in 2024 and evaluate such tests in 24,000 participants. This will lay the groundwork for an even larger trial down the road, involving up to 225,000 people.

For now, current screening procedures with established effectiveness should still be prioritized, Schrag stressed, even as MCED's possibilities are explored. Ultimately, too, “it will be important to assess whether MCED reduces mortality,” she noted. “That's the primary goal of all cancer screening.” –Alissa Poh

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