How a Multi-Cancer Screening Test Would Play Out in the Clinic

Confirming an actual cancer diagnosis in patients flagged as potentially having a malignancy by a multicancer blood test typically required multiple imaging scans and laboratory tests, suggested results from PATHFINDER, a prospective U.S. cohort study.

In a convenience sample of adults 50 and up with no signs or symptoms of cancer, the multicancer early detection (MCED) test picked up a cancer signal in 1.4%, with true positives identified in 0.5% via pathologic, laboratory, or radiographic confirmation, reported researchers led by Deb Schrag, MD, of Memorial Sloan Kettering Cancer Center in New York City.

In patients with a cancer signal detected, more than 90% underwent imaging (often multiple scans), over 80% received laboratory tests, and nearly half had a biopsy or other procedure as part of their diagnostic workup, with false positives ultimately identified in 0.9% of the cases.

The Galleri cell-free DNA test (developed by Grail), also led to false negatives in 1.3% of the more than 6,500 participants in the study, the researchers detailed in The Lancet.

“When the MCED assay was positive and cancer was present, the test accurately predicted the tumor origin, and half of all cancer diagnoses were made in less than 2 months,” wrote Schrag and colleagues. “When cancer could not be confirmed, diagnostic assessments, often with serial scans, continued for a longer duration, typically extending for 4 months.”

Many of the cancers detected — including some at early stages — would not have been covered by recommended screening tests, the researchers pointed out, with MCED identifying a tumor type without a U.S. Preventive Services Task Force (USPSTF) screening recommendation in 24 of the 35 true-positive cases.

“For example, cancers of the bile duct, small intestine, pancreas, and a spindle-cell neoplasm were detected at early stages amenable to surgical resection,” the study authors noted. “These lethal malignancies are unlikely to have been identified upon routine physical examination or screening.”

There is a considerable amount of “hype” for a blood test that could potentially reduce the complexities of established screening programs while also detecting additional cancer types, said Richard Lee, PhD, of the Institute of Cancer Research in London, and Hilary Robbins, PhD, of the International Agency for Research on Cancer in Lyon, France, writing in an accompanying editorial.

“The PATHFINDER results allow us to put numbers to some of these potential benefits of MCED testing, as well as the harms,” the duo wrote.

On the positive front, the 35 patients diagnosed because of MCED testing “represent an important increase in earlier diagnosis,” while adding that few invasive procedures were performed due to a false-positive result.

But the number of cancers diagnosed during the study by standard USPSTF guideline screening (n=29) was actually similar to those from the MCED test, Lee and Robbins pointed out. By their calculations, the assay had a “somewhat underwhelming” sensitivity of just 29%.

While studies like PATHFINDER are producing “exciting data,” the editorialists said, concerns remain over “low sensitivity, overlap with existing, proven approaches, and unknown mortality benefit and cost-effectiveness,” concluded Lee and Robbins.

“In the wider MCED setting, we must consider confidence in cancer detection versus exclusion, test convenience, testing frequency, and added value beyond existing screening approaches as well as primary cancer prevention,” they added.

PATHFINDER was conducted at oncology and primary care outpatient clinics across seven U.S. health networks and included participants age 50 years or above without signs or symptoms of cancer. A majority (56%) had an additional risk for cancer based on their smoking or cancer history, meeting guideline criteria from the National Comprehensive Cancer Network for germline testing, or due to a hereditary cancer syndrome.

Mean participant age was 63 years, nearly two-thirds were women, and the vast majority were white (91.7%). About a fourth had a previous cancer, and nearly all were up to date with cancer screening.

Of the 6,621 participants available for analysis, the MCED detected a cancer signal in 92, including 35 true positives (with six recurrences) and 57 false positives. In 97% of the true positives, the test correctly identified the primary cancer location. Fourteen of the 29 true positives (48%) that involved a new cancer diagnosis were stage I/II, including six solid tumors and eight hematologic malignancies.

After excluding two patients who developed clinical symptoms before their MCED results, imaging was performed in 92% of the 90 patients with a cancer signal detected and 53% had multiple imaging tests. Lab tests were performed in 84%. Median observed time to diagnostic resolution of a positive test was 79 days (57 days for the true positives and 162 days for the false positives).

Among the true positives, 82% underwent a procedure, as compared with 30% of the false positives. Surgeries were performed in 9% and 2% of the two groups, respectively.

Of the 6,529 negatives results with MCED, 6,235 were true negative, 86 false negatives, and 208 did not have a cancer status assessment at study end to determine whether it was true or false.

To detect a single new cancer, the number needed to screen with MCED was 189, Schrag’s and colleagues determined, and the test had a specificity and negative predictive value of 99.1% and 98.6%, respectively.

Within the 12-month study period, a total of 122 cancers were diagnosed overall in 121 patients, including the 35 by MCED testing, 38 through screening, and 48 detected clinically.

The authors acknowledged several imitations to their study, including the fact that the findings may not be generalizable because of the lack of ethnic, racial, and socioeconomic diversity in the cohort, as well as due to the high rate of adherence to cancer screening.

Moreover, they said that volunteer bias could have influenced participants’ risk or their preferences for undergoing comprehensive diagnostic assessments, and that the 12-month study period was short and that rates of later cancer diagnoses are uncertain.

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