PORTLAND, OREGON: A blood test designed to search for signals from more than 50 cancers has delivered promising results in one of the largest prospective studies of multi-cancer early detection technology conducted in North America.
The PATHFINDER 2 study enrolled 35,878 adults aged 50 and above at 32 clinical sites across the United States and Canada. None of the participants had symptoms or other clinical findings that had already raised suspicion of cancer.
Published in Nature Medicine, the study found that the test detected cancer signals across several tumour types—including cancers for which no routine population-screening programmes currently exist.
However, the researchers stressed that the findings do not yet establish whether this approach prevents cancer deaths, avoids overdiagnosis or improves survival across the general population. Randomised trials and longer follow-up will be required before multi-cancer blood testing can be considered an established part of routine screening.
How does the blood test work?
The study evaluated the Galleri multi-cancer early detection, or MCED, test developed by GRAIL Inc.
Unlike a conventional biopsy that examines tissue taken from a suspected tumour, the test analyses fragments of cell-free DNA circulating in the blood. It uses machine learning to examine methylation patterns—chemical changes associated with how genes are regulated—and distinguish signals originating from cancerous cells from those released by healthy cells.
If a cancer signal is detected, the test also predicts its likely cancer signal origin, helping doctors determine which organ or tissue should be investigated first.
Participants received either a “cancer signal detected” or “no cancer signal detected” result. Positive results included one or two predicted sites of origin drawn from 21 predefined categories. Clinicians were encouraged to begin their diagnostic investigations at the location identified by the test.
The test is not itself a cancer diagnosis. Anyone receiving a positive result still requires imaging, laboratory investigations, endoscopy, biopsy or other clinical procedures to establish whether cancer is present.
What PATHFINDER 2 found
Of the 35,878 people enrolled, 35,350 were considered analysable. A total of 32,007 completed the required 12-month cancer-status assessment and were included in the principal performance analysis.
Among them, 287 participants received a positive MCED result. Cancer was subsequently diagnosed in 173, giving the test a positive predictive value of 60.3%.
In practical terms, approximately six out of every 10 positive results were associated with a confirmed cancer within the study’s follow-up period. The remaining positive results were classified as false positives when no cancer was diagnosed during that period.
The test produced:
- A cancer detection rate of 0.54%
- A positive predictive value of 60.3%
- A negative predictive value of 99.2%
- Specificity of 99.64%
- Overall 12-month episode sensitivity of 39.3%
- Cancer-origin prediction accuracy of 91.3%
One cancer was detected for every 185 people screened
The overall sensitivity figure is important. While the test was highly specific—meaning it produced relatively few false-positive results—it did not identify every cancer later diagnosed during follow-up.
Its episode sensitivity rose to 69.8% for a predefined group of 12 cancers responsible for approximately two-thirds of US cancer deaths. Sensitivity was 66.2% for six aggressive cancers associated with low five-year survival. Performance varied considerably according to cancer type and stage.
Many detected cancers lacked routine screening
During the 12-month follow-up, 440 participants were diagnosed with cancer through MCED testing, established screening or clinical diagnosis.
The MCED test detected cancer in 173 participants. Another 31 cancers were identified through screening carrying a Grade A or B recommendation from the US Preventive Services Task Force, while 60 were detected through Grade C screening, including individually decided prostate screening. The remaining 176 cancers were diagnosed clinically.
Researchers calculated that adding the blood test to Grade A and B recommended screening increased the number of cancers identified through screening by approximately 6.5 times. When Grade C screening was included, detection increased approximately threefold.
The test detected 17 broad categories of cancer, representing 81 histologically distinct cancer types. Of the 173 MCED-detected cases, 151 involved at least one newly diagnosed primary cancer, 22 involved recurrent disease and one had an unknown primary site.
Among the newly diagnosed primary cancers:
- 53% were stage I or II
- 70.9% were stage I, II or III
- 72.8% represented cancer types without Grade A or B population-screening recommendations
The latter finding is particularly significant because many dangerous cancers—including pancreatic, ovarian, liver and bile-duct cancers—are often discovered only after symptoms appear.
Still, the study cannot yet establish that detecting these cancers through a blood test will ultimately reduce mortality. Finding a tumour earlier does not automatically prove that treatment will extend a patient’s life; this must be demonstrated through randomised studies with long-term outcomes.
What did the test miss?
The study recorded 267 false-negative results, meaning cancer was diagnosed during the 12-month follow-up despite the blood test not detecting a signal.
Many of these were early breast or prostate cancers—conditions for which established screening or clinical-detection pathways already exist. Among the false-negative cases, 163 involved cancers covered by Grade A, B or C screening recommendations, including 103 stage I or II breast or prostate cancers.
This is one reason researchers and clinicians emphasise that an MCED test must complement rather than replace mammography, cervical screening, colorectal screening, low-dose CT for eligible people at risk of lung cancer or other recommended investigations.
A negative result should not be interpreted as proof that a person is cancer-free, particularly when symptoms, examination findings, family history or another screening result indicate the need for medical investigation.
How safe was the diagnostic process?
The study’s safety analysis included 35,335 participants.
Of the 290 people who underwent further diagnostic assessment after a positive test, 213 had at least one invasive procedure. That represented 0.6% of the overall safety population.
Altogether, 295 invasive procedures were performed. More than 90% were nonsurgical, and approximately 85% of all diagnostic evaluations—including both invasive and non-invasive investigations—were non-invasive.
Four people with false-positive results underwent surgery because cancer could not otherwise be excluded. All four were ultimately found to have benign growths.
Nine participants experienced 10 adverse events during diagnostic assessment. Five were considered related to the study, but none was serious. No serious study-related adverse event was reported in the analysis.
The median time to diagnostic resolution was 37 days among participants found to have cancer and 70 days among those without a cancer diagnosis. Across all positive results, the estimated median time to resolution was 48 days.
Anxiety temporarily increased among participants whose positive tests led to a confirmed diagnosis, but reported anxiety returned to baseline by 12 months. The study did not find an increase among participants with false-positive or false-negative results.
Two patients show the test’s potential
For some participants, the research had immediate personal consequences.
Franklin Weingarten, a retired Oregon physician who enrolled at age 84, received a signal pointing toward the liver. Further investigation led to the diagnosis of cholangiocarcinoma, a rare bile-duct cancer that has no routine population-screening test and is frequently discovered after symptoms develop. According to Oregon Health & Science University, the disease was localised, and Weingarten remained cancer-free following treatment.
Another participant, 68-year-old Bart Dawkins of The Dalles, Oregon, received a positive signal that led to the diagnosis of early-stage hepatocellular carcinoma, the most common primary liver cancer. He received treatment and was later evaluated for transplantation after developing a separate cancer in another part of his liver.
These individual outcomes illustrate the technology’s potential, but they cannot establish population-wide benefit on their own.
“Promise isn’t proof”
Lead author Dr. Nima Nabavizadeh is a physician-scientist, professor of radiation medicine and director of early detection clinical research at the Oregon Health & Science University Knight Cancer Institute.
He said the greatest screening gap lies in cancers for which no recommended screening currently exists. But he also cautioned that the promise of finding multiple cancers through a single blood draw must be confirmed through rigorous trials before widespread adoption.
PATHFINDER 2 was a prospective, interventional study, but it was not randomised and did not include a comparison group. Its endpoints were descriptive, with no predefined success threshold or formal hypothesis testing.
Participants were also generally well educated, mostly non-smokers and frequently up to date with established cancer screening. That may limit how directly the findings apply to populations with different demographics, health risks or access to healthcare.
Other limitations included:
- Only one round of MCED testing was evaluated
- Follow-up for the present analysis was limited to 12 months
- Diagnostic costs were covered by the study sponsor
- The real-world financial effect on patients and health systems remains uncertain
- The test version used in the study has since been updated
- The study did not determine whether testing reduces advanced cancer diagnoses or cancer mortality
- Longer follow-up is required to assess overdiagnosis and unnecessary treatment
Researchers said future analyses will examine participants’ adherence to conventional screening over three years, their diagnostic journeys and whether treatment following cancer detection was intended to be curative or palliative.
Independent proof will be critical
The randomised NHS-Galleri trial in the United Kingdom is separately evaluating annual MCED screening through the National Health Service.
Initial performance analyses have shown broadly consistent specificity and predictive performance across the UK and North American studies. However, the central question remains whether adding the test to usual care shifts diagnoses away from advanced disease and eventually reduces cancer deaths.
Researchers writing in an accompanying Nature Medicine commentary said PATHFINDER 2 and NHS-Galleri provide valuable evidence about performance, safety and implementation, but population-level benefit still needs to be demonstrated.
Who funded the study?
PATHFINDER 2 was designed and funded by GRAIL Inc., the manufacturer of the test. The company also participated in data curation, analysis, interpretation, drafting and approval of the publication.
Several authors disclosed financial or professional relationships with GRAIL or other healthcare companies. Dr. Nabavizadeh reported serving in advisory or consulting roles for GRAIL and Exact Sciences and receiving honoraria from Roche Diagnostics and MJH Life Sciences. Three co-authors—Margarita Lopatin, Celine Marquez and Margaret McCusker—were affiliated with GRAIL.
The company’s involvement does not invalidate the findings, but it is material context. Independent research, randomised evidence and transparent regulatory evaluation will be essential when determining whether the test should become part of routine cancer screening. Nature Medicine
The PATHFINDER 2 research team
The study authors listed by Nature Medicine were Nima Nabavizadeh, Charles McDonnell, Dax Kurbegov, Marc Matrana, Shirish Gadgeel, Raymond H. Kim, Gretchen Stipec, Kevin C. Oeffinger, Michael J. Demeure, James W. Lillard Jr., Rebecca Kaltman, Jennifer Tran, Alan Roth, Sami Tahhan, Andrew Poklepovic, Donald Richards, Margarita Lopatin, Celine Marquez, Margaret McCusker and Karthik V. Giridhar.
Their affiliations included Oregon Health & Science University, Sutter Health Research Institute, HCA Healthcare Sarah Cannon Cancer Network, Ochsner Clinic Foundation, Henry Ford Health, Princess Margaret Cancer Centre, Duke University Health System, Morehouse School of Medicine, Georgetown University School of Medicine, Mayo Clinic and GRAIL, among other participating institutions. Nature Medicine
What patients should know
PATHFINDER 2 offers meaningful evidence that a single blood draw can detect signals from multiple cancers and direct doctors toward the likely source of disease.
It does not mean one blood test can reliably rule out every cancer. It does not replace existing screening, clinical examination or diagnostic testing. Nor has it yet been proven to reduce the risk of dying from cancer.
For now, its most important contribution may be showing that multi-cancer blood testing can be implemented with high specificity, a relatively low false-positive rate and manageable diagnostic follow-up—while highlighting exactly what scientists still need to prove.
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