The Largest Study of a Multi-Cancer Early Detection Blood Test

Reviewing the new data and the "liquid biopsy" field

At the European Society of Medical Oncology (ESMO) meeting last week, the largest study of multi-cancer early detection blood test (MCED) was presented for the first time. I’ve reviewed this topic in SUPER AGERS but this trial of nearly 36,000 participants represents a significant update. In this issue of Ground Truths, I’ll get into the data, implications, and where the field is headed.

The PATHFINDER 2 Trial and Results

This new study assessed the GRAIL blood test called Galleri that assesses DNA-methylation markers (side chains of DNA) in the plasma from patterns in cell-free cancer fragments, a so-called “cancer signal.” The new trial was preceded by PATHFINDER, a study of 6,602 participants published in The Lancet, and I reviewed here in Ground Truths at the time of publication in 2023.

For the new trial, 35,878 participants were enrolled from 50 sites in the US and Canada. The main inclusion criteria were age 50 and above with no prior history of cancer in the past 3 years. For more details on inclusion and exclusion criteria and analysis plan, see the clinical trials.gov registration here. The participants were encouraged to get their normal screening tests such as mammography or colonoscopy.

Of the near 36,000 enrollees, 23,161 were analyzable with 12-month follow up, which was the basis for the presentation of results.

Here are the principal findings:

1. A “cancer signal” was identified in 216 cases, 0.93%, which translates to 9.3 cases per 1,000 participants.

2. Cancer was confirmed from the Galleri test in 133 cases, which is 5.7 cases per 1,000 participants. The positive predictive value was 61.6% (Figure below)

   

3. Early cancer (Stage 1 or 2) was detected in 61 participants, equivalent to 3 cases per 1,000 participants, nearly half of those (N=133) with confirmed cancer. Note that this is the principal goal of the test, detection of early, non-metastatic cancer.

4. There were 196 false negatives—the MCED was negative but the participant was found to have cancer during the 12-month follow-up, a sensitivity of 40%.

5. The types of cancers (more than 50) detected by Galleri were diverse, as shown below, most of which aren’t picked up for by recommended mass screening mammography, colonoscopy, or chest CT (for people at high risk of lung cancer), all 3 shown in blue below.

   

   6. Mass screening (not MCED) picked up 67 cancers (breast, cervical, colon, lung or prostate). Taking out prostate, mass screening found only 20 cancers.

   7. A.I. of the methylation marker pattern correctly identified the site of origin in nearly all (92.7%) participants who had cancer, as subsequently confirmed by lab work, imaging, biopsy, or surgery..

Critique of the Trial

The yield of early cancer detection of 3 cases per 1,000 assessed is extremely low. By enrolling healthy people age 50 and older, the Galleri test was applied to a very low risk cohort. This is better than 1 or 2 cases of early cancer detected in the preceding trial, most likely achieved by enriching the participants to be of older age. (as stipulated in the protocol, and indeed 29% were age 70 and older.)

Beyond the low yield, there is an issue of false negatives. As seen in the top Figure, there were more false negative results (N=196) than true positives (N=133) for the Galleri test.

The GRAIL company promoted the trial’s results in their press release as detecting cancer more than 7-fold recommended US Preventive Services task force (USPSTF) mass screening. This is misleading for many reasons. That was not a/the primary endpoint for the trial (see the registration). The 7-fold excludes the prostate cancer diagnoses that were detected from screening. The protocol did not mandate following recommendations for mass screening by participants. And it is not at all reassuring to use USPSTF recommendations as a gold standard, since there is the common thread of a remarkable low yield, using age as the sole criterion for getting screened.

The media coverage was similarly off, some of which is shown below. The results could hardly be considered “transformative” and weren’t contextualized by the low yield or missed cancers. Yes, on the other hand, the Galleri did pick up more than 50 kinds of cancer which is certainly a big step in the right direction. And the ability to localize the tumor site of origin with machine learning in nearly all participants is quite impressive.

Going Forward

We can do far better. The first step needs to be enrolling people at high-risk, which could be distinguished in a number of ways: family history of frequent cancers, prior cancer, polygenic risk score for common cancers (see prior post), whole genome sequencing which can be performed at low cost and consistently picks up 5% or greater of people with pathogenic, cancer-causing mutations that were not suspected, use of the CHIP assay (clonal hematopoiesis of indeterminate potential; see prior post), an an immune system clock with a significant gap compared with the person’s chronological age (see prior posts here and here).

There are tens of emerging MCEDs, many with clinical trials in progress that measure different factors in the blood, as I reviewed in SUPER AGERS, such as cell-free RNA, DNA fragmentation, circulating exosomes, repeat DNA elements, proteins ,and metabolites. There are many ways that the low quantity of cell-free tumor DNA can be amplified, with priming agents to improve the signal-to-noise ratio and accuracy. But all these diverse and refined tests would similarly benefit by assessment in high-risk individuals rather than just using age as the method of selection, copying the flawed and wasteful practice of our current mass screening policies.

The GRAIL Galleri test is leading the pack, approaching testing cumulatively in a million people (commercially and in research trials). The company can be commended for taking a high road research emphasis with many trials, most notably an ongoing UK randomized trial of over 140,000 participants that has completed enrollment. But the test costs $949 and is not covered by insurance. That is a very high price for such low chance of early detection (3 out of 1,000) and high false negatives. I would not recommend a Galleri test the way it is getting done today (age 50+). But in a bona fide high-risk individual that may deserve consideration, and increasingly so as these MCED tests continue to improve.

What is being missed is the chance to go after cancer prevention, not just early detection. While it would be far better to detect cancer microscopically with a test like Galleri or other MCEDs as compared to a total body MRI, with the requisite of billions of tumor cells by the time a mass is detected by imaging, even better would be to prevent cancer altogether. We have that newfound potential of primary prevention, the premise of SUPER AGERS, and in this recent Ground Truths post. Use of the ways to define high-risk (polygenic risk, score, CHIP, whole genome sequencing, immune system assessment) would, with multimodal A.I. analytics, identify the high-risk patients that enable primary prevention, just as this would help promote much higher yield and accuracy of the multi-cancer early detection tests.

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