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Super Early Detection: Pan-Cancer Tests Aim to Catch Cancer Earlier than Ever

By Paul Nicolaus

March 16, 2022 | In recent years, the race to develop a single test that can simultaneously screen for many cancers has heated up. Dozens of companies have thrown their hats in the ring, pursuing differing approaches to search for the very earliest signs of cancer.

The concept behind all these efforts seems simple and straightforward: detect cancer sooner, when it can be effectively treated or cured. The work of bringing this ambitious goal to reality, however, is anything but simple or straightforward.

So where does this field currently stand? Where is it headed? And is extremely early cancer detection really possible? 

“Earlier Tumors are a Bigger Challenge”

Whereas certain forms of cancer have well-established screening methods, some of these methods—like mammograms or colonoscopies—can be uncomfortable, invasive, or require extensive preparation. Other forms of cancer, meanwhile, lack screening tests entirely. All too often, cancers are discovered in their later stages, when there may be fewer treatment options and a higher chance of death. For these reasons and more, some see enormous potential in the prospect of a simple, non-invasive method that could help screen for many cancers at the same time and help detect them both earlier and easier than traditional methods. 

Some versions are already being put to use, although they are far from perfect in their current iterations. Existing multi-cancer tests generally have high sensitivities when it comes to picking up on later-stage cancers, based on the performance studies published by various labs, said Michael J. Hall, professor of medicine and chair of the Department of Clinical Genetics at Fox Chase Cancer Center. But when it comes to picking up on earlier-stage disease, these tests tend to suffer from a loss of sensitivity. “So can we detect those advanced tumors right now? We can. The earlier tumors are a bigger challenge,” he said.

Another critical aspect of early detection centers on pinpointing the tissue of origin. Current technologies have gotten quite good at identifying the origin of the tumor, he said. But misclassifications are a possibility. This occurs when a test indicates the pancreas as the site of origin, for example, when it actually began in the ovary. 

There are also scenarios where test results indicate the presence of a tumor in a particular location, but when medical professionals search for it, they do not find a tumor there—and are unable to find one anywhere. This can evolve into a diagnostic odyssey as the search continues for why the signal came back as positive in the first place.

Is it because there’s a tumor hiding somewhere and it is being misclassified? Or is it due to a false positive? While this field is still emerging, these are the types of issues that still need to be figured out, Hall added.

Key Players, Differing Approaches

Currently, the pan-cancer testing space includes a small handful of large, prominent players, including GRAIL (Illumina), Thrive (Exact Sciences), and Freenome.

Sequencing giant Illumina, which formed GRAIL and spun it out back in 2016, acquired GRAIL last year in hopes of speeding along patient access to multi-cancer early-detection testing. GRAIL is developing a blood test, called Galleri, which is designed to help detect over 50 types of cancer. The test relies on a combination of machine learning and cell-free DNA (cf-DNA) to find abnormal patterns of DNA methylation.

Last year, meanwhile, Exact Sciences acquired Thrive—another of the frontrunners in this realm of multi-cancer screening. Its CancerSEEK is a multi-analyte blood test that looks at DNA mutations and cancer-related protein biomarkers.

And at the start of 2022, Freenome announced that its total funding surpassed $1 billion following an investment of nearly $300 million from Roche. Freenome has developed a machine learning-enabled multi-omics blood test for colorectal cancer screening, and is extending its platform to other cancers, with plans to launch multi-cancer clinical studies focused on “more tailored baskets of screening tests” based upon a person’s individual risk.

Plenty of others are pursuing this same challenge using (primarily) blood-based liquid biopsy samples. Many of the approaches are based in cfDNA, but other possible biomarkers, such as metabolites and autoantibodies, are being explored as well.

Can It Be Done? 

Despite the flurry of activity in this field, the question remains: Is early pan-cancer testing possible? It depends on who you ask and how the playing field is defined. 

Some say absolutely. Hall, for example, believes there’s a strong possibility that, if used at the right time and in the right population, pan-cancer tests could help diagnose cancer sooner and improve patient outcomes. There are plenty of studies underway as companies test their products in clinical trials to demonstrate efficacy and outcomes. It’s just a matter of continuing to refine existing technologies, he pointed out.

Although sensitivity and specificity vary depending on the assay, the “data so far is promising,” said Alexey Aleshin, general manager of early cancer detection at Natera. The company believes its experience with cfDNA and minimal residual disease (MRD) testing will yield results in this space and, in early 2022, announced its expansion into the early cancer detection market.

Others, like Marian Novak, believe it’s just too soon to say whether pan-cancer testing is possible. Although there have been many promising developments, there are still no FDA-approved multi-cancer early detection tests in existence, said the senior global product manager of clinical applications-oncology at SOPHiA GENETICS. We still need to figure out if screening is effective at saving lives in asymptomatic people and whether the benefits outweigh the harm, both of which remain unknown.

Still others point out that talk of pan-cancer testing would, ideally, refer to all cancers—not just some or many. While single test solutions already exist that span multiple cancers, a true all-cancer test isn’t possible just yet, according to Luca Quagliata, vice president and global head of medical affairs for clinical sequencing and oncology at Thermo Fisher Scientific.

“While I hope that will happen, it might not be available within my lifetime,” he said.

There isn’t enough data, unfortunately, to say there is a single test that can be used in this sort of pan-cancer approach. To reach that level of coverage, larger, more extensive, and better-designed clinical trials are needed. And with so many different tumor types, there is a need to ensure that all are represented in studies to show that a test truly works across all cancers.

Marty Keiser, meanwhile, called early-stage disease detection data “underwhelming, to say the least.” In theory, pan-cancer testing ought to be possible from both a technical and scientific standpoint, explained the founder and CEO of IV BioHoldings. From a technical perspective, these panels have been around for quite some time, and many of them have been successfully marketed. But he would argue that early pan-cancer panels have yet to come to market.

Whereas GRAIL’s Galleri is being marketed as a multi-cancer early detection test, for instance, its positive predictive value (PPV) in actual early-stage disease (stage I) is quite low, he pointed out. While there is clinical value in being able to diagnose disease at any stage via liquid biopsy rather than tissue biopsy, Keiser cautioned against labeling existing pan-cancer tests as early.

Market Drivers Explored

According to Keiser, there is one crucial question the market has not spent nearly enough time considering: Which type of physician is most likely to use these tests? 

Internists and primary care physicians (PCPs) may be the most likely to use a pan-cancer early detection test because the benefit would come by continuous screening with the hope that something can be found during a routine visit, but there are notable caveats worth considering.

These doctors already have narrowing reimbursement and limited bandwidth. He called the process of explaining this type of test, ensuring the patient understands the process and the potential outcomes, and managing the test results a “near-impossible lift.” Is this same medical professional expected to coordinate all follow-up visits with specialists and genetic counselors following a positive result? The sheer volume of follow-up required would likely overwhelm an already overwhelmed PCP population.

Beyond that, there are liability issues to consider. Tests that can simultaneously detect multiple forms of cancer bring about a new set of questions around false positives, false negatives, and follow-up care. If all of these challenges are figured out, the primary market driver will boil down to cost—not just the expense of the test itself, but also the expense of the test results on the overall health care system. 

How much would it cost to follow up with imaging and scans for all false positives? Is there a quantifiable clinical benefit, and does that benefit outweigh the spend? Is the test improving care and quality of life for patients? And are we genuinely finding disease that we couldn’t before? These are the types of questions that have yet to be fully addressed, he added.

Quagliata agreed that cost is a key issue. With early-stage testing, it can be difficult for any health care system to justify expenses tied to asymptomatic patient cases. If policymakers made this available for free and medical societies also supported its use, nothing would stop patients from receiving this type of testing. But this coverage hinges on the ability to prove that early intervention results in better patient outcomes, and while this may seem intuitive, it is not necessarily true in all cases. In some scenarios, this information could lead to overdiagnosis or unnecessary stress for patients who may not have experienced any symptoms or needed any treatment. 

“As we differentiate who stands to benefit most from liquid biopsy testing and early diagnosis, medical support of this testing will be key to drive adoption,” Quagliata explained. Medical associations that provide guidelines and serve as gatekeepers will be an essential element of how this form of testing is embraced—or not—in the field of oncology. 

Treatment Implications

While probably still a way off at this stage, pharmaceutical companies may begin to develop therapies that could be used at earlier stages of cancer. Early-stage cancers can often be removed with good outcomes for patients, explained Quagliata, but we may wind up seeing more therapies become available down the road that could help avoid surgery altogether. And this could drive the need for more testing earlier on to inform which patients may be eligible for these types of treatments. 

In the more immediate future, multi-cancer tests could be a useful tool for helping with treatment selection and monitoring in patients with later-stage cancers.

“Liquid biopsy in advanced cancer is likely to increasingly supplement tissue biopsy in 2022 and beyond,” said Yuri Fesko, executive medical director of medical affairs and medical oncology for Quest Diagnostics. A blood test can help doctors arrive at possible targeted therapies when there is little tissue available, or when repeat biopsy isn’t a viable option.


Paul Nicolaus is a freelance writer specializing in science, nature, and health. Learn more at