NEW YORK – Awareness and usage of blood-based minimal residual disease tests for solid tumors are on the rise in the precision oncology community, even as the field remains split on questions of technology and utility, according to a recent survey conducted by GenomeWeb.
Widespread uptake of these assays may still be hampered, though, because opinions on clinical utility, applications, and technological approaches differ.
The results track with other evidence of the growing adoption of circulating tumor DNA testing to detect occult disease, expanding applications and use cases, positive data from independent trials, and intense commercial investment and competition.
"I would say that over the past year or year and a half, there has been a huge amount of increased interest from both patients, who are now coming in and asking about these tests, as well as providers," said Heather Parsons, a breast cancer-focused medical oncologist at Dana-Farber Cancer Institute (DFCI) and assistant professor of medicine at Harvard Medical School.
"From what I understand, most [in the breast cancer care community] are not ordering these tests, though some people are … but the fact is, everyone is aware of them now," she added, citing a lack of utility studies as the main reason for her community's hesitation.
The GenomeWeb survey included oncologists, pathologists, and participants with a managerial position associated with test adoption. Of 199 respondents who fell into those groups, 17 said they order molecular testing for patients, 49 said they perform such tests, and 133 said they help make decisions around testing at their institution.
Asked if they were familiar with the use of circulating tumor DNA tests to identify or monitor minimal residual disease in patients being treated for solid tumors, nearly all said they were.
A total of 140 said they were familiar with both tumor tissue-informed and tissue-naïve assay technologies, while another 11 claimed knowledge only of tissue-informed and 12 only of tumor-agnostic tests.
The choice of tissue-informed versus tissue-agnostic testing has been a major split in the solid tumor MRD field thus far, with tumor- or tissue-informed tests purporting to offer the greatest sensitivity.
These tests use upfront sequencing of a patient's tumor DNA, which can range from targeted panels to the exome to whole-genome sequencing, to identify alterations for building a personalized MRD test.
Tissue-agnostic tests include a generic panel of common cancer alterations, potentially enhanced by informatic methods to optimize the choice of targets.
"I think it's heavily dependent on the setting," Parsons said. "I would say in breast cancer, it leans more toward the tumor-informed [tests] because almost all of the data are with that approach, and because the shedding [of tumor DNA into the blood] seems to be lower … so there is a sense that sensitivity is important."
Offered a list of commercial solid tumor MRD tests most frequently covered by GenomeWeb, survey respondents were most likely to have heard of Natera's tissue-informed Signatera and Guardant Health's tissue-agnostic Guardant Reveal tests, each of which were recognized by more than 70 percent of respondents. They were followed by NeoGenomics' tissue-informed Radar assay and Tempus' tissue-naïve xM assay, each recognized by around half of respondents.
Personalis' NeXT Personal, which uses upfront whole-genome sequencing to inform its personalized MRD panels, was also somewhat known, with about 40 percent of respondents saying they were familiar with the test.
Write-in responses included Quest's Haystack assay, Foresight Diagnostics' Clarity, Invitae's PCM (now part of Labcorp), Naveris' NavDx, and Foundation Medicine's FoundationOne Tracker. Several of those surveyed also noted the existence of laboratory-developed tests.
Interestingly, two respondents mentioned Grail, which has focused on developing a multi-cancer early detection test but recently described a method to estimate the amount of tumor-derived cell-free DNA called tumor methylated fraction (TMeF), which it believes holds promise for various MRD or monitoring applications.
Grail's methylation-based technology stands apart from both tumor tissue-informed and tissue-agnostic mutation panels and would add a third approach to the mix if brought to market.
Another method that could diversify the field uses an exome or genome sequencing step to train personalized assays but doesn't require tumor tissue samples, sequencing extracted circulating tumor DNA instead.
James Hadfield, senior director of epigenomics in Oncology Translational Medicine at AstraZeneca, said that while this approach has been less explored, it will hopefully become part of the landscape of solid tumor MRD in the future, along with even more advanced methods.
He and his colleagues have been evaluating multiple MRD approaches and recently published a commentary in the Journal of Clinical Oncology describing their approach. Most recently, they have begun to evaluate a new class of tumor-informed and bioinformatically personalized WGS methods, something they've proposed dubbing "whole-genome squared." One of the first commercial entities to adopt this approach was C2i Genomics, which has been advancing a technology developed by Dan Landau and colleagues at the New York Genome Center and Memorial Sloan Kettering Cancer Center.
Molecular diagnostics firm Veracyte acquired C2i this January, marking its first foray into MRD testing. A handful of other companies have similar approaches in development, including Labcorp, Illumina, and the newest entrant to the market, San Jose, California-based AccuraGen.
"It's exciting that the opportunity to do plasma-informed MRD instead of tissue-informed might give us the sensitivity we require with the ease of just sending in blood," Hadfield said.
Adoption growing
In the GenomeWeb survey, 46 percent of respondents said their institution does not currently offer MRD tests for solid tumor patients. Another 19 percent said they use both tumor-informed and tumor-agnostic tests, 21 percent only use tissue-based tests, 7 percent only use tissue-agnostic panels, and 10 percent were not sure what tests their institution uses.
A nearly equal number of respondents (30 and 28) said they perform testing in-house (30) and outsource it to a company (28), and another 18 said they do both.
Half of respondents who send out their tests mentioned Natera, one of the first firms to launch a clinical circulating-tumor DNA MRD test for solid tumors, while Guardant Health, also an early player, was mentioned by 30 percent. A quarter of the group said they had used none of the companies listed, writing in other options including Agena Bioscience, LabPMM, Oncomine LifeLabs, Labcorp, Burning Rock Biotech, Genomic Testing Cooperative, Hartwig Medical Foundation, and AccuraGen.
The survey also revealed that the majority of those who don't currently offer MRD testing expect to do so within the next two years, in line with Parsons' comments on increased familiarity with these tests among labs, doctors, and even patients.
Clinical utility still emerging
Even though so-called landmark testing — testing patients at a single time point after surgery to identify those with lingering disease who need chemotherapy — has been the most studied application, the most endorsed use case among those surveyed was longitudinal monitoring, picked by 76 percent of respondents.
Another 55 percent said they believe there is clinical utility in testing colorectal cancer patients in the adjuvant setting to guide the use of chemo, while 53 percent endorsed monitoring of patients during immunotherapy, and 49 percent saw value in post-surgical testing to guide adjuvant treatment in tumor types other than colorectal cancer.
Cancer types where researchers are pursuing MRD validation and utility studies include lung, breast, bladder, head and neck cancer, and melanoma.
Dana-Farber's Parsons said she was surprised by the survey result that showed more enthusiasm for long-term monitoring than for adjuvant testing to inform therapy, and said even that application is supported by little clinical utility data. In 2022, investigators led by a team at the University of Melbourne's Peter MacCallum Cancer Centre showed for the first time in a study called DYNAMIC that MRD-guided treatment of colon cancer led to less overall use of chemotherapy without compromising patient outcomes. Natera has since been able to collect similar data for its Signatera assays.
However, another study in the same cancer type, COBRA, which used Guardant Health's tissue-agnostic test, failed an interim utility analysis and closed ahead of time earlier this year, providing what Parsons called a "word of caution" to the field.
That said, there are numerous utility trials in progress that could prove out specific tests in a range of use cases.
"The one challenge is that most of those studies are going to have been done with first-generation technologies … and I hope that we don't throw out this concept if we get poor results with [these older tests]," Parsons said.
Natera's Signatera, the first tumor-informed assay to take hold in the clinic, produces personalized panels of up to 16 alterations for MRD testing. Follow-on competitors like Inivata (now Exact Sciences) boosted that number to around 50 targets. But since then, researchers have used tumor exome and even genome sequencing to create much broader MRD panels.
Parsons has worked with the Broad Institute team that developed an exome sequencing-based method they called MAESTRO, which Exact Sciences licensed in 2023. Haystack Oncology, a spinout of Johns Hopkins University, recently saw its exome-informed MRD technology acquired by Quest Diagnostics.
Meanwhile, Personalis launched a whole-genome sequencing-based MRD test, NeXT Personal, under an early-access program in 2023, later partnering with Tempus to market the test more broadly. Other WGS pioneers include Foresight Diagnostics and AccuraGen.
Parsons also referenced new data from a group at the Royal Marsden that was presented at the American Society of Clinical Oncology annual meeting this year. She participated in an expert panel discussion of the data at the conference and noted that the whole-genome sequencing-based approach that was used, Personalis' NeXT Personal, was able to detect MRD at lower mutation allele frequencies than should be possible with narrower panels. Knowing that, the field should be careful not to throw the baby out with the bathwater if current trials with smaller assays don't pan out, she argued.
In the GenomeWeb survey, respondents were almost equally split between viewing larger MRD test panels with more targets as likely to improve sensitivity or thinking that it doesn't matter.
AstraZeneca has been assessing MRD technologies for several years, and Hadfield argued that tests need to be selected to best fit the clinical application and may require different performance characteristics. He assesses MRD technologies to identify the best tools for drug studies, as well as potential platforms for future companion diagnostics. Newer tumor-naïve tests may not be as sensitive as, say, Natera's, he noted, but they don’t necessarily need to be — if they can prove clinical utility.
For treatment or recurrence monitoring, tests being done sequentially can overcome the need for lower sensitivity and often have lower costs, he said, but for an application where a patient is potentially de-escalating treatment — for example bladder cancer, where MRD might identify patients who can avoid bladder removal — high sensitivity becomes more important.
Parsons also highlighted challenges facing clinicians as patient awareness of MRD testing increases. "I wouldn't go so far as to say that these tests need the same degree of oversight and rigor that pharmaceuticals do, but … they do have a huge power to help and harm patients," she said. "My concern is that we have these less sensitive tests, and patients … want to know that they don't have ctDNA. If that's true, it's difficult because that's the exact thing we can't do with these tests right now."
Parsons said she'd feel comfortable acting on a positive test result. But telling a patient with a negative test that they should still be wary is more difficult.
She has also become aware of some MRD providers doing "very aggressive" marketing directly to patients, though she declined to name specific companies. "I worry that because some of the therapies we give are used over a long period of time and are toxic, that [negative results from these tests] could drive people's decision-making [to forgo such therapies] even though there's no data that suggests that that's a good idea," Parsons said.