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MRD in 2023: Current Capabilities, Differing Approaches, and Tests on the Horizon

By Paul Nicolaus 

March 16, 2023 | An array of diagnostics companies have set their sights on developing minimal residual disease (MRD) tests capable of detecting low levels of cancer cells remaining in the body following surgery or other types of treatment. The aim is to help measure response to therapy, identify patients at risk of relapse, or indicate when treatment can be stopped. And there appears to be plenty of interest in this field at the moment.  

During the J.P. Morgan Healthcare Conference held at the start of the year, for example, several companies emphasized recent efforts in this space or shared plans to pursue MRD testing moving forward. Invitae CEO Kenneth Knight highlighted the company’s Personalized Cancer Monitoring product, for example, and Natera CEO Steve Chapman noted the growth of its Signatera MRD test, as Diagnostics Worldreported.  

Other announcements came from Quest Diagnostics CEO and President Jim Davis, who said the company is building capabilities for MRD, and from Illumina CEO Francis deSouza, who spoke of GRAIL’s plans to launch a multi-cancer MRD test this year that is capable of identifying relapse two to three times earlier than personalized tissue biopsies.  

According to market research focused on MRD testing, the regulatory strides made by the Signatera and clonoSEQ tests led other companies to explore investment in this space. And Emergen Research has indicated that increased R&D activity and research funding from cancer institutes are expected to bolster revenue growth in the years ahead.  

Still, the companies pursuing the potential of MRD testing face plenty of challenges extending to everything from the science and technology elements to the regulatory and reimbursement hurdles involved.  

Field Overview: Examples of Existing MRD Tests  

Although MRD found its beginnings in hematological cancers and flow cytometry, other technologies—such as PCR and NGS—have been used to go after various cancer types. As scientists continue to figure out the most powerful approaches to take, a variety of tests have emerged along the way. 

Adaptive Biotechnologies’ FDA-cleared clonoSEQ test uses multiplex PCR and NGS to detect MRD in bone marrow from patients with B-cell acute lymphoblastic leukemia or multiple myeloma, and blood or bone marrow from patients with chronic lymphocytic leukemia. The company recently launched the use of clonoSEQ to assess MRD in patients with diffuse large B-cell lymphoma using circulating tumor DNA (ctDNA). 

FDA has granted Natera’s Signatera several Breakthrough Device Designations for various cancer types and indications. The company’s tumor-informed ctDNA blood test is meant to detect and quantify cancer remaining in the body “at levels down to a single tumor molecule in a tube of blood.” This year, Natera announced a new study in Nature Medicine and revealed that Medicare will extend Signatera coverage to breast cancer.  

Invitae’s Personalized Cancer Monitoring products—currently available in the US, Canada, and Australia—are tumor-informed tests that rely on NGS to monitor MRD and quantify ctDNA. The Baseline Test uses tumor exome sequencing to come up with a patient-specific test designed “to assess the presence or absence of a patient’s tumor-specific molecular signature.” Following the Baseline, its Monitoring Test can be utilized. 

Inivata’s InVisionFirst-Lung, commercially available internationally and launched in the US in 2020 through NeoGenomics, is focused on non-small cell lung cancer. The test uses NGS technology, and its detection range is “as low as 0.1% variant allele fraction with a mean read depth of 70,000,” notes a technical specifications sheet. And Inivata’s RaDaR, a multi-tumor blood test, tracks up to 48 mutations in a sample, according to a tech overview.  

Guardant Health’s Reveal is a tissue-free test that combines genomic and epigenomic signals and is designed to detect ctDNA following surgery to identify patients who could benefit from additional therapy. Initially focused on colorectal cancer, Guardant Health expanded its use for breast and lung cancers last year. The company has partnered with The Royal Marsden NHS Foundation Trust on Part C of its TRACC study, which aims to include more than 1,600 patients over a four-year timeframe. 

Powerful Capabilities, Notable Limitations 

The DNA that tumor cells spill into the bloodstream differs from the DNA of normal cells, and MRD tests can quantify these differences at incredibly low levels, explained Dale Muzzey, Chief Scientific Officer at Myriad Genetics, a Salt Lake City-based genetic testing and precision medicine company that is developing an MRD test.  

It is possible to “reliably detect one tumor DNA molecule for every 10,000 normal DNA molecules, and recent advances have enabled tumor-DNA detection down to 1 part per million,” he told Diagnostics World. Despite the technological improvements that have led up to this type of capability, experts have also pointed to the lingering limitations.  

When it comes to cancer patients treated with curative intent, the absence of ctDNA cannot be equated with cure, Ben Ho Park, director of the Vanderbilt-Ingram Cancer Center, and coauthor Donna Dang noted in a paper published last year in The Journal of Clinical Investigation (DOI: 10.1172/JCI154941). There are a variety of reasons for this, and a lot of it pertains to the nature of existing tests designed to detect MRD.  

Many of the ctDNA tests used for MRD purposes take a customized approach as NGS is applied to tumor tissue and individual mutations are used as markers. A generalized ctDNA test, on the other hand, uses “common mutated genes and/or methylated versus unmethylated DNA that has been validated across various cancer types,” they wrote.  

Both approaches come along with advantages and drawbacks. Whereas the customized test may offer sensitivity and specificity of mutations used as markers of MRD, disadvantages include potential tissue sample quality and quantity issues as well as time-related issues tied to gathering tumor tissue, performing NGS, and developing markers for every patient.  

And while generalized tests may bypass the need for tissue samples, one notable limitation is that “a negative result may be indeterminant, since the mutated/methylated genes being queried may not be present in the genetic makeup of a given patient’s cancer,” Park and Dang added. 

How Different Can One Test be from Another? 

Although MRD tests may generally fall into two main categories—those informed by the tumor genome, and others that are tumor agnostic—some see plenty of differences between tests. “The one thing all MRD tests share is the aim to detect and quantify features in DNA that differ between tumor cells and normal cells,” Muzzey said. “Aside from that foundational unifying goal, they actually differ quite a lot.”  

He added that “labs use different strategies to select which genomic regions to target, different biochemical protocols to enrich genomic regions of interest, and different algorithms to perform data analysis.” There are also variations in terms of how results are reported and how providers and patients are educated, among other variables. 

Muzzey favors “at least the incorporation of a tumor-informed approach in any assay because it develops a customized fingerprint of a patient’s cancer and puts all of its resources into detecting traces of that original fingerprint,” but acknowledged that clinical trials will ultimately demonstrate which strategies are the most effective.  

There are notable differences from one test to the next, agreed Dan Edelstein, CEO of Haystack Oncology, whose MRD test is available for early access with biopharma partners and whose CLIA MRD assay is anticipated this summer. These variations emerge in aspects like test design, technology, analytical performance, and clinical performance. And they aren’t always communicated effectively by test providers or fully recognized by the clinicians and scientists using the tests.  

In terms of analytical performance, for instance, Edelstein explained that sensitivity claims can be misleading and tend to focus on just one number, such as “0.01% limit of detection”. This tumor fraction-based measurement can be confused with % mutant allele frequency, which is used to describe mutations and not MRD. And the manner in which tumor fraction, or parts-per-million, is calculated potentially obscures and exaggerates the performance of a test. 

“The bottom line,” he added, is that “the best MRD tests have the ability to detect very few ctDNA molecules, reproducibly, even in the presence of an over-abundance of wild-type cell-free DNA molecules that originate from white blood cells—not the tumor.”  

A Look Ahead: Can Companies Deliver Better Results? 

Because of the rapid growth in the precision cancer treatment space, MRD testing will need to evolve to provide sensitive information about specific treatment targets, according to Todd Druley, Chief Medical Officer of Mission Bio, a company that has developed a single-cell multi-omics MRD assay. The goal is to give patients the best chance of curing cancer with the least residual toxicity from ineffective or unneeded treatments. 

Capturing circulating tumor cells that break free from a tumor and measuring their genetic changes is a significant challenge, Druley noted, but also an area of significant focus in this field. 

He highlighted single-cell methods as another area of interest that “can identify an entire cancer cell that will contain all of the DNA, RNA, and protein specific to the patient’s cancer.” A test built around this method may be able to offer “a more holistic picture,” Druley explained, and efforts are in the works for both solid tumors and blood cancers.  

The emergence of small molecules, engineered cells, or drugs that can target specific mutations in cancer cells is creating a need for better MRD tools that can incorporate multiple measurements while also factoring in key elements like sensitivity, specificity, ease-of-use, and cost. “There are many technologies currently in play,” he added. But right now, the field is making its way through the slow yet crucial process of showing, through clinical trials, that these new approaches can actually lead to improved outcomes for patients. 

There are tradeoffs being made in today’s MRD testing environment, Muzzey said. Maximizing a test’s sensitivity can wind up compromising factors like speed and cost, and optimizing a test’s speed and cost-effectiveness winds up compromising its sensitivity.  

Beyond that, he sees the newness of MRD testing as one of its most significant limitations at the moment; it hasn’t been around long enough to generate the data needed to become a part of routine cancer care. More studies are required to prove clinical validity and utility and help inform aspects like how frequently patients ought to undergo testing and what follow-up should be implemented in response to a positive test result.  

Despite these current challenges, Muzzey foresees continued “evolution and optimization” of technologies that will help lead to improved MRD tests that become faster, more sensitive, and more accessible over time.  

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