Understanding Molecular Residual Disease (MRD) in Solid Tumors
In the long fight against cancer, every patient wants to be declared cancer-free. But what does “cancer-free” mean? And why do some individuals relapse a few months or years later, while others remain in permanent remission? Emerging research shows that the answers to these questions are closely connected to the concept of molecular residual disease.
What is molecular residual disease (MRD)?
Molecular residual disease (MRD), also called minimal or measurable residual disease, refers to the presence of a very small number of cancer-derived molecules (such as DNA or protein) that remain in circulation during or after cancer treatment. These cancer-derived molecules can’t be detected by imaging technology like PET or CT scans, and patients often have no clinical signs of lingering disease. MRD can be used to determine how likely a patient is to relapse after treatment, and can guide decision-making when it comes to post-operative chemotherapy or targeted therapy. MRD can also be used to assess how well a given course of treatment is working. MRD has been shown to be predictive of relapse in multiple studies, making it a crucial piece of information for oncologists and patients.
How is MRD detected?
The detection of tumor DNA in circulation is one of the primary methods of identifying MRD. Circulating tumor DNA (ctDNA) is released from tumor cells as they die and has a half-life on the order of hours, so it can be used as a real-time indicator of the presence of lingering cancer post-treatment. Blood-based tests, also called liquid biopsies, are used to detect ctDNA.
Practically, liquid biopsy testing involves taking a blood (or other biological fluid) sample from a patient, isolating the DNA content, and subjecting the sample to either sequencing or PCR-based methods to identify the variant allele fraction (VAF), which refers to the percentage of DNA that is of cancerous origin. With post-operative or early cancer samples, the VAF can be under 0.1%, which means that any test used must be highly sensitive and specific to avoid false negatives and positives. This is presently one of the biggest technical hurdles in the field: designing a test that can detect VAFs below 0.1% accurately, and distinguish such low frequencies of true cancerous DNA from background non-cancerous mutated DNA in the blood.
In general, a liquid biopsy involves taking a blood draw from a patient and analyzing the circulating cell-free DNA for the presence of cancer, such as tumor-derived DNA containing mutations or epigenetic modifications. Image created with BioRender.com
When is MRD testing used?
Historically, MRD testing has been used in treatment decisions for blood cancers such as leukemias and lymphomas, because these diseases are characterized by circulating cancer cells. The first FDA approval for MRD testing to inform clinical decision-making was in 2018 for acute lymphoblastic leukemia. However, MRD in the context of solid tumors—essentially all other types of cancer—is a fast-evolving field.
Currently, solid tumor MRD testing can be done in two ways. Tumor-informed assays are designed using the patient’s own tumor sequencing results. Because only a relatively small and patient-specific set of mutations are tested for, the sensitivity of these types of tests can be very high, although the turnaround time is relatively long. In tumor-independent/tumor-agnostic liquid biopsy, a broad panel of mutations are tested for, with a resulting lower sensitivity but without the prior requirement of tumor biopsy and sequencing which may not be possible.
ctDNA-based MRD testing has a variety of uses across the patient journey. For individuals undergo cancer treatment, MRD testing can be used the monitor the response over time—if ctDNA levels go up, the tumor may still be growing, while a reduction in ctDNA could indicate the treatment is effective. After a surgical resection, MRD could be used to determine if a patient should go on adjuvant therapy to lower the risk of relapse. While adjuvant therapy is ongoing, ctDNA levels can reveal if the treatment needs to be ramped up or reduced. Finally, MRD testing can be used to monitor for recurrence after a patient has tested negative and is presumed to have no evidence of disease.
MRD testing can be used throughout the patient journey to provide actionable information. After initial treatment, MRD testing could be used to determine if a patient could benefit from additional therapy to lower the risk of relapse. During the course of treatment, ctDNA can be used the monitor patient response over time and inform decisions on whether to continue or change therapy. Finally, MRD testing can be used to monitor for recurrence after a patient has tested negative and is presumed to have no evidence of disease. Image from Moding & Diehn, Nature Cancer (2020).
What MRD tests are validated for clinical use in solid tumors?
Today, there are a handful of liquid biopsy MRD tests that a provider can use to inform patient care. Natera’s Signatera is a tumor-informed assay that is currently covered by Medicare/Medicaid for patients with colorectal cancer and muscle-invasive bladder cancer, and as a broad pan-cancer test for monitoring immunotherapy response in several different solid tumor types. Recently, the company announced that Signatera will also be reimbursed by Medicare and Medicaid for adjuvant and recurrence monitoring in patients with stage IIb or higher breast cancer of all subtypes.
Foundation Medicine’s FoundationOne Tracker, developed in collaboration with Natera, was given Breakthrough Device Status, allowing it to be used in an early-access clinical use program with plans to expand availability later in 2023. The test indications include detection of MRD in early-stage cancers after curative treatment, as well as detection of disease progression and treatment resistance in advanced cancers.
In the tumor-independent testing space, Guardant Health has Guardant360 CDx, which is FDA-approved for informing treatment decisions in certain types of advanced breast cancer and non-small-cell lung cancer (NSCLC). Another Guardant test, Guardant Reveal, is optimized for early-stage cancer MRD detection. The Reveal test is currently only validated in colorectal cancer, but clinical trials are ongoing for lung, breast and pancreatic disease. Inivata produces InVisionFirst-Lung, which tests for mutations specific to NSCLC and is covered by Medicare for that indication. Inivata also manufacturers RaDaR, a tumor-informed liquid biopsy for use in early-stage cancer for MRD detection and recurrence monitoring. Many other companies, including Archer, Twist Bioscience, C2i Genomics, produce tests available only for laboratory use or clinical research.
Where is the MRD field going?
The clinical use of MRD tests is growing every year, as evidence builds on how patients can benefit from this type of analysis. For example, Natera reported that 25% of US oncologists ordered a Signatera test in the fourth quarter of 2022, and also recorded the highest number of new patients since the test was introduced. Other companies such as GRAIL, Quest Diagnostics, and Invitae have initiated research and development into MRD, suggesting that in the near future providers and patients will have a broader range of testing options.
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