An MRD assay, or measurable residual disease assay, is a specialized, highly sensitive test used in cancer care. It detects very small numbers of cancer cells remaining after treatment, even when standard tests show no disease. These undetectable cells can lead to relapse. By identifying these traces, MRD assays monitor treatment effectiveness and predict recurrence, supporting precise, personalized patient management and guiding medical decisions.
Understanding Measurable Residual Disease (MRD)
Measurable residual disease (MRD), also known as minimal residual disease, refers to cancer cells remaining in a patient’s body after initial treatment, even if they achieve “complete remission” by traditional methods. Conventional tests, like microscopic examination or imaging, detect cancer only at a certain volume, typically around 5% blasts in bone marrow. MRD assays, however, detect far fewer cells, sometimes as few as 1 cancer cell in 10,000 to 1 million healthy cells. This sensitivity allows detection at a molecular level, long before clinical appearance.
The presence of MRD indicates that cancer cells could multiply and cause relapse. This early detection allows for accurate assessment of treatment response and helps predict relapse likelihood. Knowing MRD status guides subsequent treatment decisions, determining if therapy should be continued, intensified, or de-escalated to target remaining cells before overt relapse.
Techniques for Detecting MRD
Various sophisticated laboratory techniques detect measurable residual disease, each with distinct principles and sensitivity levels. These methods identify cancer cells in numbers too small for traditional detection. The choice of technique often depends on the cancer type and its specific genetic or protein markers.
Multiparameter Flow Cytometry (MFC)
Multiparameter Flow Cytometry (MFC) is a widely used technique that identifies cancer cells based on their unique surface markers. Cells from a patient’s blood or bone marrow sample are stained with fluorescently labeled antibodies that bind to specific markers. A laser then analyzes these cells, detecting fluorescent signals and allowing for the differentiation of normal cells from aberrant cancer cells. MFC can detect cancer cells at a sensitivity of approximately 1 in 10,000 to 1 in 100,000 cells by recognizing abnormal combinations or expressions of these markers, often referred to as leukemia-associated immunophenotypes (LAIPs).
Next-Generation Sequencing (NGS)
Next-Generation Sequencing (NGS) analyzes genetic material to find specific DNA mutations or rearrangements unique to cancer. This technology identifies millions of genetic sequences, detecting cancer-specific DNA at very low frequencies, sometimes as low as 0.001% or 1 cancer cell in 1 million healthy cells. NGS detects a broad range of genetic alterations, including gene fusions, chromosomal translocations, and single-nucleotide variants, providing a comprehensive molecular profile. The clonoSEQ assay, for example, uses NGS to quantify rearranged B-cell and T-cell receptor genes, unique identifiers of lymphoid cancers.
Polymerase Chain Reaction (PCR)-based Assays
Polymerase Chain Reaction (PCR)-based assays amplify and detect specific cancer markers from small amounts of genetic material. These assays focus on known genetic abnormalities like gene fusions or specific mutations. Droplet Digital PCR (ddPCR) is an advanced PCR technique providing absolute quantification of mutated DNA with high sensitivity, even for low abundance nucleic acids in liquid biopsies. While highly sensitive (1 in 10,000 to 1 in 1 million cells), PCR methods require prior knowledge of the specific genetic targets.
MRD’s Role in Cancer Management
MRD assays are an integral part of cancer care, especially for blood cancers like leukemias and multiple myeloma, with an expanding role in certain solid tumors. Insights from MRD testing influence a patient’s treatment journey, from initial diagnosis to long-term monitoring, helping tailor therapeutic strategies towards personalized medicine.
Risk Stratification at Diagnosis
At diagnosis, MRD levels assist in risk stratification, classifying disease aggressiveness. For instance, early MRD negativity during induction therapy in acute lymphoblastic leukemia (ALL) associates with a more favorable prognosis. Conversely, MRD presence at certain time points indicates a higher relapse risk, even if the patient appears in complete remission by traditional methods. This initial assessment guides treatment plan intensity.
Monitoring Treatment Response
Throughout treatment, MRD testing monitors response to therapy. Periodically checking MRD levels allows clinicians to track treatment effectiveness in reducing cancer cell burden. A decrease in MRD levels indicates a positive response, while persistent or increasing MRD might signal insufficient therapy. This enables early identification of patients not responding as expected, often before relapse symptoms appear.
Guiding Treatment Decisions
MRD results significantly influence treatment decisions. For AML or ALL patients, achieving MRD negativity after induction or consolidation therapy may indicate deeper remission, potentially allowing de-escalation of therapy, such as avoiding a stem cell transplant. If MRD persists, it may lead to treatment intensification, including different medications or a stem cell transplant, to eradicate remaining cancer cells. In multiple myeloma, MRD negativity associates with improved progression-free and overall survival, with ongoing trials exploring MRD-driven treatment adjustments like modifying maintenance therapy duration.
Interpreting MRD Results and Current Limitations
Interpreting MRD results requires careful consideration. An “MRD negative” result indicates a deeper remission, not always a complete cure. It means highly sensitive tests could not detect remaining cancer cells above a certain threshold, such as one cancer cell in 100,000 to 1 million healthy cells. This generally correlates with a better prognosis and lower relapse risk compared to an MRD-positive result, where detectable cancer cells persist. However, even with an MRD-negative status, relapse is possible if the disease is below the assay’s detection limit.
Different MRD assays and laboratories have varying sensitivities, meaning one test might detect disease at a lower concentration than another. For example, a 0.01% threshold for multiparameter flow cytometry and next-generation sequencing is reasonable for identifying high-risk patients in B-cell precursor acute lymphoblastic leukemia. This variability influences how results are interpreted and compared across studies or clinical settings.
Limitations of MRD Testing
MRD testing faces several limitations. A primary issue is the lack of universal standardization across laboratories and techniques. Variations exist in specific markers used, cells analyzed, and criteria for defining MRD positivity, affecting comparability and reproducibility. This makes establishing uniform guidelines for clinical action based on MRD status challenging across all cancer types.
Tumor heterogeneity, where cancer cells within the same patient have varying characteristics, also presents a challenge. This can lead to false-negative results if the assay targets only a subset of cells. Research addresses these limitations, exploring new technologies like liquid biopsies that analyze circulating tumor DNA (ctDNA) for a more comprehensive disease picture. Further studies are needed to establish optimal MRD testing time points and define clear actionability of results for all cancer types, especially solid tumors, where MRD detection is still evolving.