Minimal residual disease (MRD), also known as molecular residual disease, or measurable residual disease, is the medical condition in which small number of cancer cells persist in a patient either during or after treatment when the patient is in remission and that cannot be detected with current medical imaging or routine screening options (occult stage of cancer progression).
MRD detection is strongly associated with cancer recurrence, often with a lead time of several months relative to other forms of clinical evidence. The presence and quantity of MRD are significant because these residual cells can potentially multiply and cause the cancer to relapse, and therefore detecting MRD has significant clinical and diagnostic potential. Sensitive molecular tests, typically minimally invasive and done through a liquid biopsy, are either in development or available to test for MRD. These can measure minute levels of cancer cells in tissue samples, sometimes as low as one cancer cell in a million normal cells, either using DNA, RNA or proteins. Monitoring is performed every three to six months. MRD assessment is increasingly used, particularly in hematological malignancies like leukemia and multiple myeloma, as a powerful prognostic marker and to help guide treatment decisions. MRD monitoring may also be performed as part of research or clinical trials.
Background MRD was originally described in hematological cancers such as adult acute myeloid leukemia. Subsequently, MRD research has broadened out to other hematological malignancies such as multiple myeloma, as well as to solid tumors. In leukemia, a genetic abnormality in a single cell can cause it to then multiply rapidly, leading to a proliferation of specific cell types in the blood, and symptoms may not occur until the disease is advanced. While initial treatment with for example BCL2-inhibitors, FLT3-inhibitors, or IDH1/2-inhibitors, may kill leukemic cells, pre-leukemic clones may survive treatment and persist at frequencies of less than 0.1% in the bone marrow for months or years. This minimal residual disease can be identified by sensitive molecular tests such as DNA sequencing, but not by other methods such as viewing cells under a microscope. Hence the alternative name, molecular residual disease.
Clinical significance In cancer treatment, MRD testing has several important roles:
determining whether treatment has eradicated the cancer or whether traces remain monitoring patient remission status as well as detecting recurrence of cancer comparing the efficacy of different treatments helping patients and doctors make decisions about treatment regimen (start, stop or change)
Detection
DNA-based tests DNA tests are based on detecting circulating tumor DNA in the blood that contains cancer-specific DNA sequences. Modern techniques use next-generation sequencing to detect MRD. The detection method may be "tumor-informed", using mutation information from sequencing an individual's tumor tissue biopsy samples before subsequent MRD monitoring. Or they may be "tumor-agnostic", also known as "tumor-naive" or "tumor-uninformed", using a fixed panel of known cancer driver mutations. The tumor-agnostic approach is chosen when mutation information from an individual's primary tumor tissue is not available. The tumor-informed approach is a form of personalized medicine. Typically tens or hundreds of mutations are chosen for MRD monitoring, and these tests can have a limit of detection of 0.001%, or one cell in 100,000. The DNA sequences chosen in this approach may contribute to the genesis of the cancer, or may simply be linked to it (i.e. a mutation that is carried by cancer cells, but is not a driver of carcinogenesis). The markers used for DNA-based testing can be single nucleotide polymorphisms or chromosomal translocations. In the case of leukemia, this may be t(14;18) involving BCL2 and t(11;14) involving BCL1 (CCND1). Other methods for MRD detection include microsatellites, immunoglobulin and T cell receptors.
RNA-based tests These are based on detecting a cancer-specific RNA sequence. Generally, this is achieved through the use of reverse transcription of the RNA followed by polymerase chain reaction. RNA-based tests are normally utilized when a DNA test is impractical. For example, the t(9;22) BCR-ABL translocation may occur over a large length of the chromosome which makes DNA-based testing difficult and inefficient. However, RNA is a much less stable target for diagnostics than DNA and requires careful handling and processing. The markers used for RNA-based testing are almost exclusively chromosomal translocations such as t(9;22) BCR-ABL, t(15;17) PML-RARA and t(12;21) ETV6-RUNX1 (TEL-AML1).
Patient-specific testing Patient-specific MRD detection using immunoglobulin (IG) or T-cell receptors (TCR) is gaining popularity as a way of measuring MRD in leukemias that do not contain a chromosomal translocation or other leukemic specific marker. In this case, the leukemic-specific IG or TCR clone is amplified using PCR and the variable region of the IG or TCR is sequenced. From this sequence, PCR primers are designed that will only amplify the specific leukemic clone from the patient. Both the DNA- and RNA-based tests require that a pathologist examine the bone marrow to determine which leukemic specific sequence to target. Once the target is determined, a sample of blood or bone marrow is obtained, nucleic acid is extracted, and the sample analyzed for the leukemic sequence. These tests are very specific and detect leukemic cells at levels down to one cell in a million, though the limit typically achieved is one in 10,000 to one in 100,000 cells. For comparison, the limit of what one can detect using traditional morphologic examinations using a microscope is about one cell in 100.
Immunological tests Immunological-based testing of leukemias utilizes proteins on the surface of the cells. White blood cells (WBC) can show a variety of proteins on the surface depending upon the type of WBC. Leukemic cells often show quite unusual and unique combinations (leukemic phenotype) of these cell surface proteins. These proteins can be stained with fluorescent dye labeled antibodies and detected using flow cytometry. The limit of detection of immunological tests is generally about one in 10,000 cells and cannot be used on leukemias that don't have an identifiable and stable leukemic phenotype.
Common biomarkers
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