Minimal residual disease (MRD) testing is becoming an important aspect of cancer treatment, particularly for blood cancers. It offers a deeper insight into a patient’s response to therapy than traditional methods. Understanding what “MRD negative” signifies is key to comprehending modern cancer care.
What Minimal Residual Disease Is
Minimal residual disease (MRD), also known as measurable residual disease, refers to the small number of cancer cells that may remain in the body after treatment, even when standard diagnostic tests no longer detect them. Despite a patient appearing to be in complete remission, these hidden cells have the potential to multiply over time and lead to a cancer relapse.
Detecting these minute populations of cancer cells is important for several reasons. The presence of MRD indicates that some cancer cells survived initial therapies, posing a risk for future recurrence. Monitoring MRD helps clinicians assess the effectiveness of treatment at its deepest level. It provides an early warning system, as MRD detection can precede clinical relapse by several months, offering an opportunity for earlier intervention.
How MRD Negativity is Determined
Determining minimal residual disease negativity requires highly sensitive laboratory techniques that can identify cancer cells even when they are extremely rare, sometimes as few as one cancer cell among a million healthy cells. They focus on specific markers unique to cancer cells, which allows for their detection at very low frequencies.
One common method is multiparameter flow cytometry (MFC), which analyzes cells based on their unique surface proteins. This technique uses lasers to identify and count cancer cells that display abnormal combinations of markers or abnormal levels of normal markers. Flow cytometry can detect one cancer cell in 10,000 to 100,000 healthy cells (10^-4 to 10^-5 sensitivity).
Polymerase chain reaction (PCR)-based methods, including quantitative PCR (qPCR) and digital PCR (dPCR), detect specific genetic abnormalities or rearrangements found in cancer cells. These methods work by amplifying minute amounts of cancer-specific DNA or RNA sequences. PCR-based tests can achieve sensitivities comparable to or even greater than flow cytometry, down to one cancer cell in 100,000 to 1,000,000 cells (10^-5 to 10^-6 sensitivity).
Next-generation sequencing (NGS) is another technique that can identify cancer cells by looking for specific DNA mutations or rearrangements, such as those in immunoglobulin or T-cell receptor genes. NGS offers high sensitivity, detecting cancer cells at levels as low as one in a million (10^-6), and can track multiple genetic markers simultaneously. An “MRD negative” result using these sensitive tests means that no detectable cancer cells were found within the limits of the assay’s sensitivity.
What an MRD Negative Result Means for Patients
An MRD negative result is a favorable outcome for patients undergoing cancer treatment. It indicates that therapy has been effective in reducing the cancer cell burden to undetectable levels using the most sensitive available tests. Achieving MRD negativity is associated with a higher probability of long-term remission and improved overall survival in various blood cancers.
This deep level of response provides information for guiding subsequent treatment decisions. In some cases, achieving MRD negativity may allow for de-escalation of therapy, potentially reducing treatment intensity or duration, which can decrease side effects and improve quality of life. Conversely, if MRD remains detectable, it might prompt clinicians to consider intensifying treatment, modifying the current regimen, or exploring alternative therapies to prevent relapse.
While an MRD negative result is an encouraging sign, it does not always guarantee a cure or mean that cancer will never return. The sensitivity of current tests, though high, still has limits, meaning a few cancer cells could theoretically remain below the detection threshold. Therefore, ongoing monitoring remains necessary for patients who achieve MRD negativity to monitor for recurrence. The duration of MRD negativity is also being studied, with sustained negativity over several years correlating with long-term outcomes in some cancers.