How MRD Is Being Used to Guide Treatment Decisions

Minimal residual disease (MRD)—minute populations of cancer cells undetectable by conventional imaging—remains the chief driver of relapse for patients. For years, detecting MRD has relied on invasive tissue biopsies or bone marrow aspirations, procedures that carry risks and often offer only a localized, snapshot view of the disease.¹

The clinical landscape is being transformed by a less-invasive, highly sensitive biomarker: circulating tumor DNA (ctDNA). ctDNA is the fragmented DNA released into the bloodstream by dying tumor cells, providing a liquid biopsy that captures a systemic, real-time reflection of the patient's cancer burden. By specifically identifying and quantifying tumor-specific genomic alterations within the overall pool of cell-free DNA, ctDNA analysis offers an unprecedented tool for monitoring MRD.

In part 1 of an interview with Targeted Oncology®, Stefania Morganti, MD, PhD, research fellow at Dana-Farber Cancer Institute, explained how MRD is being used to guide treatment decisions in both early-stage and metastatic settings.

Targeted Oncology: As a clinician, how do you ensure that your testing strategy uses an appropriate MRD-specific assay?

Stefania Morganti, MD, PhD: Over the past years, there have been many different MRD assays that have been developed. I would say we have 2 major categories of MRD assays. We have the tumor-agnostic and the tumor informed. Tumor-informed ones use the primary tumor to identify the mutations that are then used to design a patient-specific assay to track these mutations in blood. Instead, the tumor-agnostic uses mostly computational tools to understand what proportion of the [cf]DNA that's present in all individuals is represented by [ct]DNA, so it doesn't need that extra step of finding the tissue and designing the assay, and it's the same for every patient. Data that have been generated so far show that tumor-informed assays are more sensitive than tumor-agnostic assays, so especially in the early-stage setting, when we know that the amount of MRD, if present, is very low, we want to think about using tumor-informed assays instead of tumor-agnostic assays.

Then, in the category of tumor-informed assays, we have first-generation assays that attract few mutations and new-generation assays that are ultrasensitive and track thousands of alterations, and we know can get very low in terms of limit of detection. And to your question, which assay should we use? It really depends on the question that we are asking. And just to be clear, we don't have proof of clinical utility of any MRD assay for patients with early-stage breast cancer. So we should not really routinely use them, but thinking of even designing clinical trials with these assays to prove the clinical utility that we need depends really on the question of, for instance, de-escalating therapy, meaning stopping or giving less that what we are currently using during standard of care, we should think of using ultrasensitive assays that go very low inside for treatment escalation. Maybe we don't need such a deep sensitivity, and something that's less sensitive might be enough.

How does the limit of detection influence your counseling of a patient who receives an MRD negative result, especially given the risk of a false negative?

We know that the amount of [ct]DNA of [MRD] can be very low for patients with early-stage breast cancer. The risk of false negative results, it's really there. When we talk about these to our patients, we stress the importance of the risk of false negatives and for instance, for different tests, the fact that they have different limits of detection, it means that the lowest we can get the path, the lower the chance to have a false negative result. Instead, if we have a higher limit of detection, we really cannot be sure that there is something there, but just we weren't able to detect it.

Almost all the data generated so far is retrospective, meaning that there have been no clinical trials that showed that we can use ctDNA and make a difference in terms of outcome for patients with early-stage breast cancer. That's why we don't recommend routinely using them. But the data that we generated so far retrospectively show that for patients who have MRD-positive disease, the risk of recurrence is much, much higher than for patients who remain, especially, sitting at ctDNA-negative, and not just negative at a single time point. We really need to design clinical trials to intervene…and see if we, by giving more or switching therapy, can improve outcomes in this patient.

REFERENCE

1.Morganti S. Is MRD poised to transform oncology? Powerful tool has unanswered questions. Oncology News Central. November 21, 2024. Accessed November 17, 2025. https://tinyurl.com/7wueaya5