The Future of MRD in Breast Cancer Treatment

The presence of minimal residual disease (MRD), specifically circulating tumor DNA (ctDNA) positivity, in patients achieving complete remission (CR) poses a significant clinical challenge. Currently, standard follow-up imaging (CT/PET) is not approved for early-stage breast cancer, creating a diagnostic dilemma for MRD-positive but image-negative patients.¹

For these MRD-positive patients without detectable metastatic disease on imaging, the current recommendation is enrollment in clinical trials exploring the addition of novel therapeutic agents, aiming for MRD eradication.

The use of MRD to guide treatment de-escalation is promising but lacks current data for widespread clinical recommendation. Trials are being considered to explore de-escalation or treatment breaks in both the early-stage and metastatic settings, such as using sustained ctDNA clearance to shorten neoadjuvant therapy duration or manage treatment in exceptional metastatic responders.

The future of ctDNA/MRD testing is bright due to the rapid advancement of highly sensitive technology. However, clinical implementation requires robust evidence of clinical utility: that these tests can safely and effectively stratify recurrence risk and therapeutic response at the individual patient level, thereby improving outcomes and preventing unsafe de-escalation or unwarranted escalation.

Stefania Morganti, MD, PhD, at Dana-Farber Cancer Institute, discussed treatment scenarios and the future of MRD use in patients with breast cancer in the second part of her interview with Targeted Oncology®.

Read part 1 of the interview here.

Targeted Oncology: How would you address a scenario where a patient achieves a CR based on conventional tests, but remains MRD positive?

Stefania Morganti, MD, PhD: We really don't know what to do with these patients. We keep monitoring them more closely [but], for instance, CT scans, PET scans, and imaging are not approved in the follow-up for patients with early-stage breast cancer. So, if patients are ctDNA-positive during follow-up, we usually stage them to see whether there is evidence of metastatic disease or not, and in case there is none, so they are truly MRD-positive, without metastatic disease that's detectable at imaging. We really recommend these patients for clinical trials in which we are adding treatment, different treatment compared to what they were receiving before, hoping that that can cure [MRD].

What evidence or criteria do you use to determine if a patient who achieves MRD negativity can safely undergo treatment de-escalation?

Unfortunately, we don't have data yet to recommend de-escalation for patients who achieve ctDNA clearance or are negative at specific time points. But we are thinking about clinical trials. For instance, we know that in a metastatic setting, there are patients who are exceptional responders, so we are switching now early to the metastatic setting. But still, we know there are some patients who, despite the diagnosis of metastatic disease, remain on the same type of treatment for years, if not decades. So, we are thinking, could we eventually use MRD to stop treatment in these patients, or even just give breaks that are guided by MRD? That could be a potential use upon proof of clinical utility for the metastatic setting, in the early-stage setting, instead of in the neoadjuvant space, if patients achieve clearance and clearance is maintained. We think about shortening the duration of the neoadjuvant therapy and moving to surgery early on.

Could you expand on the future of MRD use in breast cancer?

I think ctDNA is really, really promising. MRD tests are incredible and getting more and more sensitive. There is always a new test that is orders of magnitude more sensitive than the test that was out there a year ago. All of the field is very excited. The technology is moving very, very fast. We really need to again prove the clinical utility, meaning that we can use these tasks that really stratify the risk of recurrence and the response for specific therapy on a single patient level. That's something that we really are missing in most scenarios for patients with breast cancer, in which we are moving using a probabilistic approach, in which we say the likelihood of recurrence is 10% to 20%, but we don't know for that specific patient what's the risk of recurrence. We think that MRD could be it's very promising in that specific situation, that both in the neoadjuvant, adjuvant spaces and even in the metastatic setting, for some specific situations, but we need to design clinical trials to prove that this is safe and this leads to an improved outcome for patients with breast cancer, because otherwise, the risk is to de-escalate in an unsafe way, on a negative result and stop treatment, or even avoid treatment and the other way around, escalate and give treatments that, at the end of the day, don't really improve outcomes. Before really implementing this test clinical practice, we need these clinical utilities showing us that we can make a difference for patients with breast cancer.

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