<p>Blood-based testing that detects circulating tumor DNA (ctDNA) has moved quickly from concept to clinic, especially for estimating recurrence risk after curative-intent therapy in patients with early-stage breast cancer. At the <strong>2025 San Antonio Breast Cancer Symposium (SABCS 2025)</strong>, new analyses sharpened the prognostic signal and offered early proof that intervention may reduce or clear detectable ctDNA.</p> <p><br></p> <p><em>Following these presentations, featured expert Seth A. Wander, MD, PhD, was interviewed by </em>Conference Reporter<em> Associate Editor-in-Chief Christopher Ontiveros, PhD. Clinical perspectives from Dr Wander on these findings are presented here.</em></p>

In the current era, we have several emerging tools focused on measurable residual disease (MRD) testing. These include genomic tests that create personalized tumor-informed DNA fingerprints (ie, genetic changes) for each individual cancer and, with a high degree of sensitivity, identify fragments of tumor DNA in the blood, suggesting the presence of cancer cells. Other approaches utilize “tumor-uninformed assays.” They are not “fingerprinting” or “barcoding” a specific tumor; instead, they are detecting low levels of tumor DNA in the blood without a previously assigned genetic sequence. Both types of tools are rapidly becoming important in the clinic.

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It is of great interest to understand whether patients have MRD, as it may help identify recurrent tumors in the breast or elsewhere in the body earlier than we might achieve with conventional imaging. In the future, this may help guide clinicians toward the escalation of therapy in specific instances, as compared with patients who have completely cleared their ctDNA, which suggests a better long-term prognosis.

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We currently understand these prognostic implications of MRD-positive and -negative results, but we do not yet have great prospective therapeutic guidance. In the setting of a positive test, we do not yet have the validated guidance needed to suggest what sort of escalation we should pursue, while, in the setting of a negative test, we do not know what sort of deescalation might be safely pursued. These types of trials are being done across the United States and internationally. Like gene expression testing, which is both prognostic and predictive, we hope to deploy ctDNA MRD testing in the future that is able to predict risk and assign beneficial therapeutic approaches for individual patients.

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ctDNA monitoring is not currently standard, although it is becoming increasingly used in clinics around the country. There is tremendous interest in this approach from both clinicians and patients, and guidelines will be needed to provide an important conceptual framework for this test in the coming months and years.

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There were a variety of interesting studies on this topic presented at SABCS 2025. These included the tumor-informed ctDNA analysis from the phase 3 PALLAS trial, which was discussed in an oral presentation by Heather A. Parsons, MD, MPH (abstract RF3-04). Investigators used tumor-informed ctDNA analysis to assess MRD for prognosis and prediction of benefit from palbociclib in patients with HR+/HER2- early-stage breast cancer. As previously demonstrated, there was no benefit for inclusion of adjuvant palbociclib observed in the overall population; however, at this 7-year follow-up, investigators noted a very strong association between the presence or absence of ctDNA and the subsequent likelihood of recurrence at various time points. Very few patients were ctDNA positive at baseline, as these individuals had already undergone surgery and other potential treatments (eg, chemotherapy). At both cycle 1 day 1 and end of treatment, ctDNA-positive patients had significantly lower rates of distant recurrence-free survival compared with ctDNA-negative patients. These were substantial differences in recurrence between ctDNA-positive and -negative status in this very large prospective study.

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Another important study presented at the recent SABCS meeting was by Arielle J. Medford, MD, and colleagues (poster PD5-01). The phase 2 LEADER trial was a personalized ctDNA testing intervention and a temporal dynamics study in patients with ER+/HER2- early-stage breast cancer. Compared with the PALLAS study, this was a smaller effort, but it did provide additional insights into potential intervention once ctDNA positivity occurred. Here, patients on endocrine therapy who had a positive ctDNA test during surveillance were identified. In this trial, ctDNA-positive patients received 1 year of treatment with the CDK4/6 inhibitor ribociclib plus ongoing treatment with an aromatase inhibitor. The end point of this study was ctDNA clearance. It is important to remember that, when this study was designed, adjuvant ribociclib was not yet the standard of care. This change to standard therapy occurred while the study was being pursued.

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In the LEADER trial, investigators noted a ctDNA detection rate of approximately 11% during surveillance. Additionally, of the 15 positive cases, 5 patients were ineligible because they had metastatic disease that was noted via imaging at the time of ctDNA positivity. After treatment with ribociclib, 6 of 9 patients demonstrated a decrease in ctDNA, and 3 of 9 experienced total ctDNA clearance. Patients with ctDNA clearance or substantial decreases had better outcomes and more favorable long-term recurrence profiles.

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This was a small cohort but an important proof-of-concept study. These results suggest that, if ctDNA can be identified before overt metastatic disease occurs, therapeutic adjustments can result in ctDNA reduction or clearance with the potential for better longer-term outcomes. Future efforts will explore these findings in larger cohorts of patients with emerging antiestrogen agents and novel targeted therapies. It remains our hope that ctDNA will emerge as a dynamic and personalized tool to both inform prognosis and guide treatment changes in this large patient population.