ctDNA in Early Breast Cancer: Prognostic Power vs Clinical Actionability

Circulating tumor DNA (ctDNA) is a blood-based signal that is drawing a lot of attention in early breast cancer because it may help estimate the risk of recurrence after curative treatment. It can sometimes detect minimal residual disease, meaning tiny amounts of cancer that remain after surgery or systemic therapy. That makes ctDNA attractive,but raises the ultimate question whether this piece of information helps make better decisions regarding treatment options for patients to improve their outcomes or just creates confusion. Existing reviews and clinical trials suggest high predictive power but yet unclear clinical utility of ctDNA.

Why It Matters

For many years, adjuvant treatment decisions in early breast cancer have relied on tumor size, lymph node status, hormone receptor status, HER2 status and tissue based genomic tests. ctDNA adds something different. Instead of looking only at the original tumor, it gives a real time blood snapshot of whether cancer DNA is still circulating after treatment. Positive findings for ctDNA after therapy have been consistently associated with increased risk of recurrence, whereas a negative finding is often indicative of favorable outcomes. This is where the debate begins. A prognostic test tells us who is at higher risk. A clinically actionable test tells us what to do next in a way that improves outcomes. In early breast cancer, ctDNA is very promising as a prognostic marker, but there is still limited evidence that changing treatment because of ctDNA results clearly improves survival or reduces recurrence in routine care. This is why the area is considered both exciting and underdeveloped. Molecular recurrence detected through ctDNA may allow for detection of cancer recurrence months prior to any clinical manifestation. This knowledge may assist doctors in deciding how to proceed next regarding their patient’s condition. However, at the same time, getting the results of a positive test may put pressure on making decisions in favor of rapid action, regardless of whether there is an immediate course of action that could be taken. ctDNA is a probability signal, not a guarantee. A positive test does not tell you exactly where residual disease is hiding, and a negative test does not rule out recurrence with perfect certainty. Test performance also varies by assay design, timing of sampling, and disease biology. Reviews of early breast cancer ctDNA stress that the field still needs standardization before results can be used with confidence across all clinics and laboratories.

Who It Affects

Patients are at the center of this discussion. A ctDNA-negative result after surgery or adjuvant therapy may bring relief, but it can also lead to the question of whether follow-up can be safely reduced. A positive ctDNA test may be more challenging to bear as it signals the presence of microscopic recurrence before overt disease becomes evident. The meaning of ctDNA can vary by breast cancer subtype. In hormone receptor–positive disease, the challenge may be deciding whether a positive result should lead to earlier or more intensive therapy. In HER2-positive or triple-negative disease, the question may be whether to move quickly into a clinical trial or use a targeted strategy if one is appropriate. In each case, ctDNA is only one piece of the picture, not the whole answer. All of these professions such as oncologists, surgeons, pathologists, genetic counselors, and primary care doctors may be impacted when ctDNA tests become more prevalent in the future. These professionals must have the opportunity to provide patients with explanations regarding what the test can reveal, as well as cannot reveal, about their health. In addition to that, they have to be able to agree on a unified procedure to ensure that the test will not be misused. The utilization of ctDNA testing could lead to increased workload in laboratories, increased costs, and reduced accessibility to follow-up medical services. As long as the coverage policies remain vague, certain patients will receive a ctDNA test while other patients will not receive one, thus leading to a disparity issue. Another practical issue is clonal hematopoiesis, or age-related mutations in blood cells that can appear in liquid biopsy testing and be mistaken for tumor DNA if the assay is not designed carefully. This is a known source of noise in ctDNA interpretation and one reason that assay choice, laboratory quality control, and expert review matter so much.

What Changes

• The clearest near-term value of ctDNA is better risk sorting. It can help identify patients who seem to have a higher chance of relapse after treatment and those who remain ctDNA-negative and may not need extra escalation. This does not replace standard pathology or genomic testing, but it may add another layer of detail that helps refine follow-up planning.
• The finding of ctDNA can drive the discussion for further systemic treatments, particularly in cases where there is an available target or where the patient is eligible for a trial. For certain individuals, a good action to take is simply increased monitoring rather than changing their course of treatment. The key here is that ctDNA will serve as an indicator of what action needs to be taken, but not necessarily as an independent prescription itself.
• The use of prospective trials is crucial. Results from the c-TRAK TN study have proven that ctDNA monitoring is viable in high-risk cases of early-stage triple-negative breast cancer; however, the findings also emphasize the disparity between detecting ctDNA and achieving outcome improvements with an intervention. It is for this reason that many scientists consider using ctDNA as the best option at present in research and care protocols.
• Earlier detection of molecular relapse may sound reassuring, but it can also lead to overtreatment. More therapy can mean more toxicity, more clinic visits, more imaging, and more emotional stress. The risk is not only physical. Patients may feel trapped between doing too little and doing too much. Good counseling should explain that a ctDNA result shows risk, not certainty, and that the best response is not always immediate escalation.
• If ctDNA is used more widely, health systems will need clear rules for when to order it, how to report it, and what to do with borderline or positive results. Multidisciplinary review will likely become more important, especially when molecular pathologists, medical oncologists, and genetic counselors interpret results together. Standardized reporting and clinician education will be key to keeping care safe and consistent.
• Right now, ctDNA in early breast cancer is best seen as a powerful prognostic tool that is moving steadily toward clinical use, but not as a fully proven decision-maker for routine treatment changes in every patient. The best approach is careful interpretation, honest discussion about uncertainty, and use within protocols or trials when possible. That is how the field can grow without creating avoidable harm.

Bottom line ctDNA offers a more sensitive way to watch for hidden breast cancer after treatment, but its real-world value depends on whether acting on the result improves outcomes. At the moment, its prognostic strength is clear, while its routine clinical actionability is still being defined. The next step is not just better testing, but better evidence on how to use the test wisely for the right patient at the right time.

References

1. Turner NC, Swift C, Jenkins B, et al; c-TRAK TN investigators. Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate- and high-risk early-stage triple-negative breast cancer. Annals of Oncology. 2023. https://www.annalsofoncology.org/article/S0923-7534(22)04735-4/fulltext04735-4/fulltext)
2. ClinicalTrials.gov. NCT03145961: A Trial Using ctDNA Blood Tests to Detect Cancer Cells After Standard Treatment to Trigger Additional Treatment in Early Stage Triple Negative Breast Cancer Patients (c-TRAK-TN). ClinicalTrials.gov. 2022. https://clinicaltrials.gov/study/NCT03145961
3. Nader-Marta G, Monteforte M, Agostinetto E, et al. Circulating tumor DNA for predicting recurrence in patients with operable breast cancer: a systematic review and meta-analysis. ESMO Open. 2024. https://pubmed.ncbi.nlm.nih.gov/38460249
4. Chan HT, Chin YM, Nakamura Y, Low SK. Clonal Hematopoiesis in Liquid Biopsy: From Biological Noise to Valuable Clinical Implications. Cancers (Basel). 2020. https://pmc.ncbi.nlm.nih.gov/articles/PMC7463455