Current perspectives on circulating tumor DNA in breast cancer: a narrative review

Introduction

Cell-free DNA (cfDNA) is DNA present in the blood and bodily fluids that originates from apoptotic or necrotic cells. In healthy individuals, cfDNA is mainly released from cells of the hematopoietic system, such as erythrocytes, or from normal cells undergoing apoptosis or necrosis. The cfDNA derived from damaged or apoptotic cancer cells or circulating tumor cells in the blood is referred to as circulating tumor DNA (ctDNA), and ctDNA constitutes only a fraction of cfDNA. In recent years, extensive research has explored the use of cfDNA and ctDNA as cancer biomarkers for diagnosis, prognosis, and monitoring of therapeutic response. The use of liquid biopsy, which is used to interrogate biological materials including ctDNA in body fluids, has played an important role in the development of cancer therapies.

In this narrative review, we discuss the current status and future prospects of ctDNA in breast cancer. We present this article in accordance with the Narrative Review reporting checklist (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-23/rc).

Methods

We used PubMed to search for reports of ctDNA in breast cancer. We also searched the clinicaltrials.gov database and the Cochrane Library for clinical trials involving ctDNA analysis in breast cancer and other cancer types up to November 30, 2025 (reviewed November 30, 2025). We reviewed all articles written in English, including clinical trials, meta-analyses, and prospective and retrospective studies. The search strategy is outlined in Table 1.

Results

Perspectives on ctDNA analysis in breast cancer

In breast cancer research, the uses of ctDNA can currently be broadly classified into the following categories: (I) cancer screening; (II) prediction of treatment response in the neoadjuvant setting; (III) monitoring of minimal residual disease (MRD); (IV) assessment of the genomic landscape for treatment selection; and (V) monitoring clonal evolution. We discuss these categories below.

Cancer screening

The current mainstream methods for the early detection and screening of breast cancer are mammography and other imaging tests. However, small case studies have reported that ctDNA can be useful in screening for breast cancer. In a study examining the value of cfDNA for breast cancer screening, Zanetti-Dällenbach et al. compared cfDNA in patients with breast cancer, patients with benign breast disease, and healthy individuals (1). The authors reported higher levels of GAPDH cfDNA in blood, as detected by reverse transcription-polymerase chain reaction (RT-PCR), in patients with stage I–IV breast cancer compared with healthy subjects. No significant difference in cfDNA was observed between patients with benign breast tumors and healthy controls. Bechmann et al. used quantitative RT-PCR to compare β2-microglobulin cfDNA between patients with breast cancer (n=50) and healthy controls (n=50) prior to preoperative chemotherapy (2). Total cfDNA did not differ significantly between the breast cancer group and the healthy group. Other methods to detect DNA fragments of different lengths and specific oncogenic mutations such as in PIK3CA and different types of ctDNA assays have also been investigated, but no method has been established for use in clinical practice (3). The Evaluation of the ctDNA LUNAR Test in an Average Patient Screening Episode (ECLIPSE; NCT04136002) is an ongoing study that is evaluating the utility of Guardant’s ctDNA test, Shield^TM, for the screening of colorectal cancer (4). The company GRAIL is also developing an assay called Galleri^® as a ctDNA screening test for multiple types of cancers (5).

Prediction of treatment response in the neoadjuvant setting

ctDNA clearance

ctDNA clearance during preoperative chemotherapy has been associated with treatment response and risk of recurrence in patients with breast cancer. Studies that have evaluated ctDNA during preoperative chemotherapy for breast cancer are summarized in Table 2.

In the study by Magbanua et al., ctDNA levels in patients with stage II/III breast cancer who preoperatively received MK-2206 (an AKT inhibitor) in the I-SPY2 trial were evaluated at several timepoints to assess ctDNA clearance and prognosis, including T0 (preoperatively, before starting treatment), T1 (3 weeks after starting paclitaxel), and T2 (after paclitaxel, before anthracycline therapy) and T3 (after anthracycline therapy and before surgery). Approximately 83% of patients with ctDNA positivity after neoadjuvant therapy did not achieve a pathological complete response (non-pCR), and all patients who achieved pCR were ctDNA-negative. ctDNA-negative patients with non-pCR had a similar prognosis [hazard ratio (HR) =1.4] to that of patients with pCR, indicating ctDNA negativity as a prognostic factor (6).

An analysis of 241 patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer in the I-SPY2 trial showed that the pCR rate of hormone receptor-positive breast cancer was 14.5% and that of triple negative breast cancer (TNBC) was 23.2%. While there was no significant association between ctDNA clearance and pCR in hormone receptor-positive (HR⁺) breast cancer, the pCR rate was higher in TNBC cases that were ctDNA-negative at T1 than in those negative at T2 or still positive at T2 (7).

In a study by Li et al., 21 of 44 patients with breast cancer were ctDNA-positive preoperatively; those who became ctDNA-positive postoperatively were characterized by estrogen receptor negativity and a large tumor diameter (8). ctDNA-positive cases after preoperative chemotherapy had a lower pCR rate than negative cases (47.6% vs. 73.9%). Patients with ctDNA positivity at T0 had a worse prognosis than patients with ctDNA negativity, with HRs of 5.72 for disease-free survival (DFS) and 11.2 for overall survival (OS).

Liu et al. reported a neoadjuvant chemotherapy (NAC) response prediction model using five single nucleotide variant mutations (TP53, SETBP1, PIK3CA, NOTCH4, and MSH2) and four copy number variation mutations (FOXP1-gain, EGFR-gain, IL7R-gain, and NFKB1A-gain) in a prospective observational study (9). The authors showed that adding ctDNA-positive status before neoadjuvant treatment and genetic features to the model improved its stratification for NAC response and prognosis. In the ctDNA analysis of the IMpassion031 trial, the rate of ctDNA negativity before NAC in stage II–III TNBC was 6%, and the outcome was excellent. Only one patient experienced recurrence by the time the data was cut off (10). Approximately 87% of patients with baseline ctDNA positivity showed ctDNA-negative status after NAC at surgery, which was associated with improved DFS and OS. Chen et al. reported early clearance of ctDNA as a better predictive and prognostic marker in early-stage TNBC compared with circulating tumor cell levels (12). The PREDICT-DNA trial TBCRC 040 showed that TNBC patients with detectable ctDNA prior to surgery were approximately 12 times more likely to experience a recurrence regardless of pCR (11).

A meta-analysis by Papakonstantinou et al. showed that positivity for ctDNA at baseline (before NAC) was a predictor of non-pCR in patients with breast cancer. The random effects model had a sensitivity of 0.34, specificity of 0.66, positive predictive value of 0.28, and negative predictive value of 0.67 for the prediction of pCR (16).

Monitoring MRD, a predictor of risk of postoperative recurrence

MRD refers to the presence of circulating tumor material, such as circulating tumor cells and ctDNA, that remains in the body even after anticancer drugs or radical resection surgery have achieved some degree of efficacy. MRD has long been recognized as a risk factor for relapse in hematological cancers such as acute myeloid leukemia. In recent years, attempts have been made to use ctDNA to assess MRD and to determine whether ctDNA analysis can be used to determine whether therapeutic intervention improves prognosis in solid tumors. A summary of the clinical trials investigating the association between ctDNA and MRD in breast cancer is shown in Table 3.

Regarding postoperative MRD, in the Exploratory Breast Lead Interval Study (EBLIS) by Shaw et al., ctDNA was positive prior to the detection of tumor recurrence by imaging, with a sensitivity of 88.2% (17). The lead interval from ctDNA positivity to recurrence was up to 38 months [median 10.5 (range, 0–38) months], and ctDNA positivity was associated with shorter recurrence-free survival (RFS) and OS. Overall, 7 out of 23 patients with TNBC who were ctDNA-positive had a median RFS of 8 months (range, 0–19 months), while non-relapsed patients remained ctDNA-negative during a median follow-up of 58 months. Additionally, 4 of 18 recurrent patients with HR⁺ breast cancer were ctDNA-negative, and 5 of 122 non-recurrent patients were ctDNA-positive on at least one occasion.

The CHiRP study analyzed ctDNA positivity and recurrence in patients with stage I–III HR⁺ breast cancer more than 5 years after radical treatment (18). Eight patients (10% of the total) were ctDNA-positive and six of them had distant metastatic recurrence. The sensitivity of ctDNA for detecting clinical recurrence was 85.7% and the negative predictive value was 98.7%; these results indicated that ctDNA positivity is useful for the early detection of clinical recurrence.

The I-SPY2 study discussed above also evaluated postoperative ctDNA. The ctDNA analysis showed that ctDNA-negative patients had a better prognosis than ctDNA-positive patients, regardless of the presence or absence of residual disease (6).

The c-TRAK TN study was a randomized, controlled trial of pembrolizumab in patients with stage II–III TNBC treated with preoperative chemotherapy and positive for ctDNA postoperatively (22). The endpoints of this study were ctDNA identification rate and clearance of ctDNA during adjuvant therapy. The ctDNA clearance rate was 0%. Given the speed with which ctDNA positivity transitions to metastasis in postoperative TNBC, there is a need for more sensitive testing methods and drug selection that can achieve ctDNA clearance.

To detect MRD, both tumor-informed assays and tumor-agnostic assays are used. Tumor-informed assays analyze a patient’s blood for specific genetic mutations or alterations that are unique to their tumor; this approach requires tumor tissue for analysis. Tumor-agnostic approaches do not require tumor tissue or information on its genetics; however, this method is less sensitive for detecting ctDNA. Recently, a whole-genome sequencing (WGS)-powered ultra-sensitive MRD assay was validated for early breast cancer (23).

Treatment selection and monitoring

The detection of mutations in ctDNA has become important in treatment selection. Breast tumors with certain genetic mutations in ESR1 and the PIK3CA/AKT1/PTEN pathway are resistant to conventional endocrine therapy. In recent years, targeted agents such as elacestrant, imulunestrant, alpelisib, and capivasertib have been introduced (24). Acquired ESR1 mutations in breast tumors are a mechanism of resistance to endocrine therapy. Imulunestrant, a next-generation oral selective estrogen receptor degrader, was associated with prolonged progression-free survival (PFS) in an ESR1 mutation cohort compared with standard endocrine therapy (fulvestrant or exemestane) (25). In the PADA-1 trial, when ESR1 mutations were detected in blood ctDNA during treatment with aromatase inhibitors plus palbociclib, switching the aromatase inhibitor to fulvestrant, a selective estrogen receptor degrader, resulted in prolonged PFS (11.9 vs. 5.3 months, HR =0.61) (26). The phase II study JBCRG-M08 AMBER trial is underway to evaluate the usefulness of treatment determined by detection of ESR1 mutations in ctDNA in patients with metastatic breast cancer treated with abemaciclib and aromatase inhibitors as primary therapy (27). The phase III study SERENA-6 is evaluating the efficacy of AZD9833 (camizestrant) + CDK4/6 inhibitor in hormone receptor-positive breast cancer cases with ESR1 mutation detected in ctDNA (28). The median PFS was 16.0 months in the camizestrant group and 9.2 months in the aromatase-inhibitor group (HR =0.44). This showed that patients who were switched to camizestrant with continuation of a CDK4/6 inhibitor when ESR1 mutation was detected during first-line therapy had a significantly longer PFS than those who were maintained on the aromatase-inhibitor combination.

The use of ctDNA for determining de-escalation of treatments has been studied. A de-escalation study in HER2-positive breast cancer (NCT06450314) is planned to evaluate the feasibility of using ctDNA for therapeutic de-escalation (temporary or complete discontinuation) in patients with HER2-positive metastatic breast cancer whose disease was controlled after 2 years of maintenance treatment with anti-HER2 targeted therapy and showing a negative ctDNA test result (29).

Types and characteristics of ctDNA assays

Given that ctDNA is present at low concentrations in the blood and accounts for <0.1% of total cfDNA in early-stage cancer, a highly sensitive method is needed for ctDNA detection. The current methods for ctDNA detection include PCR and next-generation sequencing, WGS, and whole-exosome sequencing (WES) (30). Tumor-informed assays require the use of tumor tissue in addition to blood samples to detect mutations based on the genomic profile of tumor tissue. PCR is used to assess specific genes, while WGS and WES can detect numerous nonspecific gene mutations. The currently available ctDNA assays are summarized in Table 4.

ctDNA in drug development

The U.S. Food and Drug Administration (FDA) has developed guidance regarding the use of ctDNA in therapeutic development (31). It describes the applications of ctDNA in clinical trials as follows.

Use of ctDNA for patient selection

ctDNA can be used for patient selection for clinical trials.

ctDNA can also be used as a stratifier in clinical trials in which both ctDNA-positive and negative populations are enrolled.

If no variants are detected in the ctDNA analysis, tumor testing may need to be performed to confirm the negative result.

Tests using ctDNA/MRD for patient population enrichment

A ctDNA test after surgery or adjuvant therapy may determine study eligibility of a positive population.

The ctDNA status at baseline can also be used as a stratification factor in trials enrolling both ctDNA-negative and ctDNA-positive patients. Such stratification in trials for testing both the ctDNA-positive group and the intent-to-treat population (including both ctDNA-positive and -negative groups) can also be conducted.

Clinical trial designs include escalation designs that add the treatment under study to standard treatment, compared with standard treatment alone, for ctDNA-positive patients (high-risk population), or de-escalation designs in ctDNA-negative patients (low-risk population).

The primary endpoints should be DFS if only adjuvant therapy is given, event-free survival if NAC is given (with or without postoperative therapy), or OS. The FDA did not recommend any early interim efficacy analyses of the primary endpoints because of limited events.

ctDNA as a measure of treatment efficacy

ctDNA may aid in the search for signals of drug activity in early clinical trials and may be useful in drug development planning.

The FDA encourages the pursuit of evidence on the utility of ctDNA response in addition to information on pathologic complete response after preoperative chemotherapy.

ctDNA as an early endpoint

Further data are needed to support the use of ctDNA as an endpoint that can reasonably predict long-term prognosis (DFS/event-free survival/OS).

Types of MRD detection methods

For tumor-informed assays, there is a delay between tumor testing and ctDNA panel creation, and sensitivity and specificity may depend on the clinical cut-off values, analytical sensitivity of the instrument, and the number of tumor-informative targets to be assayed.

For tumor-naïve panels, WGS can be used.

Discussion

We reviewed the utility and current status of ctDNA application in breast cancer in this review. Many clinical trials exploring ctDNA in breast cancer are ongoing. While many trials have evaluated ctDNA and MRD and showed that ctDNA was strong prognostic factor for patients with breast cancer, appropriate ctDNA-guided therapy is still under investigation. ctDNA-guided treatment selection will become a standard care for patients with metastatic breast cancer.

Many trials of ctDNA-guided therapy and additional therapy for ctDNA-positive cases are currently underway. The clinical trials using ctDNA in breast cancer are listed in Table 5. While ctDNA-guided adjuvant therapy with atezolizumab has led to significantly longer DFS and OS in patients with muscle invasive bladder cancer (32), there is little evidence for this approach in breast cancer. Some studies have evaluated de-escalation strategies using ctDNA. In Japan, the MONSTAR-SCREEN 3 project is underway to perform WGS/whole tumor sequencing analysis of cancer tissue, multi-omics analysis of blood (WGS/whole tumor sequencing/proteomics), and MRD evaluation in preoperative patients with solid cancer (33). In this project, MRD evaluation by WGS is possible, and it is anticipated that clinical trials for MRD-positive cases will be planned. Further evidence is needed to determine whether ctDNA-guided therapy is effective for breast cancer.

ctDNA is a strong prognostic factor in breast cancer. However, there is a lack of evidence that ctDNA as an endpoint that can reasonably predict long-term prognosis like OS. For example, the SERENA-6 and EMBER-3 trials showed PFS benefit in ESR-mutated breast cancer; however, the data for OS benefit are immature (25,28). As indicated in FDA guidance, a long follow-up is needed to evaluate which ctDNA will be a surrogate biomarker for OS (31).

This review has several limitations. First, this was a narrative review and not a systematic review; therefore, the methods for the selection and analysis of studies were less extensive. There may be bias in our review. We also did not discuss the cost-effectiveness of ctDNA assay. Li et al. showed that the application of ctDNA testing to guide the use of adjuvant chemotherapy for post-surgery patients with stage II colon cancer provided cost savings to both U.S. commercial and Medicare Advantage payers (34). A de-escalation strategy using ctDNA testing may save costs of chemotherapy in the perioperative setting.

Conclusions

ctDNA has become important as a source of biomarkers in clinical trials. Clinical trials are underway in breast cancer for ctDNA-guided therapy and interventions for ctDNA-positive cases with poor prognosis, especially in the perioperative period. ctDNA tests are also being developed by several companies, and the clinical and research significance of ctDNA is expected to grow.

Acknowledgments

We thank Gabrielle White Wolf, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-23/rc

Peer Review File: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-23/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-23/coif). C.F. reports grants or contracts from Daiichi Sankyo, Eli Lilly, and MSD; honoraria from Daiichi Sankyo, Eisai, Pfizer, Chugai, MSD, and Eli Lilly; and receipt of materials from Daiichi Sankyo. Y.N. reports grants or contracts from ABBVIE, Ono, Daiichi Sankyo, Taiho, Pfizer, Boehringer Ingelheim, Eli Lilly, Eisai, AstraZeneca, Chugai, Bayer, Takeda, Anthos Therapeutics, and Gilead; consulting fees from AstraZeneca, Eisai, Gilead, Eli Lilly, Novartis, Pfizer, Chugai, Taiho, Bayer, and Daiichi Sankyo; payment or honoraria for lectures from AstraZeneca, Eisai, Ono, Guardant, Takeda, Eli Lilly, Novartis, Pfizer, Chugai, PDR pharma, Nihon Kayaku, Taiho, Bristol, Bayer, Daiichi Sankyo, MSD, and Gilead. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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