3 Things You Should Know About Translating ctDNA Into Clinical Decisions in Breast Cancer

LEARNING OBJECTIVES

Upon successful completion of this activity, you should be better prepared to:

• Interpret ctDNA and molecular residual disease data from clinical trials to inform patient-centered decision-making in early-stage and metastatic breast cancer

• Apply evidence from ctDNA-guided studies to determine when liquid biopsy testing may appropriately inform clinical decision-making in breast cancer

RELEASE DATE: June 10, 2026

EXPIRATION DATE: June 10, 2027

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This activity is supported by an educational grant from Natera, Inc.

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The landscape of breast oncology is being fundamentally reshaped by the liquid biopsy, the analysis of cell-free DNA and, within it, the fraction derived specifically from malignant cells, circulating tumor DNA (ctDNA). ctDNA testing is emerging as a promising tool for refining risk assessment, monitoring molecular residual disease, and informing treatment decisions for patients with breast cancer.^1-3 As assay sensitivity advances and clinical trial data expand, clinicians must understand how to translate emerging evidence into practical, patient-centered care. Here are 3 things you should know about translating ctDNA into clinical decisions for patients with breast cancer.

1) ctDNA positivity is a powerful prognostic marker across treatment settings.

In the neoadjuvant therapy (NAT) setting, ctDNA has proven to be a potent tool for refining prognosis, often outperforming traditional clinicopathological factors. Data from the I-SPY2 trial (NCT01042379) and the PREDICT-DNA (NCT03736502) study highlight the need to look beyond pathologic complete response (pCR) to understand a patient’s true risk (Table).^4,5

The I-SPY 2 trial, a retrospective analysis of 723 patients with high-risk early-stage breast cancer, revealed that pre-NAT ctDNA positivity is a definitive predictor of distant recurrence–free survival (DRFS). Patients who were ctDNA-positive at diagnosis had a significantly higher risk of metastatic recurrence compared with those who were ctDNA-negative (HR, 4.40; P < .001). Furthermore, baseline ctDNA status helped refine risk stratification even for patients whose tumors were resistant to NAT. Among patients with moderate or extensive residual disease (RCB-II and RCB-III), those who were ctDNA-negative prior to treatment still demonstrated excellent 3-year DRFS rates (98% and 94%, respectively) compared with those who were ctDNA positive (81% and 59%, respectively).⁴ This suggests that baseline molecular burden is a vital surrogate for metastatic potential.

The PREDICT-DNA trial tested the prognostic value of post-NAT ctDNA, specifically in triple-negative breast cancer (TNBC). While the trial failed to meet its primary end point of finding a correlation between ctDNA clearance and pCR, it showed that patients with undetectable ctDNA post NAT had an excellent prognosis, and patients with TNBC who had detectable ctDNA were approximately 12 times more likely to experience a recurrence regardless of their pCR status (HR, 12.8; 95% CI, 2.3-71.5).⁵ Ultimately, post-NAT ctDNA detection proved to be a stronger predictor of recurrence than pCR.

2) ctDNA surveillance informs recurrence risk but should not guide therapy de-escalation (yet).

The promise of longitudinal ctDNA monitoring lies in lead time, the window between molecular detection and radiologic recurrence (Figure 1).⁶ However, the question of whether early detection has meaningful clinical relevance requires weighing the short lead time vs the risk of simply documenting the inevitable earlier.²

The DARE trial (NCT04567420) followed 507 high-risk, estrogen receptor–positive patients on adjuvant endocrine therapy. The trial demonstrated that ctDNA could identify recurrence before it was clinically detectable via imaging in 73% of positive patients (Figure 1).⁶ Although this provides a significant lead time, the conversion rate found, of approximately 3% per year, should be considered in planning the clinical strategy.⁶ For patients who remained persistently negative, the negative predictive value for relapse-free survival was a reassuring 99.5%.⁶The study emphasizes the potential in ctDNA monitoring for disease surveillance and risk stratification. However, interim data from the study showing a correlation between escalating treatment in the early stage and ctDNA clearance were based on a small study group. Until prospective trials demonstrate an overall survival benefit, we must counsel patients that rising ctDNA levels indicate high risk but do not yet mandate a change in standard-of-care therapy outside of a trial.

3) In metastatic disease, ctDNA complements but does not replace tissue testing.

In metastatic breast cancer, liquid biopsies are highly effective at identifying actionable driver mutations and tracking clonal evolution under therapeutic pressure. For instance, ctDNA is routinely used to detect emergent resistance mutations like ESR1 and PIK3CA alterations.⁷ Trials such as PADA-1 (NCT03079011) and SERENA-6 (NCT04964934) have even explored the strategy of monitoring ESR1 mutations in plasma to initiate early therapeutic switches before radiographic progression occurs.^7-9 These trials suggest that we can outmaneuver the tumor by changing treatment at the first sign of molecular escape. However, despite the sensitivity of ctDNA, tissue remains the gold standard for assessing phenotype. Tumor heterogeneity and the risk of receptor conversion mean that ctDNA cannot entirely replace standard tissue biopsy and imaging. If a liquid biopsy indicates an activating ESR1 mutation but a subsequent tissue biopsy of a progressing lesion shows a loss of estrogen receptor and progesterone receptor expression (indicating conversion to TNBC), the discordance must be managed by basing the treatment plan on the tissue biology (Figure 2).^7-9

Key References

4. Magbanua MJM, Manon NA, Wolf DM, et al. Circulating tumor DNA refines risk stratification of neoadjuvant therapy-resistant breast tumors. Nat Commun. 2025;16:9945. doi:10.1038/s41467-025-65432-5

6. Pusztai L, Scalise CB, Kalashnikova E, et al. Circulating tumor (ct)DNA monitoring of ER+/HER2- high-risk breast cancer during adjuvant endocrine therapy. J Clin Oncol. 2025;43(suppl 16):1010. doi:10.1200/JCO.2025.43.16_suppl.1010

7. Bidard FC, Mayer EL, Park YH, et al; SERENA-6 Study Group. First-line camizestrant for emerging ESR1-mutated advanced breast cancer. N Engl J Med. 2025;393:569-580. doi:10.1056/NEJMoa2502929
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CME Posttest Questions

1) A patient with high-risk stage III hormone receptor–positive/HER2-negative (HR+/HER2–) early breast cancer presents for a second opinion before starting neoadjuvant therapy. She brings a tumor-informed ctDNA assay report showing a positive result at diagnosis. Based on the I-SPY 2 retrospective analysis, which of the following best describes the prognostic significance of this result?

A. Predictive of pCR but not distant recurrence

B. Not validated as a prognostic marker in HR+/HER2– disease

C. Associated with a substantially higher risk of distant recurrence

D. Not informative because most patients are ctDNA-positive before treatment

2) A 52-year-old woman with high-risk stage IIIA estrogen receptor (ER)–positive/HER2– breast cancer is 12 months into adjuvant letrozole plus abemaciclib. Serial tumor-informed ctDNA testing every 6 months has been negative. She asks whether she can shorten her endocrine therapy. Based on DARE trial data, which of the following is the most appropriate response?

A. Discontinue endocrine therapy early, given negative ctDNA results

B. Continue current therapy and ctDNA surveillance as part of recurrence monitoring

C. Discontinue ctDNA surveillance because serial negative results indicate cure

D. Extend endocrine therapy to 10 years based on ctDNA results alone

3) A patient with HR+/HER2– metastatic breast cancer experiences disease progression while on a first-line aromatase inhibitor plus CDK4/6 inhibitor regimen. Liquid biopsy detects an activating ESR1 mutation, but biopsy of a progressing metastasis is ESR1 wild-type and ER 0%, progesterone receptor 0%. What is the most appropriate course of action?

A. Initiate chemotherapy/antibody-drug conjugate based on tissue testing results

B. Initiate an oral SERD based on the ESR1 mutation on ctDNA

C. Switch to a different CDK4/6 inhibitor

D. Initiate everolimus plus exemestane

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