3 Things You Should Know About Circulating (Cell-Free) Tumor DNA in Breast Cancer From the International Congress on the Future of Breast Cancer 2025 Annual Meeting

Learning Objectives

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

• Describe the utility of genomic and molecular biomarker assays in supporting individualized treatment selection in early-stage and metastatic breast cancer settings

• Evaluate efficacy and safety data from pivotal clinical trials to optimize treatment plans for patients with early-stage and advanced/metastatic breast cancer

RELEASE DATE: February 1, 2026

EXPIRATION DATE: February 1, 2027

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Circulating, or cell-free, tumor DNA (ctDNA) is a powerful tool that can be leveraged to empower many patients with breast cancer (BC). However, given the heterogeneity of BCs, prospective data are needed to validate potential indications for this noninvasive biomarker. Here are 3 things you should know about ctDNA in BC.

1) ctDNA can be used to predict recurrence for some patients with early BC.

Multiple prospective studies have evaluated the prognostic and predictive value of ctDNA levels for patients with early BC. However, multiple factors make the application of these data highly nuanced (Figure 1).

The prospective PREDICT-DNA trial (NCT02743910) assessed the negative predictive value of ctDNA for treatment response to neoadjuvant therapy (NAT) in patients with stage II/III HER2+ or triple-negative BC (TNBC).¹ Forty-five of the 112 participants with undetectable ctDNA prior to surgery had residual disease, resulting in a negative predictive value of just 60%. However, landmark analyses of invasive disease-free survival (IDFS) revealed excellent survival for patients with a negative post-NAT ctDNA despite the presence of residual disease (3-year IDFS, 95.8% for TNBC and 92.6% for HER2+ disease) and poor outcomes for those with a positive post-NAT ctDNA with residual disease (3-year IDFS, 48.9% for TNBC and 60.0% for HER2+ disease).

Investigators for the I-SPY2 trial (NCT01042379) compared serial ctDNA levels from patients receiving neoadjuvant chemotherapy (NAC) for hormone receptor (HR)–positive/HER2-negative vs TNBC.² Levels of ctDNA before, during, and after NAC were higher for patients with TNBC, and clearance of ctDNA 3 weeks after initiation of NAC predicted a favorable treatment response only for patients with TNBC. Positive ctDNA, on the other hand, had a significant association with inferior distant recurrence-free survival for both HR subtypes.

In the prospective, randomized interventional DARE trial (NCT04567420), ctDNA levels were collected every 6 months from patients receiving adjuvant endocrine therapy (ET) for high-risk, estrogen receptor (ER)–positive/HER2-negative BC.³ Patients who had ctDNA positivity with no evidence of metastatic disease on imaging were randomly assigned to switch to fulvestrant plus palbociclib (arm A, n=16) vs continuing with adjuvant therapy (arm B, n=18). On interim analysis, ctDNA clearance rates were 63% in arm A vs 22% in arm B.

2) ctDNA can be used to detect mutations indicating resistance to ET for patients with advanced, HR-positive/HER2-negative BC.

The ER, CDK4/6, and PI3K pathways drive oncogenesis and therapy resistance in HR-positive, advanced BC.^4,5 Endocrine therapies place selective pressure on HR-positive BCs to evolve into treatment-resistant tumors (Figure 2).^5,6 By detecting alterations signifying resistance to ET, ctDNA analysis may guide treatment.⁷

The oral selective ER degrader (SERD) elacestrant was evaluated vs standard of care therapy in the phase 3 EMERALD study (NCT03778931) of 477 patients with ER-positive/HER2-negative locoregionally recurrent or metastatic BC that had progressed on a previous CDK4/6 inhibitor (CDK4/6i) in combination with either fulvestrant or an aromatase inhibitor (AI).⁸ Elacestrant improved progression-free survival (PFS) for all patients (hazard ratio, 0.70; 95% CI, 0.55-0.88; P = .002), a benefit that was found to be driven by the patients with a ctDNA ESR1 mutation (hazard ratio, 0.55; 95% CI, 0.39-0.77; P = .0005). In January 2023, elacestrant gained FDA approval for patients with advanced/metastatic ER-positive/HER2-negative, ESR1-mutated BC with disease progression following at least 1 line of ET.⁹

The phase 3 EMBER-3 study (NCT04975308) evaluated another oral SERD, imlunestrant, as monotherapy and in combination with abemaciclib for patients with ER-positive/HER2-negative advanced BC that recurred or progressed during or after AI therapy with or without a CDK4/6i.¹⁰ A total of 874 patients were randomly assigned to receive imlunestrant monotherapy, standard single-agent ET, or imlunestrant plus abemaciclib. Among patients with ESR1 mutations (n=256), the median PFS was 5.5 months with imlunestrant vs 3.8 months with standard ET (hazard ratio, 0.62; 95% CI, 0.46-0.82; P = .0008). In September 2025, the FDA approved imlunestrant monotherapy for use in patients with ER-positive/HER2-negative, ESR1-mutated advanced or metastatic BC that had progressed following at least 1 line of ET.¹¹

Mutations in PIK3CA occur in about 40% of HR-positive/HER2-negative BCs.¹² The phase 3 SOLAR-1 (NCT02437318) and INAVO120 (NCT04191499) studies evaluated the efficacy of the PI3Kα inhibitors alpelisib and inavolisib, respectively, for patients with PIK3CA-mutated, HR-positive/HER2-negative, locally advanced or metastatic BC who had received prior ET.^12,13 The addition of these drugs to a combination treatment demonstrated a significant PFS benefit, leading to FDA approvals for both drugs.^14,15

3) Initiating treatment for ctDNA positivity prior to progression of disease on imaging may extend the benefit of ET for patients with advanced, HR-positive/HER2-negative BC.

In some patients with advanced, HR-positive/HER2-negative BC, a rise in ESR1-mutant ctDNA indicating the development of resistance to ET may precede overt progression of disease on imaging (Figure 3).¹⁶

The open-label, phase 3 PADA-1 study (NCT03079011) enrolled patients to undergo mutant ESR1 ctDNA and imaging assessment while receiving an AI plus palbociclib for advanced, ER-positive/HER2-negative BC.¹⁷ Patients with newly positive or increased mutant ESR1 ctDNA and no synchronous disease progression on imaging (n=172) were randomly assigned to continue with the same therapy vs switching to fulvestrant plus the same dose of palbociclib. Median PFS from randomization was 11.9 months in the fulvestrant plus palbociclib group vs 5.7 months in the AI plus palbociclib group (hazard ratio, 0.61; CI, 0.43-0.86; P = .0040).

Investigators for the double-blind, placebo-controlled phase 3 SERENA-6 study (NCT04964934) surveilled 3256 patients receiving an AI plus a CDK4/6i for HR-positive/HER2-negative advanced BC.¹⁸ Upon detection of mutant ESR1 ctDNA with negative imaging, 315 patients remained on the same CDK4/6i but were then randomly assigned to switch to camizestrant vs continuing with the same AI. Median PFS was significantly improved for the group randomly assigned to receive camizestrant (median PFS, 16.0 vs 9.2 months; hazard ratio, 0.44; 95% CI, 0.31-0.60, P < .00001). At 27% maturity, PFS2 also trended toward favoring a switch to camizestrant (hazard ratio reported at 27% maturity, 0.52; 95% CI, 0.33-0.81).

Key References

1. Hunter N, Parsons HA, Cope L, et al. Circulating tumor DNA, pathologic response after neoadjuvant therapy, and survival: first results from TBCRC 040 (the PREDICT-DNA trial).
J Clin Oncol.2025;43(suppl 16):1009. doi:10.1200/JCO.2025.43.16_suppl.1009

10. Jhaveri KL, Neven P, Casalnuovo ML, et al. Imlunestrant with or without abemaciclib in advanced breast cancer. N Engl J Med. 2025;392(12):1189-1202. doi:10.1056/NEJMoa2410858

18. Turner NC, Mayer EL, Park YH, et al; EMBER-3 Study Group. Camizestrant + CDK4/6 inhibitor (CDK4/6i) for the treatment of emergent ESR1 mutations during first-line (1L) endocrine-based therapy (ET) and ahead of disease progression in patients (pts) with HR+/HER2- advanced breast cancer (ABC): phase 3, double-blind ctDNA-guided SERENA-6 trial. J Clin Oncol. 2025;43(suppl 17):LBA4. doi:10.1200/JCO.2025.43.17_suppl.LBA4

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CME Posttest Questions

1. Your 42-year-old patient with TNBC who has a 4-cm tumor with involvement of a single lymph node is curious about ctDNA minimal residual disease (MRD) testing in the neoadjuvant setting. Based on findings from the PREDICT-DNA study, which of the following statements can be used to counsel her on the implications of ctDNA testing?

A. She is likely to have detectable disease by ctDNA even if she achieves a pathologic complete response (pCR).

B. She is likely to have a low risk of recurrence even if she has detectable disease by ctDNA.

C. She is likely to have a high risk of recurrence even if she has no detectable disease by ctDNA.

D. She is likely to have a low risk of recurrence if she has no detectable disease by ctDNA, even if she does not achieve pCR.

2. Based on recent evidence, which of the following statements best describes the clinical utility of ctDNA monitoring in the management of metastatic breast cancer?

A. Assess tumor genotype evolution and identify actionable alterations to guide treatment selection.

B. Enhance radiographic imaging methods.

C. Monitor time to next treatment.

D. Prolong time on treatment.

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