Despite compelling prognostic associations across multiple retrospective data sets, no interventional trial has demonstrated that acting on circulating tumor DNA testing results in early breast cancer improves patient outcomes. Clinicians should therefore proceed with caution until such evidence emerges, according to Heather A. Parsons, MD, MPH, Program Head of Breast Oncology, Associate Professor and Maudslien Endowed Chair in Breast Cancer Precision Oncology Research at the Fred Hutch Cancer Center and University of Washington, Seattle.
Speaking at the 43rd Annual Miami Breast Cancer Conference, sponsored by Physicians’ Education Resource, Dr. Parsons said the promise of circulating tumor DNA (ctDNA) to guide treatment decisions in early-stage breast cancer is real—but, for now, remains just that: a promise. “It all sounds exciting, but we have a lot of work still to do,” she said. “Multiple retrospective studies show a strong association between ctDNA presence and distant recurrence, but no studies that I am aware of have shown that intervening on a positive test improves outcomes for patients, nor that stopping therapy based on a negative test is safe.”
Dr. Parsons is optimistic that ctDNA will eventually play a key role. Testing may be approaching an inflection point, where ultrasensitive detection platforms are converging with effective treatments. Still, she emphasized, prognostic association is not the same as clinical utility, and—at present—conflating the two risks treatment-related harm.
A New Generation of Technology and Why It Matters
Blood-based biomarkers are not new to oncology. CA 27-29, CA 15-3, CEA, and circulating tumor cells (CTCs) have all been investigated as indicators of disease status. The most instructive cautionary tale, Dr. Parsons noted, remains SWOG S0500, which examined whether switching chemotherapy in patients with metastatic breast cancer based on CTC status would improve outcomes.1 It did not: no benefit was observed in either progression-free or overall survival.
What distinguishes today’s ctDNA platforms is their sensitivity—orders of magnitude greater than that of prior technologies—combined with therapies that are far more effective than the routine chemotherapy regimens studied in SWOG S0500. “When we pair highly accurate diagnostics with highly effective therapies, we may be able to change things,” Dr. Parsons predicted.
Cell-free DNA consists of single- and double-stranded fragments in circulation, released largely through apoptosis and rapidly cleared by the liver. ctDNA is the fraction of cell-free DNA originating from cancer cells, identifiable through sequencing methods that distinguish tumor-derived fragments from normal DNA. ctDNA levels correlate with cancer subtype, disease burden, and specific metastatic sites.
In early-stage disease, the relevant clinical concept is measurable residual disease (MRD) not visible on imaging. In breast cancer, this is further complicated, Dr. Parsons noted, by the lack of routine surveillance imaging and the challenge of detecting vanishingly small ctDNA fractions. Newer “ultrasensitive” assays, with reported detection limits as low as one to three parts per million, represent meaningful advances. By comparison, using conventional platforms, more than 50% of samples during monitoring fell below the detection threshold.2
What the Data Show—and What They Do Not
Dr. Parsons reviewed a series of data sets across multiple disease settings, each illustrating a consistent pattern: ctDNA status is a powerful prognostic marker but has not yet been shown to guide actionable treatment decisions.
In the neoadjuvant setting, data from the I-SPY 2 trial’s triple-negative cohort showed that early ctDNA clearance was associated with improved distant recurrence–free survival (P < .0001).3 The curves separated meaningfully, but confidence intervals were wide, and the discriminatory value for pathologic complete response (pCR) remained insufficient for clinical decision-making: 11 patients with early clearance achieved pCR, but so did 8 who did not clear.
The PREDICT-DNA study (TBCRC 040), presented at the 2025 ASCO Annual Meeting, enrolled patients with stage II and III triple-negative or HER2-positive breast cancer receiving standard neoadjuvant chemotherapy.4 The primary endpoint—post-neoadjuvant ctDNA prediction of pCR (negative predictive value > 90%)—was not met, but the prognostic signal in the triple-negative cohort was striking. Patients who cleared ctDNA had a hazard ratio for disease-free survival of 9.6 compared with those who did not (P = .0006), meaning they were nearly 10 times less likely to experience recurrence, independent of pCR status. Notably, patients who were ctDNA-negative despite residual disease still fared extremely well—an “exciting” finding that warrants prospective evaluation, Dr. Parsons added.
In the adjuvant setting, the PALLAS study, a randomized phase III trial of adjuvant palbociclib in hormone receptor–positive, HER2-negative breast cancer, provided a large, unselected cohort for translational analysis.5 Using whole-genome sequencing, Dr. Parsons and colleagues observed a hazard ratio for recurrence-free interval of 15.1 in patients who were ctDNA-positive at cycle 1, day 1 (many of whom had already initiated endocrine therapy) (P < .0001), rising to 21.5 at the end of treatment (P < .0001). About 5% of patients who were ctDNA-negative at the end of treatment still experienced recurrence, serving as a reminder that a negative test does not confer immunity from relapse, she cautioned.
Perhaps the most striking data in the late adjuvant setting came from updated results of CHiRP, a cohort study also presented at ASCO 2025, in which all 8 of 83 high-risk hormone receptor–positive patients with detectable ctDNA at baseline or any subsequent time point developed metastatic recurrence.6 The median lead time from first positive test to clinical recurrence was 1.4 years—a window that, in theory, could be exploited therapeutically if an effective intervention were available.
The DARE study is the first prospective interventional trial, enrolling 585 patients, but only very preliminary data have been reported and cannot yet be interpreted.7
Guidance for Clinicians Facing Real-World Pressure
While Dr. Parsons advised against the routine use of ctDNA in practice, she acknowledged, “I know these tests are being ordered. I am seeing a lot of patients with these tests in hand or coming to me with questions about them.”Her message to such patients and their physicians is that their use is not evidence-based. In the absence of definitive evidence, however, she offered a pragmatic framework for their application in practice:
- Positive ctDNA result: Perform a staging scan, since many of these patients will have metastatic disease.
- Positive ctDNA and positive scan: Treat according to the metastatic guidelines.
- Positive ctDNA and negative scan: Choose one of three options:
- Enroll in a clinical trial
- Continue therapy: Decide whether to monitor ctDNA status regularly and continue to restage
- Change therapy
- Negative ctDNA result: Stick with therapy (under most circumstances)
Her guidance regarding negative results was emphatic. “This is the most important thing to take away today,” she said. “When we have established, evidence-based care, I would strongly recommend not deviating from standard treatment. We simply do not have data showing that a single test is sensitive enough to compel us to change therapy. It probably is not picking up all recurrences, even in retrospective studies.”
Special Circumstances, and the Future
Dr. Parsons did identify a narrow set of scenarios in which a ctDNA-negative result might inform difficult decisions: curative-intent local therapy planning in oligometastatic, hormone receptor–positive disease following initial systemic treatment; and consideration of treatment breaks in patients with metastatic breast cancer who achieve a complete response but face significant toxicity or have family-planning considerations. These are special situations requiring careful clinical judgment and do not represent an endorsement of routine de-escalation.
Multiple trials are underway globally to test whether ctDNA status can guide treatment intensification and de-escalation. Others are evaluating approaches to increase ctDNA yield in the blood, a biological constraint that remains a key limiting factor in early-stage detection. “These studies are essential to determining where appropriate assay use lies,” she said.
DISCLOSURE: Dr. Parsons had personal disclosures for Exact Sciences, SAGA Diagnostics, Foresight Diagnostics, Daiichi Sankyo, Gilead Sciences, Natera, Pfizer, Genentech, Illumina, and NeoGenomics.
REFERENCES
1. Smerage JB, Barlow WE, Hortobagyi GN, et al: Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol 32:3483-3489, 2014.
2. Garcia-Murillas I, Abbott CW, Cutts RJ, et al: Whole genome sequencing-powered ctDNA sequencing for breast cancer detection. Ann Oncol 36(6):673-681, 2025.
3. Magbanua MJM, Brown Swigart L, Ahmed Z, et al: Clinical significance and biology of circulating tumor DNA in high-risk early-stage HER2-negative breast cancer receiving neoadjuvant chemotherapy. Cancer Cell 41(6):1091-1102, 2023.
4. 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 43(16_suppl):1009-1009, 2025.
5. Parsons HA, Ballman K, Heitzer E, et al: Tumor-informed circulating tumor DNA analysis to assess molecular residual disease for prognosis and prediction of benefit from palbociclib in the PALLAS trial. 2025 San Antonio Breast Cancer Symposium. Abstract RF3-04. Presented December 10, 2025.
6. Yoo T-K R, Heiling H, Santos K, et al: Circulating tumor DNA and late recurrence in high-risk, hormone receptor-positive, HER2-negative breast cancer: An updated analysis of the CHiRP study. J Clin Oncol 43(16_suppl):3055-3055, 2025.
7. 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 43(16_suppl):1010, 2025.
