The clinical utility of circulating tumor DNA (ctDNA) in early-stage breast cancer is approaching a critical inflection point, according to Heather A. Parsons, MD, MPH.
“What if we could reliably identify molecular residual disease [MRD] in early breast cancer? It's important to think about: We can deliver our therapies to patients who need them right now, especially in our adjuvant studies,” she explained in a presentation at the 43rd Annual Miami Breast Cancer Conference.1
“We could tailor our therapies to individual patients, therefore reducing overtreatment. [However], that also enables reducing undertreatment because we can target those therapies better. We can determine whether we can cure patients with MRD, and then…if this works, reduce size and timing of clinical trials. This is all sounds exciting, but we have a lot of work still to do,” Parsons, program head, breast oncology; associate professor; Maudslien Endowed Chair in Breast Cancer Precision Oncology Research, University of Washington in Seattle, added.
What is the unmet need with liquid biopsy in early breast cancer?
While historical blood-based biomarkers like CA 27-29 and circulating tumor cells offered limited sensitivity, next-generation ctDNA assays now provide the resolution necessary to detect MRD well before macroscopic recurrence is visible on imaging.
However, as oncologists increasingly encounter patients requesting these tests, the gap between prognostic capability and proven clinical actionability remains a significant hurdle for standard practice.
“When we're thinking about early disease, we have very, very low amounts of ctDNA, and this requires very sensitive assays,” Parsons explained.
At the Miami Breast Cancer Conference, she detailed the evolving landscape of ctDNA assays, emphasizing that while ctDNA can be a powerful prognostic tool, its role as a predictive biomarker for treatment escalation or de-escalation is still being defined.
What do the data show in the clinical utility of ctDNA in early breast cancer?
Recent data underscore the potent association between ctDNA detection and distant recurrence risk across breast cancer subtypes. While these findings suggest ctDNA could eventually refine neoadjuvant and adjuvant treatment strategies, Parsons cautioned that evidence demonstrating improved patient outcomes through ctDNA-guided interventions is still forthcoming.
ctDNA for MRD in Early Breast Cance
- Although ctDNA has shown prognostic value in early-stage breast cancer, the therapeutic benefit of acting on a ctDNA result remains unclear.
- Trials including I-SPY2 and PREDICT-DNA demonstrate that ctDNA clearance correlates with improved pCR and recurrence outcomes, but ctDNA status alone is not yet reliable enough to guide treatment selection.
- Although ctDNA assays can detect MRD earlier than imaging, no studies have yet shown that acting on a positive result improves outcomes or that de-escalating therapy based on a negative test is safe, so routine use remains limited to clinical trials.
In the neoadjuvant setting, the phase 2 I-SPY2 study (NCT01042379) evaluated 138 patients with stage II to III triple-negative breast cancer (TNBC).2 The study demonstrated that early ctDNA clearance during neoadjuvant therapy was a strong predictor of achieving a pathologic complete response (pCR) and was associated with superior distant recurrence-free survival (DRFS).
“Looking at pCR [is] still not something that you would want to use for selection, because 11 patients had pCR in the group [with early ctDNA clearance], but 8 patients did not,” Parsons noted.
Conversely, the phase 2 PREDICT-DNA (TBCRC 040) trial (NCT07069595), which aimed to determine the negative predictive value (NPV) of ctDNA for pCR in patients with TNBC and HER2-positive disease who were intended to undergo standard chemotherapy, failed to meet its primary end point of an NPV greater than 90%.3 Despite this, patients with TNBC who were ctDNA negative after neoadjuvant therapy were 10 times less likely to experience recurrence compared with those with detectable ctDNA, independent of their pCR status.
“Just looking at the CtDNA results, patients who cleared CtDNA by that preoperative time point did extremely well compared with those who didn't, with a hazard ratio of 9.6,” Parsons explained. “And when you look at that and include pathologic complete response in that assessment, patients who are ctDNA negative and had MRD still did extremely well. This is a really exciting study. It is time to put it into a prospective clinical trial, which is in the works in a couple of different settings.”
In the adjuvant setting for hormone receptor–positive, HER2-negative disease, investigators conducted an analysis of ctDNA status at the end of treatment in the PALLAS trial (NCT02513394). The cohort study showed a hazard ratio for distant recurrence of 21.5 (95% CI, 10.3-44.8; P < .0001) for ctDNA-positive patients compared with those who were ctDNA-negative.4 The 5-year distant recurrence-free interval (DRFI) for ctDNA-positive patients at the end of treatment was only 31.6%, compared with 95.4% for those without detectable ctDNA.
Further, preliminary results from the phase 2 DARE trial (NCT04567420), which aimed to determine if ctDNA-guided treatment adjustments improve clinical outcomes, showed that 6 of 10 patients with increasing ctDNA experienced relapse, while 1 of 9 with ctDNA clearance or decrease experienced relapse.5 Of note, the 3-month clearance rates in arms A and B were 56.3% and 25.0%, respectively.
“So, we don't know which arm is which here [in the DARE trial].… I think some important questions are: Does clearance in arm B represent spontaneous clearance? Is it assay sensitivity? Is it something else going on? We have a lot more to learn, and we'll look forward to the more definitive results,” Parsons said.
How should oncologists interpret the clinical utility of ctDNA in breast cancer?
While the prognostic value of ctDNA is clear, the therapeutic benefit of acting on a positive result remains unproven. Parsons emphasized that “no study has shown intervening on a positive test improves outcomes," and "no study has shown stopping therapy based on a negative test is safe.” Consequently, clinical guidelines currently discourage routine ctDNA testing outside of clinical trials. In cases where a positive result is obtained, Parsons advised for providers to perform staging scans; if no macroscopic disease is found, the primary options are enrollment in an interventional trial or continued surveillance. In cases with negative test results, she recommends not deviating from standard treatment based on these results.
The next phase of research involves interventional, ctDNA-guided trials, Parsons noted. Escalation trials like are investigating whether changing therapy upon ctDNA detection can delay or prevent metastatic recurrence. Simultaneously, de-escalation strategies are exploring whether adjuvant chemotherapy can be safely omitted in patients who remain ctDNA-negative post-surgery.
“In early breast cancer, multiple retrospective studies show a strong association between ctDNA presence and distant recurrence, but benefits of intervening upon ctDNA status are not yet proven,” Parsons concluded. “ctDNA assay characteristics vary significantly, and using a fit-for-purpose test is critical. Interventional studies proving the benefit of intervening upon ctDNA status are underway and essential to determining appropriate assay use.”
References
- Parsons HA. ctDNA in early-stage breast cancer: ready for prime time? Presented at: 43rd Annual Miami Breast Cancer Conference; Miami, Florida; March 5-8, 2026.
- Magbanua M, 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. 2023;41(6):1091-1102.e4. doi:10.1016/j.ccell.2023.04.008.
- 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(16_suppl):1009-1009. doi:10.1200/JCO.2025.43.16_suppl.1009.
- 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. Presented at: 2025 San Antonio Breast Cancer Symposium; San Antonio, Texas; December 9-12, 2025. Abstract RF3-04.
- 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
