Early and sustained clearance of circulating tumor DNA (ctDNA) was strongly associated with achieving pathologic complete response (pCR) in patients with early HER2-positive breast cancer receiving neoadjuvant HER2-directed therapy, according to findings presented at the San Antonio Breast Cancer Symposium (SABCS) 2025.

The analysis also revealed that both the absence of detectable baseline ctDNA and ctDNA clearance during neoadjuvant therapy predicted improved invasive disease-free survival (DFS) at 3 years.

The findings highlight the promise of ctDNA assessment for “refining tumor staging and informing treatment decisions in early HER2-positive breast cancer,” said principal investigator Antonio Llombart-Cussac, MD, PhD, chairman of the Medical Oncology Service, Hospital Arnau de Vilanova, Valencia, Spain.

ctDNA is an emerging tool for risk stratification and real-time monitoring in early breast cancer, offering the potential to personalize treatment decisions, explained Llombart-Cussac, who presented the results.

Previous findings from the PHERGain study demonstrated that a PET-guided, pCR-adapted strategy could help certain patients safely omit chemotherapy. The study focused on patients with stage I-IIIA HER2-positive early breast cancer undergoing neoadjuvant trastuzumab and pertuzumab.

The PET- and pCR-guided approach allowed 38% of these patients to skip chemotherapy. Overall, patients in this de-escalated group had a 3-year invasive DFS rate of almost 95%, despite many not receiving chemotherapy.

In the current substudy, PHERGuide, Llombart-Cussac and colleagues used the Guardant Reveal assay to assess how ctDNA detection and clearance relate to treatment response and long-term patient outcomes.

Among 288 plasma samples, 204 (71%) were ctDNA-positive and 84 (29%) were ctDNA-negative at baseline.

Detecting ctDNA at baseline correlated significantly with disease stage. Detection rates were 33% in stage I, 71% in stage II, and reached 93% in stage III tumors. ctDNA detection at baseline also correlated significantly with nodal stage — 55% of N0 tumors and 88% of N+ tumors were ctDNA-positive.

Notably, said Llombart-Cussac, there was a significant correlation between ctDNA and patients’ response to treatment. Among the 71% of patients who were ctDNA-positive at baseline, only about 24% remained ctDNA-positive after two treatment cycles, while 76% were ctDNA-negative. ctDNA clearance was strongly associated with PET response (P < .001) and pCR (P = .003).

Analysis of late ctDNA dynamics showed that 83% of patients with baseline ctDNA showed clearance just prior to surgery, which was significantly associated with achieving pCR.

No patient with detectable ctDNA prior to surgery achieved pCR, underscoring the high negative predictive value of late ctDNA persistence for pathologic response, Llombart-Cussac noted.

Long-term outcomes were similarly influenced by ctDNA results. Baseline ctDNA positivity was associated with worse 3-year invasive DFS (92.5% vs 100%, hazard ratio [HR], 4.1; P = .046).

While acknowledging the need for confirmatory prospective studies, these findings can pave the way for using liquid biopsy as a “noninvasive tool to know the status of the patients’ disease,” Llombart-Cussac said in a news release. “By being able to know the status and response of the disease in real time, we could make more personalized and efficient treatment decisions for the patients.”

But, based on this study, should ctDNA be used to guide therapy in HER2-positive early breast cancer in the clinic on Monday morning?

Study discussant Heather A. Parsons, MD, MPH, said no.

Although “ctDNA is a promising biomarker for treatment tailoring,” Parsons said, the study did not demonstrate clinical utility or that intervention upon the biomarker improves patient outcomes, “which is really what we want to see.”

“To truly realize the vision of precision medicine, we require application of the same rigor to biomarker development as to therapeutic development,” Parsons, program head of the Breast Oncology Program at the Fred Hutch Cancer Center, Seattle, told attendees.

Support for this study was provided by Guardant Health, Roche, and MEDSIR. Llombart-Cussac reported consulting relationships with Eli Lilly and Company, Roche, Pfizer, and Novartis. Parsons reported consulting relationships with Exact Sciences, Pfizer, and Genentech and receiving research support to her institution from Merck and SAGA Diagnostics.