In patients with early triple-negative breast cancer (TNBC), the presence of circulating tumour (ct)DNA after neoadjuvant therapy but before surgery is strongly associated with poor response and distant recurrence outcomes, according to the substudy of the NSABP B-59/GBG-96-GeparDouze trial.
Whole-exome sequencing-based analyses of blood samples collected between 2 and 4 weeks after completion of neoadjuvant therapy showed that 84.6 percent of patients with positive ctDNA status did not achieve pathologic complete response (pCR). Meanwhile, 69.1 percent of patients with negative ctDNA status did achieve pCR. [AACR 2026, abstract CT013]
Post-neoadjuvant therapy ctDNA positivity predicted non-pCR with a specificity of 97.9 percent (95 percent confidence interval [CI], 92.8–99.4) and a positive predictive value of 85.7 percent (95 percent CI, 60.1–96), reported lead investigator Dr Marija Balic from the NSABP Foundation in Pittsburgh, Philadelphia, US, during a clinical trial mini symposium session at the annual AACR meeting.
Additionally, post-neoadjuvant therapy ctDNA positivity was associated with a tenfold higher likelihood of distant recurrence (HR, 10.2, 95 percent CI, 3.8–27.3; p<0.0001). Distant recurrence occurred in 54 percent of patients with positive ctDNA status presurgery as opposed to 6 percent of those who had ctDNA clearance presurgery.
The association, according to Balic, mirrors the negative prognostic impact previously observed and presented for post-surgery ctDNA, where post-surgery ctDNA positivity was associated with a 30-fold increase in the risk of distant recurrence (HR, 30.3, 95 percent CI, 10.4–88.7; p<0.0001). [SABCS 2025, abstract RF4-03]
Moreover, the high positive predictive value of post-neoadjuvant therapy ctDNA positivity for non-pCR highlights its “potential utility as an early indicator of treatment resistance, risk stratification, and, potentially, adaptation of treatment,” Balic said.
“These [ctDNA] studies will help define suitable time points for [treatment] escalation and de-escalation strategies,” she added.
When asked to clarify which therapies might be adjusted, Balic pointed to the potential for de-escalating the duration of neoadjuvant therapy in patients with ctDNA clearance, as well as escalating treatment in patients who remain ctDNA-positive to improve their survival.
“The neoadjuvant window serves as a biological stress test,” said Prof Kenneth Watanabe from Harvard Medical School, Boston, Massachusetts, US, who was not involved in the study.
“We’re getting real-time readout of how a specific tumour biology responds to a specific targeted intervention. And readouts like ctDNA can provide very significant prognostic consequences,” Watanabe added.
The parent NSABP B-59/GBG-96-GeparDouze trial involved 1,550 early TNBC patients. It consisted of 12 weeks of treatment with either atezolizumab or placebo in addition to paclitaxel plus carboplatin, followed by 8–12 weeks of atezolizumab or placebo in combination with doxorubicin plus cyclophosphamide or epirubicin plus cyclophosphamide, surgery, and then post-surgery atezolizumab or placebo to complete 1 year of therapy.
The substudy assessed post-neoadjuvant therapy as a treatment response decision point and included 155 patients with presurgery ctDNA data.