ctDNA Positivity Displays Utility as a Treatment Resistance and Risk-Stratification Biomarker in TNBC

Circulating tumor DNA (ctDNA) positivity via tumor-informed whole-exome sequencing following neoadjuvant chemotherapy but before surgery was strongly associated with non–pathologic complete response (pCR) and inferior distant recurrence outcomes in patients with early triple-negative breast cancer (TNBC) in a sub-study of the phase 3 NSABP B-59/GBG-96-GeparDouze trial (NCT03281954), according to Priya Rastogi, MD.

“[Minimal residual disease (MRD) testing is] going to reshape our whole [methodology] of clinical care and clinical trials, and [this prospect] is exciting,” Rastogi said in an interview with OncLive®.

In the interview, Rastogi discussed key findings from the sub-study presented at the 2026 AACR Annual Meeting, data to note from a prior readout of the study that assessed patient outcomes based on ctDNA assessments from a different treatment time point, and where the future of MRD testing in breast cancer may be headed.

Rastogi is an associate professor of medicine at the University of Pittsburgh School of Medicine, as well as a medical oncologist at the University of Pittsburgh Medical Center Hillman Cancer Center in Pennsylvania.

OncLive: What was the design of the NSABP B-59/GBG-96-GeparDouze trial?

Rastogi: NSABP B-59/GBG-96-GeparDouze was a neoadjuvant trial with 1550 patients with early-stage breast cancer.¹ The patients received carboplatin with paclitaxel, followed by doxorubicin plus cyclophosphamide or epirubicin plus cyclophosphamide with or without atezolizumab [Tecentriq]. We were evaluating chemotherapy with the addition of immune therapy. In our sub-study, we had 212 patients, and we collected ctDNA at various time points, including at baseline, after neoadjuvant therapy but prior to surgery, after surgery, and at 12 and 24 months after random assignment.

What data from this sub-study were previously reported at the 2025 San Antonio Breast Cancer Symposium (SABCS)?

We’re excited about the data that were presented at SABCS 2025. We saw a strong relationship between ctDNA [positivity] after surgery and the risk of recurrence. Patients who that were ctDNA positive after surgery had a significantly higher risk of distant recurrence compared with patients who were ctDNA negative.

Specifically, post-surgical ctDNA positivity was strongly associated with a high risk of recurrence, with an approximately 30-fold increase in the risk of distant recurrence compared with patients who were ctDNA negative. In total, 95% of patients who were ctDNA negative after surgery continued to stay ctDNA negative and did not have a distant recurrence at year 3, which shows that these patients had a good prognosis. Our study also demonstrated that the combined post-surgical ctDNA status with pathological outcomes—surgical outcomes—was helpful for risk stratification.

What updated findings from this sub-study were presented at AACR 2026?

[We were] also excited about the data that were presented at AACR 2026. With these additional data, we looked at ctDNA after neoadjuvant therapy, but prior to surgery, a little different than our time point from SABCS 2025. ctDNA detected before surgery was strongly associated with the presence of residual disease at the time of surgery. In patients who had detectable ctDNA after completing neoadjuvant therapy, the test predicted a lack of a pCR with an 85.7% positive predictive value [95% CI, 60.1%-96.0%].² Also at this time point, we saw that ctDNA [positivity] was strongly associated with distant recurrence, so similar to our results from SABCS 2025, but from a different time point.

What do the NSABP B-59/GBG-96-GeparDouze sub-study findings mean for breast cancer clinical practice?

In practice, MRD gives us a much more precise and personalized way to talk with our patients. Instead of just relying on clinical and pathological features at baseline, we can incorporate a dynamic and biological marker that works with us regarding how the body reacts as it receives treatment for breast cancer. For patients with MRD-positive disease, it can open the door to potential discussions for clinical trials, or, as we learn more, more intensive therapy. For patients with MRD-negative disease, it helps us reassure them that they are going to [have good therapeutic outcomes] and may also avoid over-treatment.

What does the future look like for evaluating ctDNA or other biomarkers in TNBC?

MRD testing is going to become a foundational tool for precision oncology. We’re moving to a future where treatment decisions will happen based on real-time monitoring of disease biology, so MRD could help guide escalation for patients who have high-risk disease, as well as de-escalation for patients who have low-risk disease. As the evidence continues to grow, MRD has the potential to reshape how we manage recurrence, how we monitor patients, and how [conduct] long-term disease management.

References

1. Balic M, Tang G, Young G, et al. Evaluation of a whole-exome sequencing tumor-informed circulating tumor DNA MRD assay in patients with early triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy (NAC) with or without atezolizumab: a prospective sub study of the NSABP-B59/GBG-96-GeparDouze trial. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; Houston, TX. Poster RF4-03.
2. Balic M, Tang G, Rastogi G, et al. Whole-exome sequencing tumor-informed circulating tumor DNA detection after completion of neoadjuvant treatment predicts non-pCR and distant recurrence in patients with early triple-negative breast cancer (TNBC)—results from a sub-study of the NSABP B-59/GBG-96-GeparDouze trial. Cancer Res. 2026;86(suppl 8):CT013. doi:10.1158/1538-7445.AM2026-CT013