On December 16, 2025 Natera, Inc. (NASDAQ: NTRA), a global leader in cell-free DNA and precision medicine, together with Quantum Leap Healthcare Collaborative, reported the publication of new findings from the I-SPY 2 trial in Nature Communications.

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The study examined how Signatera can refine risk assessment in patients with early-stage breast cancer whose tumors resist neoadjuvant therapy (NAT). These cancers often leave behind substantial residual disease and carry a higher risk of metastasis, though only about 15–30% recur within three years1-3. Distinguishing which NAT-resistant tumors are more likely to recur could guide treatment decisions to potentially prevent or delay metastatic recurrence.

Researchers used Signatera to measure personalized circulating tumor DNA (ctDNA) in 723 women with high-risk, early-stage breast cancer receiving NAT at four time points: 1) before treatment; 2) after three weeks of paclitaxel with or without an investigational agent; 3) between paclitaxel- and anthracycline-based regimens; and 4) after completing neoadjuvant therapy. Key findings include:

Signatera ctDNA testing improved prognostic precision beyond residual cancer burden (RCB) alone in patients with high RCB (RCB-II/III) following neoadjuvant therapy (NAT).
Signatera-negative patients, at either pretreatment or post-NAT, had a much lower risk of metastasis:
RCB-II: Post-NAT, pre-surgery (T3) 3-year DRFS = 88% (ctDNA–) vs. 57% (ctDNA+), adj HR = 0.29, p = 0.001
RCB-III: Post-NAT, pre-surgery (T3) 3-year DRFS = 83% (ctDNA–) vs. 22% (ctDNA+), adj HR = 0.14, p < 0.001
Persistent Signatera positivity post-NAT (T3) was a strong independent predictor of metastatic recurrence (adj HR = 5.20, p < 0.001).
Early Signatera ctDNA clearance at week 3 (T1) was strongly associated with favorable response to NAT, including regimens containing immune checkpoint inhibitors and HER2-targeted therapies, supporting its potential as an early, dynamic biomarker of treatment sensitivity.
Personalized Signatera assay variants remained highly stable despite tumor evolution, with median conservation rates of 94–97% between pretreatment and post-NAT tumor samples.
"These findings show that ctDNA provided critical insight into which therapy-resistant tumors were most likely to recur and, importantly, which were not," said Laura Esserman, M.D., MBA, and Laura van ‘t Veer, Ph.D., professors at the UCSF and principal investigators of the I-SPY study. "That distinction is vital because it can help us identify who remains at higher risk for recurrence and who may not need more aggressive treatment. Our next step is to integrate these findings and examine how ctDNA, pathology and imaging can complement each other. The I-SPY trial provides a framework to optimize all of the information for the benefit of patients."

"The I-SPY 2 publication adds to a growing body of evidence supporting Signatera’s role in early breast cancer," said Minetta Liu, M.D., chief medical officer of oncology and early cancer detection at Natera. "Building on our previous studies, this work provides further validation that Signatera can improve risk assessment for therapy-resistant disease. We are grateful for our ongoing collaboration with the I-SPY investigators on research that brings us closer to more personalized and effective care for patients."

(Press release, Natera, DEC 16, 2025, View Source [SID1234661473])