Natera, Inc., a leading company in cell-free DNA and precision medicine, announced in collaboration with Quantum Leap Healthcare Collaborative that new findings from the I-SPY 2 trial have been published in Nature Communications. The study focused on the use of Signatera to better assess recurrence risk in patients with early-stage breast cancer whose tumors show resistance to neoadjuvant therapy. These therapy-resistant cancers can leave significant residual disease and carry a higher risk of metastasis, although only a minority of cases recur within three years. Identifying which patients are most likely to experience recurrence could guide more tailored treatment decisions and potentially prevent disease progression.

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The study included 723 women with high-risk early-stage breast cancer undergoing neoadjuvant therapy. Researchers measured personalized circulating tumor DNA using Signatera at four time points: before treatment, after three weeks of paclitaxel with or without investigational agents, between paclitaxel and anthracycline regimens, and after completing therapy. Key results revealed that Signatera improved risk prediction beyond residual cancer burden alone for patients with higher residual disease. Patients who tested negative for Signatera at any point showed significantly lower risk of metastasis. For instance, among patients with RCB-II disease, those who were Signatera-negative after therapy had a three-year distant recurrence-free survival of 88 percent compared to 57 percent in Signatera-positive patients. For RCB-III patients, the difference was even more pronounced with 83 percent versus 22 percent. Persistent Signatera positivity after therapy strongly predicted metastatic recurrence, highlighting its role as an independent prognostic marker.

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Early clearance of ctDNA after three weeks of therapy was associated with favorable responses, including treatments involving immune checkpoint inhibitors and HER2-targeted regimens. The assay demonstrated high stability over time, with a median conservation rate of 94 to 97 percent, confirming that the personalized variants remained reliable even as tumors evolved.

Laura Esserman, M.D., MBA, and Laura van ‘t Veer, Ph.D., professors at UCSF and principal investigators of the I-SPY study, stated that the findings allow clinicians to distinguish which therapy-resistant tumors are likely to recur and which are not. This distinction is crucial for guiding treatment intensity and preventing unnecessary aggressive interventions. They emphasized that integrating ctDNA results with pathology and imaging could further optimize patient care.

Minetta Liu, M.D., chief medical officer of oncology and early cancer detection at Natera, said that the I-SPY 2 publication strengthens the evidence for Signatera’s role in early-stage breast cancer. She highlighted that the study validates Signatera’s ability to refine risk assessment for therapy-resistant tumors and underlined the value of ongoing collaboration with I-SPY investigators to advance personalized care strategies that improve patient outcomes.

This study reinforces Signatera as a dynamic biomarker that can inform real-time treatment decisions, guide therapy selection, and identify patients who may safely avoid more aggressive interventions, marking an important step toward precision medicine in breast cancer.

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