Natera, Inc. will present groundbreaking data from the I-SPY 2 clinical trial at the upcoming 2025 ESMO Breast Cancer Annual Congress in Munich, Germany, demonstrating the predictive power of its Signatera circulating tumor DNA (ctDNA) test in early-stage, high-risk breast cancer patients.
The study, which included 712 patients with early-stage, high-risk breast cancer, evaluated the association between distant recurrence-free survival (DRFS) and ctDNA concentration at diagnosis, before patients received neoadjuvant systemic therapy and curative-intent surgery.
Key Findings from the I-SPY 2 Trial
The data revealed that patients who tested Signatera-positive at diagnosis had a threefold higher risk of recurrence compared to Signatera-negative patients (HR 3.1, p< 0.001%). Importantly, this risk could be significantly reduced based on response to subsequent therapy.
Among patients who were Signatera-positive at diagnosis, higher ctDNA quantities at the time of diagnosis were significantly correlated with a higher risk of recurrence. However, effective treatment can affect ctDNA levels as well as pathologic response status, both of which further refine risk of recurrence.
This represents the first time that pre-treatment absolute ctDNA quantity has been shown to correlate with clinical outcomes in breast cancer. A multivariate analysis identified Signatera status as the most significant factor in predicting DRFS among all clinicopathologic risk factors available at diagnosis, regardless of disease subtype (p<0.001).
"The I-SPY 2 trial is uncovering insights that may allow us to tailor treatment plans for breast cancer patients based on their individual genomic profiles and better identify patients who may be more likely to experience adverse outcomes," said Laura Esserman, M.D., MBA, and Laura van 't Veer, Ph.D., professors at the University of California, San Francisco, and principal investigators of the I-SPY 2 study.
Clinical Implications
The findings suggest potential new approaches to breast cancer treatment stratification. Angel Rodriguez, M.D., medical director of oncology at Natera, noted, "Signatera was able to predict excellent clinical outcomes in a high risk population at the time of diagnosis. This may give rise to new protocols, evaluating whether some patients can avoid chemotherapy or other intensive treatments, if they test Signatera-negative at diagnosis."
This could represent a significant advancement in personalized medicine for breast cancer patients, potentially sparing some patients from unnecessary treatment toxicity while ensuring those at highest risk receive appropriate therapy.
Additional Research Presentations
Natera will present an additional six abstracts at the ESMO Breast conference, highlighting real-world evidence and genomic landscaping from its multi-modal database of de-identified clinical and genomic data in over 200,000 early- and late-stage cancer patients.
These presentations include studies on:
- Real-world testing patterns of ctDNA in early-stage triple-negative breast cancer
- Longitudinal ctDNA monitoring in patients with early-stage triple-negative breast cancer
- De-escalation of medical therapies in HER2-positive metastatic breast cancer with undetectable minimal residual disease
- The influence of genetic ancestry and tumor mutations on ctDNA detection rates in breast cancer
- Assessment of antibody-drug conjugate utilization in patients with breast cancer undergoing ctDNA testing
About Signatera Technology
Signatera is a personalized, tumor-informed, molecular residual disease test for patients previously diagnosed with cancer. The test is custom-built for each individual patient and uses circulating tumor DNA to detect and quantify cancer left in the body, identify recurrence earlier than standard of care tools, and help optimize treatment decisions.
The technology has been clinically validated across multiple cancer types and indications, with published evidence in more than 100 peer-reviewed papers. It has coverage by Medicare across a broad range of indications, making it increasingly accessible to patients.
Future Directions
The investigators hope these findings will encourage future interventional trials in breast cancer, specifically in the neoadjuvant setting. The ability to predict recurrence risk at diagnosis could fundamentally change how breast cancer is treated, potentially leading to more personalized treatment approaches that balance efficacy with quality of life considerations.
As precision medicine continues to evolve in oncology, tools like Signatera that provide molecular insights into individual cancer biology may increasingly guide treatment decisions, moving beyond traditional clinicopathologic factors to more nuanced, personalized risk assessment and treatment planning.
The full presentation of the I-SPY 2 trial data will take place on May 16, 2025, at the ESMO Breast Cancer Annual Congress, with Mark Magbanua, Ph.D., from UCSF Helen Diller Family Comprehensive Cancer Center presenting the findings.
