Natera Unveils First Translational Insights From Phase III PALLAS Trial, Demonstrating Strong Prognostic Power of Signatera MRD Testing in HR+/HER2- Breast Cancer
A global leader in cell-free DNA–based testing and precision oncology, has released the first translational research findings from the large international Phase III PALLAS study. Conducted in collaboration with Alliance Foundation Trials, LLC (AFT) and the Austrian Breast and Colorectal Cancer Study Group (ABCSG), the early results focus on the prognostic role of molecular residual disease (MRD) detection using the Signatera Genome test in patients with stage II–III hormone receptor-positive, HER2-negative breast cancer.
The data were presented at the San Antonio Breast Cancer Symposium (SABCS) and derived from an initial U.S. biomarker cohort of 420 patients. According to the analysis, MRD status measured after surgery—and after adjuvant chemotherapy and/or radiation when given—showed a strong ability to predict distant recurrence risk. These results reinforce Natera’s strategy to make personalized MRD testing a routine component of post-surgical risk assessment for patients with early-stage HR+ breast cancer. Data from an ex-U.S. cohort, including insights by treatment subgroup, will be shared at a future date.
Study Overview
The PALLAS trial evaluated whether adding two years of palbociclib, a CDK4/6 inhibitor, to standard endocrine therapy could further reduce recurrence in patients with stage II–III HR+/HER2- breast cancer. As part of the translational research component (TransPALLAS), Signatera MRD testing was performed at three key timepoints:
- Baseline – after surgery, on the first day of protocol-directed therapy
- C6D1 – approximately six months after starting treatment
- EOT (End of Treatment) – after completion of two years of endocrine ± targeted therapy
The goal was to determine whether ctDNA-based MRD detection could reliably stratify recurrence risk and identify patients who might benefit from more individualized treatment strategies.
Key Findings
1. Signatera accurately identified patients with low recurrence risk
At baseline, roughly 92% of patients were MRD-negative. These individuals experienced excellent outcomes, with a five-year distant recurrence-free interval (DRFI) of 93%.
Patients who were MRD-negative at the end of treatment demonstrated an even stronger outlook, with a five-year DRFI of 95%. These results highlight that patients with no detectable ctDNA after surgery and adjuvant therapy have a very low chance of developing distant metastases.
2. MRD-positive patients showed high recurrence risk despite standard therapy
Only about 8% of patients were MRD-positive at baseline, yet this subgroup faced substantially worse outcomes. Their five-year DRFI was just 28%, corresponding to a hazard ratio of approximately 15 compared with MRD-negative patients.
The poor prognosis persisted at later timepoints: MRD-positive patients at the end of therapy had a five-year DRFI of 32%, and hazard ratios exceeded 20 versus MRD-negative patients. These findings show that the presence of ctDNA after surgery is a strong indicator of micrometastatic disease that is not addressed by current standard treatments.
3. Strong prognostic value across all post-operative timepoints
MRD status measured at baseline, six months, and at the end of treatment consistently correlated with recurrence outcomes. Across all timepoints, MRD-positive patients demonstrated hazard ratios between 13.4 and 21.5, even after adjusting for clinicopathologic features.
The risk separation achieved through ctDNA testing was substantially greater than what can be obtained with traditional factors (tumor size, lymph node involvement, grade), underscoring the powerful prognostic utility of personalized MRD monitoring.
Expert Commentary
Dr. Heather Parsons, M.D., MPH—first author and TransPALLAS investigator, and associate professor in the breast oncology program at Fred Hutch Cancer Center—emphasized the significance of the findings.
ctDNA has emerged as one of the most promising biomarkers in early-stage breast cancer,” she explained. “The TransPALLAS collaboration provides a uniquely powerful opportunity to evaluate ctDNA in the adjuvant setting. These results help advance our understanding of recurrence risk for patients with HR+/HER2- disease.”
Dr. Minetta Liu, M.D., chief medical officer of oncology and early cancer detection at Natera, highlighted the implications for clinical practice.
These results support Natera’s vision for individualized management of early-stage HR+/HER2- breast cancer,” she said. Longitudinal post-surgical ctDNA testing allows us to move beyond a one-size-fits-all approach. ctDNA-negative patients may be able to avoid unnecessary treatment and related toxicity, while ctDNA-positive patients can be prioritized for more intensive or innovative therapies. It represents a fundamental shift toward truly MRD-informed care.”
