Breakthrough in Breast Cancer Risk Prediction: Signatera MRD Testing Shows Dramatic Stratification Power in HR+/HER2- Disease

Natera Inc. (NTRA) has revealed compelling translational research findings from the PALLAS trial, presented at the San Antonio Breast Cancer Symposium. The study demonstrates that molecular residual disease (MRD) assessment—measured via the Signatera Genome test—is a powerful predictor of recurrence outcomes in stage II-III HR+/HER2- breast cancer patients.

The Clinical Challenge and Research Response

Early-stage HR+/HER2- breast cancer represents a heterogeneous patient population with widely variable outcomes despite receiving standard adjuvant therapy. Traditional clinical and pathological features alone have limited ability to identify which patients will experience distant recurrence. The PALLAS trial sought to evaluate whether circulating tumor DNA (ctDNA) detection could improve risk stratification in this population, with patients randomized to receive two years of palbociclib (a CDK4/6 inhibitor) combined with endocrine therapy.

Key Findings: Dramatic Risk Separation

Analysis of 420 U.S. biomarker cohort patients revealed striking differences between MRD-negative and MRD-positive individuals. Approximately 92% of patients showed MRD-negative status at baseline, with an exceptional five-year distant recurrence-free interval (DRFI) of 93%. This proportion remained favorable at end-of-treatment (EOT), where MRD-negative patients achieved a five-year DRFI of 95%.

The contrast was stark among the remaining 8% with baseline MRD positivity. These patients faced a five-year DRFI of just 28%—representing a hazard ratio of approximately 15 compared to MRD-negative counterparts. By treatment completion, MRD-positive individuals showed minimal improvement, with a five-year DRFI of 32% and hazard ratios exceeding 20 relative to the MRD-negative group.

Consistent Predictive Power Across Assessment Timepoints

The Signatera ctDNA status demonstrated remarkable consistency in predicting recurrence risk across all measurement windows—baseline, approximately six months on-treatment (C6D1), and EOT. Even after adjusting for conventional clinical and pathological prognostic factors, MRD-positive patients maintained hazard ratios spanning 13.4 to 21.5 compared with MRD-negative patients. This magnitude of risk separation substantially exceeds what is typically observed using clinicopathologic parameters alone.

Clinical Translation and Personalized Therapy

These findings support the integration of MRD testing into routine post-operative risk assessment protocols for early-stage HR+ breast cancer. By identifying the small subset of patients at genuinely high recurrence risk, clinicians can implement more targeted, personalized management strategies—potentially escalating interventions for MRD-positive individuals while sparing MRD-negative patients from unnecessary treatment intensification.

Data from the parallel cohort outside the U.S., along with detailed subgroup analyses, will be presented subsequently. For more information, visit my.natera.com.