Signatera ctDNA Assessment Reveals Sharp Recurrence Risk Stratification in Advanced HR+/HER2- Breast Cancer

Molecular residual disease (MRD) detection has emerged as a critical prognostic indicator for early-stage breast cancer management. Recent findings from Natera’s Phase III PALLAS trial, presented at the San Antonio Breast Cancer Symposium, demonstrate compelling evidence that MRD status—measured via Signatera genome sequencing—fundamentally reshapes how clinicians should assess recurrence risk in stage II-III HR+/HER2- breast cancer patients receiving combination endocrine and targeted therapy.

The Clinical Paradox: MRD Negativity Quotes Strong Protection, Positivity Signals Danger

The trial’s biomarker analysis from 420 U.S. patients reveals a striking stratification pattern. Approximately 92% of patients achieved MRD-negative status at baseline (before or early in palbociclib and endocrine therapy initiation), and these individuals experienced a five-year distant recurrence-free interval (DRFI) of 93%. This negativity quotes a remarkably low recurrence rate—substantially outperforming traditional risk stratification alone.

The inverse finding proves equally striking: the 8% of patients who were MRD-positive at baseline faced dramatically elevated risk, with a five-year DRFI plummeting to just 28%. This represents a hazard ratio of approximately 15 compared to MRD-negative counterparts, indicating that baseline MRD positivity is an extraordinarily powerful predictor of distant metastatic disease.

Sustained MRD Negativity Reinforces Long-Term Protection

By end-of-treatment (EOT) assessment after two years of palbociclib combination therapy with endocrine management, MRD-negative patients achieved a five-year DRFI of 95%—an improvement from baseline, suggesting that sustained negativity quotes increasing clinical confidence. Meanwhile, MRD-positive patients at EOT demonstrated a five-year DRFI of only 32%, with hazard ratios exceeding 20 relative to MRD-negative patients.

This risk separation far surpasses what traditional clinicopathologic features provide in isolation. Across all measurement timepoints—baseline, mid-treatment (approximately six months, labeled C6D1), and EOT—Signatera ctDNA status maintained consistent and robust association with recurrence outcomes, even after statistical adjustment for conventional prognostic variables.

Clinical Implementation: Personalizing Post-Surgical Breast Cancer Strategy

The PALLAS trial enrolled patients with stage II-III HR+/HER2- breast cancer randomized to receive two years of palbociclib (a CDK4/6 inhibitor) combined with endocrine therapy. MRD assessments via Signatera were conducted at three standardized post-operative points, creating a longitudinal risk profile for each patient.

These translational findings support an integrative approach: incorporating MRD testing into routine post-surgical risk assessment workflows enables more granular patient stratification. MRD-negative status—particularly when sustained throughout treatment—offers strong prognostic reassurance and potential opportunity for therapy de-escalation discussions. Conversely, MRD positivity, with hazard ratios ranging from 13.4 to 21.5 across timepoints, identifies a cohort requiring intensified surveillance or treatment intensification strategies.

Data from parallel international cohorts remain under analysis and will be reported subsequently, potentially extending these findings’ applicability across diverse healthcare settings and populations.

The ability to translate these MRD insights into clinical practice represents a meaningful step toward personalized early-stage breast cancer management, moving beyond one-size-fits-all adjuvant strategies toward molecularly informed decision-making.