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<p>Metastatic breast cancer (MBC) remains an incurable disease with a 5-year overall survival below 25%. Metastases often emerge from subclinical, disseminated tumor cells that persist after primary therapy, referred to as minimal residual disease (MRD). Detecting MRD is critical for identifying patients at high risk of recurrence and enabling timely intervention. We constructed MammaTrace, a plasma-only, tumor-naive cfDNA methylation assay for MRD surveillance in breast cancer. Candidate differentially methylated regions (DMRs) associated with metastasis and recurrence were identified directly from plasma cfDNA using whole genome bisulfite sequencing (WGBS) of MBC, healthy controls, and treatment-naive patients with stage I–III breast cancer who either developed recurrence or remained disease-free. These DMRs were incorporated into a targeted capture panel and used to train a binary classification model. The assay was evaluated in an independent longitudinal cohort of 107 early-stage breast cancer (EBC) patients treated with curative intent, with serial plasma samples collected prior to recurrence. MammaTrace demonstrated strong performance in distinguishing MBC from healthy samples, achieving a ROC AUC of 0.96. For MRD detection in EBC samples collected more than 9 months after surgery, MammaTrace achieved a sensitivity of 91% and specificity of 83% (AUC = 0.88). A positive MammaTrace score preceded clinically confirmed recurrence by a median of 457 days, providing substantial lead time for therapeutic intervention. MammaTrace enables detection of MRD in breast cancer patients, providing substantial lead time prior to clinical recurrence. This approach may improve risk stratification and support earlier therapeutic intervention to delay or prevent metastatic progression.</p>

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MammaTrace – a tumor naïve cell-free DNA methylation test for minimal residual disease in breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月23日

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  • David N. Buckley,
  • Alex J. Kalfa,
  • Gerald Gooden,
  • Juan Pablo Lewinger,
  • Marissa Pacheco,
  • Jessica Gayton,
  • Darcy Spicer,
  • John Carpten,
  • Daphne Stewart,
  • Heinz-Josef Lenz,
  • Chanita Hughes Halbert,
  • Caryn Lerman,
  • Joyce O’Shaughnessy,
  • Barbara Pockaj,
  • Bodour Salhia

摘要

Metastatic breast cancer (MBC) remains an incurable disease with a 5-year overall survival below 25%. Metastases often emerge from subclinical, disseminated tumor cells that persist after primary therapy, referred to as minimal residual disease (MRD). Detecting MRD is critical for identifying patients at high risk of recurrence and enabling timely intervention. We constructed MammaTrace, a plasma-only, tumor-naive cfDNA methylation assay for MRD surveillance in breast cancer. Candidate differentially methylated regions (DMRs) associated with metastasis and recurrence were identified directly from plasma cfDNA using whole genome bisulfite sequencing (WGBS) of MBC, healthy controls, and treatment-naive patients with stage I–III breast cancer who either developed recurrence or remained disease-free. These DMRs were incorporated into a targeted capture panel and used to train a binary classification model. The assay was evaluated in an independent longitudinal cohort of 107 early-stage breast cancer (EBC) patients treated with curative intent, with serial plasma samples collected prior to recurrence. MammaTrace demonstrated strong performance in distinguishing MBC from healthy samples, achieving a ROC AUC of 0.96. For MRD detection in EBC samples collected more than 9 months after surgery, MammaTrace achieved a sensitivity of 91% and specificity of 83% (AUC = 0.88). A positive MammaTrace score preceded clinically confirmed recurrence by a median of 457 days, providing substantial lead time for therapeutic intervention. MammaTrace enables detection of MRD in breast cancer patients, providing substantial lead time prior to clinical recurrence. This approach may improve risk stratification and support earlier therapeutic intervention to delay or prevent metastatic progression.