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Circulating tumor DNA refines risk stratification of neoadjuvant therapy-resistant breast tumors

Author

Listed:
  • Mark Jesus M. Magbanua

    (University of California San Francisco, Department of Laboratory Medicine)

  • Nayelis A. Manon

    (University of California San Francisco, Department of Laboratory Medicine)

  • Denise M. Wolf

    (University of California San Francisco, Department of Laboratory Medicine)

  • Samuel Rivero-Hinojosa

    (Natera Inc.)

  • Ziad Ahmed

    (University of California San Francisco, Department of Laboratory Medicine)

  • Rosalyn W. Sayaman

    (University of California San Francisco, Department of Laboratory Medicine)

  • Antony Tin

    (Natera Inc.)

  • Derrick Renner

    (Natera Inc.)

  • Ekaterina Kalashnikova

    (Natera Inc.)

  • Lamorna Brown-Swigart

    (University of California San Francisco, Department of Laboratory Medicine)

  • Gillian L. Hirst

    (University of California San Francisco, Department of Surgery)

  • Christina Yau

    (University of California San Francisco, Department of Surgery)

  • Wen Li

    (University of California San Francisco, Department of Radiology)

  • Claudine Isaacs

    (Georgetown University Medical Center, Lombardi Comprehensive Cancer Center)

  • Rebecca A. Shatsky

    (University of California San Diego, Department of Medicine)

  • Amy S. Clark

    (University of Pennsylvania, Division of Hematology/Oncology)

  • Alexandra Zimmer

    (Oregon Health and Science University, Division of Hematology/Oncology)

  • Amy L. Delson

    (University of California San Francisco, Breast Science Advocacy Core)

  • Angel Rodriguez

    (Natera Inc.)

  • Minetta C. Liu

    (Natera Inc.)

  • Paula R. Pohlmann

    (University of Texas MD Anderson Cancer Center, Department of Breast Medical Oncology)

  • Laura J. Esserman

    (University of California San Francisco, Department of Surgery)

  • Hope S. Rugo

    (University of California San Francisco, Division of Hematology/Oncology)

  • Angela DeMichele

    (University of Pennsylvania, Division of Hematology/Oncology)

  • Laura van ‘t Veer

    (University of California San Francisco, Department of Laboratory Medicine)

Abstract

Early-stage breast cancers resistant to neoadjuvant therapy (NAT), characterized by high residual cancer burden (RCB) after treatment, have an increased risk of metastatic recurrence. Here, we show that circulating tumor DNA (ctDNA) detected using a tumor-informed test (1) can improve risk stratification of patients with NAT-resistant tumors (RCB-II/RCB-III) and (2) predict response to NAT. Stratification using ctDNA status at pretreatment or post-NAT and ctDNA dynamics identified NAT-resistant tumors with a significantly decreased risk of metastatic recurrence. ctDNA clearance as early as week 3 across receptor subtypes predicted favorable responses to NAT, including immunotherapies. Interestingly, less than a fifth of patients with NAT-resistant tumors were ctDNA-positive post-NAT. Serial mutation profiling of NAT-resistant tumors revealed that patient-specific ctDNA assay variants remained detectable over time, including in tumors of patients ctDNA-negative post-NAT. Refining risk stratification for NAT-resistant tumors using ctDNA and understanding ctDNA shedding in these tumors could guide treatment decisions to prevent or delay metastatic recurrence.

Suggested Citation

  • Mark Jesus M. Magbanua & Nayelis A. Manon & Denise M. Wolf & Samuel Rivero-Hinojosa & Ziad Ahmed & Rosalyn W. Sayaman & Antony Tin & Derrick Renner & Ekaterina Kalashnikova & Lamorna Brown-Swigart & G, 2025. "Circulating tumor DNA refines risk stratification of neoadjuvant therapy-resistant breast tumors," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65432-5
    DOI: 10.1038/s41467-025-65432-5
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