Circulating tumor DNA refines risk stratification of neoadjuvant therapy-resistant breast tumors
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.
Authors
- Angela M. DeMichele (ORCID: https://orcid.org/0000-0003-1297-4251)
- Denise M. Wolf (ORCID: https://orcid.org/0000-0002-3676-653X)
- Laura van ‘t Veer (ORCID: https://orcid.org/0000-0002-9838-8298)
- Derrick Renner (ORCID: https://orcid.org/0000-0002-1349-8050)
- Paula Raffin Pohlmann (ORCID: https://orcid.org/0000-0001-7914-5162)
- Lamorna Brown Swigart (ORCID: https://orcid.org/0000-0003-2076-5177)
- Minetta C. Liu (ORCID: https://orcid.org/0000-0002-8206-5232)
- Samuel Rivero-Hinojosa (ORCID: https://orcid.org/0000-0002-3595-8273)
- Rebecca Shatsky (ORCID: https://orcid.org/0000-0003-2289-6234)
- Ekaterina Kalashnikova (ORCID: https://orcid.org/0000-0003-1078-0656)
- Amy L. Delson (ORCID: https://orcid.org/0000-0002-2837-3218)
- Christina Yau (ORCID: https://orcid.org/0000-0002-1937-0859)
- Amy S. Clark (ORCID: https://orcid.org/0000-0002-3685-6535)
- Mark Jesus M. Magbanua (ORCID: https://orcid.org/0000-0003-2113-3593)
- Claudine J. Isaacs (ORCID: https://orcid.org/0000-0002-9646-1260)
- Laura J. Esserman (ORCID: https://orcid.org/0000-0001-9202-4568)
- Rosalyn W. Sayaman (ORCID: https://orcid.org/0000-0003-1343-0619)
- Gillian L. Hirst (ORCID: https://orcid.org/0000-0002-4502-0035)
- Alexandra S. Zimmer (ORCID: https://orcid.org/0000-0001-6789-0982)
- Ziad Ahmed (ORCID: https://orcid.org/0000-0003-1379-5124)
- Hope S. Rugo (ORCID: https://orcid.org/0000-0001-6710-4814)
- Angel Rodriguez (ORCID: https://orcid.org/0000-0003-0735-3039)
- Wen Li (ORCID: https://orcid.org/0000-0001-6584-363X)
- Antony Tin (ORCID: https://orcid.org/0009-0007-1602-2123)
- Nayelis A. Manon
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Oregon Health & Science University (US)
- University of California, San Francisco (US)
- Georgetown University (US)
- Georgetown University Medical Center (US)
- University of California San Diego (US)
- Natera (United States) (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-09
- DOI
- https://doi.org/10.1038/s41467-025-65432-5
- Citations
- 1
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- Breast Cancer Research Foundation
- National Institutes of Health
- National Cancer Institute