Blood-Based Circulating DNA Testing Maps Metastatic Breast Cancer
Publication Title: Actionable genetic landscape and dynamics in circulating DNA from 12,827 patients with metastatic breast cancer
Summary
- Question
- This study examined the genetic makeup of metastatic breast cancer—cancer that has spread beyond the breast to other parts of the body—using cell-free DNA (cfDNA), fragments of tumor DNA that circulate in the bloodstream. The researchers analyzed blood samples from 12,827 patients to map which genetic mutations were present, how those mutations changed over time, and which were linked to resistance to treatment.
- Why it Matters
- Understanding the genetic landscape of metastatic breast cancer is critical for matching patients to targeted therapies—treatments designed to attack cancer cells carrying specific mutations. Traditional tissue biopsies capture only one tumor site and can miss mutations that arise under treatment pressure. Blood-based cfDNA testing samples DNA shed from multiple tumor sites simultaneously, offering a more complete picture. This dataset—the largest publicly available cfDNA cohort in metastatic breast cancer to date—provides a resource to guide the design of future clinical trials and inform treatment decisions.
- Methods
- The researchers analyzed 15,564 cfDNA blood samples from 12,827 patients with metastatic breast cancer collected between 2016 and 2020. A targeted sequencing panel covering 74 clinically relevant genes identified mutations in each sample. Because most patients lacked clinical records of breast cancer subtype—estrogen receptor-positive, HER2-positive, or triple-negative—the researchers developed a machine-learning classifier to predict subtype from genomic data. A subset of 83 patients treated with selective estrogen receptor degraders (SERDs), drugs that break down a protein driving breast cancer growth, at one institution was analyzed for survival outcomes.
- Key Findings
- Sixty-four percent of all patients had at least one mutation qualifying as actionable under established clinical criteria, meaning a targeted therapy exists for that mutation. Among patients with estrogen receptor-positive disease, 85% had such mutations, compared with 60% of HER2-positive patients and 35% of triple-negative patients. In patients receiving SERD therapy, those with co-occurring resistance mutations had a median progression-free survival—the time before cancer worsened—of 3.6 months, compared with 15.4 months in those without resistance mutations.
- Implications
- These findings suggest that co-occurring resistance mutations substantially limit the effectiveness of targeted therapies used alone and that serial cfDNA testing—repeat blood draws over time—can detect newly emerging resistance mutations before clinical progression. The publicly released dataset may help clinical trial investigators estimate how many patients carry specific targetable mutations and anticipate resistance mechanisms that could undermine trial outcomes.
- Next Steps
- The authors note that this dataset can serve as a resource for planning genomically targeted clinical trials, estimating eligible patient populations based on genomic inclusion criteria, and identifying resistance mechanisms. They highlight the need to develop targeted therapies for HER2-positive and triple-negative subtypes, which had far fewer actionable mutations under current approvals. They also suggest that future studies, such as metabolomic analyses, could help explain the co-occurrence patterns of specific mutations observed in advanced disease.
- Funding Information
- This research was supported by the National Institutes of Health (K12 grant K12CA087723) and the American Cancer Society (IRG-21-130-10). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support was provided by the Dahod Breast Cancer Research Grant, the Grunebaum Faculty Research Fellowship, and the Paul C. Zamecnick, MD, Chair in Oncology at MGH. Yale University also provided funding and support for this research.
Full Citation
Leshchiner I, Medford AJ, Cha J, Kiedrowski LA, Niemierko A, Keenan JC, Dai CS, Spring LM, Moy B, Wander SA, Vidula N, Isakoff SJ, Juric D, Miller M, Davis AA, Gerratana L, Shah A, Park BH, Brufsky A, O’Shaughnessy J, Nagy RJ, Ellisen LW, Cristofanilli M, Bardia A, Getz G. Actionable genetic landscape and dynamics in circulating DNA from 12,827 patients with metastatic breast cancer. Nature Communications 2026 DOI: 10.1038/s41467-026-75976-9.
Authors
Ignaty Leshchiner
First Author