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Peer-reviewedCC BYNature communications

Actionable genetic landscape and dynamics in circulating DNA from 12,827 patients with metastatic breast cancer.

  • Ignaty Leshchiner1,2
  • Arielle J Medford1,3,4,5
  • Justin Cha1
  • Lesli A Kiedrowski6
  • Andrzej Niemierko5,7
  • Jennifer C Keenan5
  • Charles S Dai3,4,5
  • Laura M Spring3,4,5
  • Beverly Moy3,4,5
  • Seth A Wander3,4,5
  • Neelima Vidula3,4,5
  • Steven J Isakoff3,4,5
13 more authors
  • Dejan Juric3,4,5
  • Mendy Miller1
  • Andrew A Davis8
  • Lorenzo Gerratana9,10
  • Ami Shah11
  • Ben H Park12
  • Adam Brufsky13
  • Joyce O'Shaughnessy14
  • Rebecca J Nagy6
  • Leif W Ellisen3,4,5
  • Massimo Cristofanilli15
  • Aditya Bardia16
  • Gad Getz17,18,19,20
20 affiliations
  1. 1Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  2. 2Department of Medicine, Boston University, Boston, MA, USA.
  3. 3Harvard Medical School, Boston, MA, USA.
  4. 4Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  5. 5Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
  6. 6Guardant Health, Palo Alto, CA, USA.
  7. 7Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.
  8. 8Washington University in St Louis, St Louis, MO, USA.
  9. 9Department of Medicine, University of Udine, Udine, Italy.
  10. 10Department of Medical Oncology, CRO di Aviano, National Cancer Institute, IRCCS, Aviano, Italy.
  11. 11Northwestern University, Chicago, IL, USA.
  12. 12Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
  13. 13University of Pittsburgh, Pittsburgh, PA, USA.
  14. 14Baylor University Medical Center, Texas Oncology, Dallas, TX, USA.
  15. 15Weill Cornell Medicine, New York, NY, USA.
  16. 16UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. [email protected].
  17. 17Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
  18. 18Harvard Medical School, Boston, MA, USA. [email protected].
  19. 19Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. [email protected].
  20. 20Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. [email protected].
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Abstract

Plasma cell-free DNA (cfDNA) is a sensitive, noninvasive tool for monitoring the genomic landscape, heterogeneity, and evolution of cancer, aggregating genetic information from multiple metastatic sites. Here, we study 15,564 cfDNA samples from 12,827 patients with metastatic breast cancer (MBC). We classify samples, deep-sequenced with Guardant360, into MBC subtypes using our trained random forest model. Most patients have variants associated with therapeutic resistance and targetability of approved and experimental therapies, including in PIK3CA, ESR1, PTEN, and AKT1. Frequencies of multiple actionable alterations differed from primary disease, and multiple variants per gene suggest independent resistant clones. The large cohort size enables uncovering clonal co-behaviors, including co-existence and exclusivity of alleles and correlation of allele fractions. cfDNA testing is now recommended in multiple advanced malignancies, including eligibility assessment for clinical trials. We envision this large collection of MBC cfDNA data as an invaluable resource for the design and planning of future clinical trials.

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Cite

BibTeXRIS
BibTeX
@article{leshchiner2026actionable,
  title = {{Actionable genetic landscape and dynamics in circulating DNA from 12,827 patients with metastatic breast cancer.}},
  author = {Ignaty Leshchiner and Arielle J Medford and Justin Cha and Lesli A Kiedrowski and Andrzej Niemierko and Jennifer C Keenan and Charles S Dai and Laura M Spring and Beverly Moy and Seth A Wander and Neelima Vidula and Steven J Isakoff and Dejan Juric and Mendy Miller and Andrew A Davis and Lorenzo Gerratana and Ami Shah and Ben H Park and Adam Brufsky and Joyce O'Shaughnessy and Rebecca J Nagy and Leif W Ellisen and Massimo Cristofanilli and Aditya Bardia and Gad Getz},
  journal = {Nature communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-75976-9},
  url = {https://europepmc.org/article/MED/42907427},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Actionable genetic landscape and dynamics in circulating DNA from 12,827 patients with metastatic breast cancer.
AU  - Ignaty Leshchiner
AU  - Arielle J Medford
AU  - Justin Cha
AU  - Lesli A Kiedrowski
AU  - Andrzej Niemierko
AU  - Jennifer C Keenan
AU  - Charles S Dai
AU  - Laura M Spring
AU  - Beverly Moy
AU  - Seth A Wander
AU  - Neelima Vidula
AU  - Steven J Isakoff
AU  - Dejan Juric
AU  - Mendy Miller
AU  - Andrew A Davis
AU  - Lorenzo Gerratana
AU  - Ami Shah
AU  - Ben H Park
AU  - Adam Brufsky
AU  - Joyce O'Shaughnessy
AU  - Rebecca J Nagy
AU  - Leif W Ellisen
AU  - Massimo Cristofanilli
AU  - Aditya Bardia
AU  - Gad Getz
PY  - 2026
DA  - 2026/09/22
JO  - Nature communications
DO  - 10.1038/s41467-026-75976-9
UR  - https://europepmc.org/article/MED/42907427
AB  - Plasma cell-free DNA (cfDNA) is a sensitive, noninvasive tool for monitoring the genomic landscape, heterogeneity, and evolution of cancer, aggregating genetic information from multiple metastatic sites. Here, we study 15,564 cfDNA samples from 12,827 patients with metastatic breast cancer (MBC). We classify samples, deep-sequenced with Guardant360, into MBC subtypes using our trained random forest model. Most patients have variants associated with therapeutic resistance and targetability of approved and experimental therapies, including in PIK3CA, ESR1, PTEN, and AKT1. Frequencies of multiple actionable alterations differed from primary disease, and multiple variants per gene suggest independent resistant clones. The large cohort size enables uncovering clonal co-behaviors, including co-existence and exclusivity of alleles and correlation of allele fractions. cfDNA testing is now recommended in multiple advanced malignancies, including eligibility assessment for clinical trials. We envision this large collection of MBC cfDNA data as an invaluable resource for the design and planning of future clinical trials.
SN  - 2041-1723
ER  -