Plasma DNA as a “liquid biopsy” incompletely complements tumor biopsy for identification of mutations in a case series of four patients with oligometastatic breast cancer



Circulating tumor DNA in plasma may present a minimally invasive opportunity to identify tumor-derived mutations to inform selection of targeted therapies for individual patients, particularly in cases of oligometastatic disease where biopsy of multiple tumors is impractical. To assess the utility of plasma DNA as a “liquid biopsy” for precision oncology, we tested whether sequencing of plasma DNA is a reliable surrogate for sequencing of tumor DNA to identify targetable genetic alterations.


Blood and biopsies of 1–3 tumors were obtained from 4 evaluable patients with advanced breast cancer. One patient provided samples from an additional 7 tumors post-mortem. DNA extracted from plasma, tumor tissues, and buffy coat of blood were used for probe-directed capture of all exons in 149 cancer-related genes and massively parallel sequencing. Somatic mutations in DNA from plasma and tumors were identified by comparison to buffy coat DNA.


Sequencing of plasma DNA identified 27.94 ± 11.81% (mean ± SD) of mutations detected in a tumor(s) from the same patient; such mutations tended to be present at high allelic frequency. The majority of mutations found in plasma DNA were not found in tumor samples. Mutations were also found in plasma that matched clinically undetectable tumors found post-mortem.


The incomplete overlap of genetic alteration profiles of plasma and tumors warrants caution in the sole reliance of plasma DNA to identify therapeutically targetable alterations in patients and indicates that analysis of plasma DNA complements, but does not replace, tumor DNA profiling.

Trial Registration: Subjects were prospectively enrolled in trial NCT01836640 (registered April 22, 2013).

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Allelic frequency


Cell-free circulating tumor DNA


Formalin-fixed and paraffin-embedded


Genome Analysis Toolkit




Positron emission tomography


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We are grateful to the patients who participated in this study and their family members who supported them. We thank the Norris Cotton Cancer Center Genomics and Pathology Shared Resources for assistance.


This study was funded by Norris Cotton Cancer Center (Hopeman Foundation Pilot Grant to MDC and TWM), and the NIH (F30CA216966 to KS; R01CA200994 and R01CA211869 to TWM; Dartmouth College Norris Cotton Cancer Center Support Grant P30CA023108).

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Correspondence to Mary D. Chamberlin or Todd W. Miller.

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Chamberlin, M.D., Wells, J.D., Shee, K. et al. Plasma DNA as a “liquid biopsy” incompletely complements tumor biopsy for identification of mutations in a case series of four patients with oligometastatic breast cancer. Breast Cancer Res Treat 182, 665–677 (2020).

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  • Circulating tumor DNA
  • Advanced breast cancer
  • DNA sequencing
  • Cell-free DNA