Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer

N Engl J Med. 2013 Mar 28;368(13):1199-209. doi: 10.1056/NEJMoa1213261. Epub 2013 Mar 13.

Abstract

Background: The management of metastatic breast cancer requires monitoring of the tumor burden to determine the response to treatment, and improved biomarkers are needed. Biomarkers such as cancer antigen 15-3 (CA 15-3) and circulating tumor cells have been widely studied. However, circulating cell-free DNA carrying tumor-specific alterations (circulating tumor DNA) has not been extensively investigated or compared with other circulating biomarkers in breast cancer.

Methods: We compared the radiographic imaging of tumors with the assay of circulating tumor DNA, CA 15-3, and circulating tumor cells in 30 women with metastatic breast cancer who were receiving systemic therapy. We used targeted or whole-genome sequencing to identify somatic genomic alterations and designed personalized assays to quantify circulating tumor DNA in serially collected plasma specimens. CA 15-3 levels and numbers of circulating tumor cells were measured at identical time points.

Results: Circulating tumor DNA was successfully detected in 29 of the 30 women (97%) in whom somatic genomic alterations were identified; CA 15-3 and circulating tumor cells were detected in 21 of 27 women (78%) and 26 of 30 women (87%), respectively. Circulating tumor DNA levels showed a greater dynamic range, and greater correlation with changes in tumor burden, than did CA 15-3 or circulating tumor cells. Among the measures tested, circulating tumor DNA provided the earliest measure of treatment response in 10 of 19 women (53%).

Conclusions: This proof-of-concept analysis showed that circulating tumor DNA is an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer. (Funded by Cancer Research UK and others.).

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / blood*
  • Breast Neoplasms / blood
  • Breast Neoplasms / genetics
  • Breast Neoplasms / secondary*
  • DNA, Neoplasm / blood*
  • Female
  • Genome-Wide Association Study
  • Humans
  • Mucin-1 / blood*
  • Mutation
  • Neoplasm Metastasis / diagnosis*
  • Neoplasm Metastasis / diagnostic imaging
  • Neoplasm Metastasis / genetics
  • Prognosis
  • Radiography
  • Sensitivity and Specificity
  • Sequence Analysis, DNA / methods
  • Tumor Burden

Substances

  • Biomarkers, Tumor
  • DNA, Neoplasm
  • Mucin-1