Circulating Cell-Free DNA Reflects the Clonal Evolution of Breast Cancer Tumors

Simple Summary Liquid biopsy of cell-free DNA (cfDNA) is proposed as potential method for the early detection of breast cancer (BC) metastases and following the clonal evolution of BC. Though the use of liquid biopsy is widely discussed, only few studies have demonstrated such usage so far. The aim of this study was to evaluate how accurately cfDNA resembles the genetic profile of tumor DNA and how liquid biopsy reflects the clonal evolution of 18 Eastern-Finnish BC cases with locoregional or distant metastases. Although notable discordance between the sequenced cfDNA and tumor DNA was observed, our results show that liquid biopsy reflects the heterogeneity and clonal evolution of BC and may help to identify potential driver variants and therapeutic targets that are not detected with the sequencing of tumor DNA. This information may be used to detect metastatic BC earlier and to support decision-making in clinical practice. Liquid biopsy of cell-free DNA (cfDNA) is proposed as a potential method for the early detection of breast cancer (BC) metastases and following the clonal evolution of BC. Though the use of liquid biopsy is a widely discussed topic in the field, only a few studies have demonstrated such usage so far. We sequenced the DNA of matched primary tumor and metastatic sites together with the matched cfDNA samples from 18 Eastern Finnish BC patients and investigated how well cfDNA reflected the clonal evolution of BC interpreted from tumor DNA. On average, liquid biopsy detected 56.2 +/- 7.2% of the somatic variants that were present either in the matched primary tumor or metastatic sites. Despite the high discordance observed between matched samples, liquid biopsy was found to reflect the clonal evolution of BC and identify novel driver variants and therapeutic targets absent from the tumor DNA. Tumor-specific somatic variants were detected in cfDNA at the time of diagnosis and 8.4 +/- 2.4 months prior to detection of locoregional recurrence or distant metastases. Our results demonstrate that the sequencing of cfDNA may be used for the early detection of locoregional and distant BC metastases. Observed discordance between tumor DNA sequencing and liquid biopsy supports the parallel sequencing of cfDNA and tumor DNA to yield the most comprehensive overview for the genetic landscape of BC.

Automated summary

The study evaluated the concordance between cfDNA and tumor DNA genetic profiles, showing that liquid biopsy can reflect the heterogeneity and clonal evolution of BC, potentially identifying driver variants and therapeutic targets that may be missed in tumor DNA sequencing. Liquid biopsy may aid in the early detection of metastatic BC and support clinical decision-making, despite observed discordance between the two sources of DNA.