Cell-free circulating tumour DNA as a liquid biopsy in breast cancer

Abstract

Recent developments in massively parallel sequencing and digital genomic techniques support the clinical validity of cell-free circulating tumour DNA (ctDNA) as a 'liquid biopsy' in human cancer. In breast cancer, ctDNA detected in plasma can be used to non-invasively scan tumour genomes and quantify tumour burden. The applications for ctDNA in plasma include identifying actionable genomic alterations, monitoring treatment responses, unravelling therapeutic resistance, and potentially detecting disease progression before clinical and radiological confirmation. ctDNA may be used to characterise tumour heterogeneity and metastasis-specific mutations providing information to adapt the therapeutic management of patients. In this article, we review the current status of ctDNA as a 'liquid biopsy' in breast cancer.

Keywords: Breast cancer; Circulating cell-free tumour DNA; Heterogeneity; Monitoring; Resistance; Stratification.

Figure 1

Schematic for assessing plasma cell‐free circulating tumour DNA (ctDNA) and tumour tissue biopsies using massively parallel sequencing and digital genomic technologies. Note that for digital PCR it is essential to know a priori the genomic alteration to be targeted. WGS, whole genome sequencing, WES, whole exome sequencing, TS, targeted sequencing.

Figure 2

The roles of cell‐free circulating tumour DNA (ctDNA) in breast cancers. A. Genomic stratification of patients; B. Monitoring of tumour burden and mechanisms of therapeutic resistance; C. Early detection of recurrence; D. Deciphering intra‐ and inter‐tumour heterogeneity. Clonal and subclonal events are depicted in both the x‐axis and y‐axis for primary tumour and metastasis. The red circle represents clonal events in both the primary tumour and metastasis.

Figure 3

Longitudinal monitoring of cell‐free circulating tumour DNA (ctDNA) derived from plasma. Detection of early relapse or progression as compare to imaging methods, and the emergence of genomic events associated with therapeutic resistance to chemotherapeutics and targeted therapy. The genomic alterations revealed by ctDNA can anticipate the development of clinical or radiologic relapse or progression in early‐stage and advanced‐stage breast cancers.

Figure 4

Clonal hierarchy of mutations captured by plasma ctDNA. A. Schematic representation of a metastatic breast cancer patient subjected to multisampling during warm autopsy. B. Illustrative heatmap showing non‐synonymous mutations in metastatic deposits (M1‐8) and plasma ctDNA. C. Diagram depicting that ubiquitous and clade mutations are more likely to be detected in plasma ctDNA than private mutations.