Liquid biopsy: a new window on the BRCA genes

Abstract

The Breast Cancer Susceptibility Gene (BRCA)-associated tumors represent a constantly evolving and intriguing scenario in oncology, in which the availability of novel systemic treatment, mainly including the poly (ADP-ribose) polymerase (PARP) inhibitors, has enabled an improved survival benefit in clinical subgroups. The expanding regulatory approvals of PARP inhibitors have inevitably reshaped the clinical indications for BRCA testing, moving the BRCA1/2 profiling from the traditional and preventive workflows to therapeutic paths. Despite advances in technology and treatment, substantial limitations remain in current genetic and genomic tools for the detection of deleterious BRCA1/2 variants. Germline and tumor tissue testing provide only a snapshot of a patient’s disease, failing to capture the dynamic and longitudinal aspects of tumor clonal evolution. In this scenario, liquid biopsy (LB) profiling of BRCA1/2 genes, primarily as circulating tumor DNA, represents a highly active area of research potentially affecting many aspects of cancer screening, diagnosis, and monitoring in individuals who are carriers of BRCA1/2 deleterious variants. Beyond the attractive potential to surrogate the tumor tissue testing, to overcome the cancer spatial and temporal heterogeneity, and to monitor the tumor mutational profile over time, accurately detecting all clinically relevant BRCA genetic variants and epigenetic modifications using LB remains technically challenging.