The current standard for breast cancer screening (for non–high-risk patients) is an annual or semiannual mammogram for women aged 40 and older. 1 However, mammography-based screening can give false-positive or false-negative results. This can lead to excessive use of invasive tissue biopsies and unnecessary exposure to ionizing radiation—which can also become expensive and time-consuming for patients. 2
Both normal and cancerous cells shed cell-free DNA (cfDNA) into the blood circulation. 3 Circulating tumor DNA (ctDNA) are fragments of DNA derived from tumor cells that circulate in the blood together with cfDNA. The ctDNA originates directly from a tumor or from circulating tumor cells (and carries information from the tumor cell genome), whereas cfDNA enters the bloodstream after apoptosis or necrosis and carries genome-wide DNA information. The amount of ctDNA in the blood has been shown to be elevated in patients with cancer. 3 Different cancers release varying levels of ctDNA; the amount of ctDNA released depends on the number of tumor cells that are in senescence vs undergoing apoptosis. 4
The possibility of incorporating this biomarker obtained from a “liquid biopsy” is currently being studied and will hopefully become a standard of care for breast cancer screening and monitoring. The liquid biopsy detects ctDNA that has been released into the bloodstream from tumor regions and helps identify intratumoral heterogeneity and clonal evolution. 5 Additionally, sequencing tumor DNA has opened new possibilities for precision oncology. 6 Detection of somatic gene mutations, amplifications, and gene fusions helps to deliver targeted therapies. 6 Analysis of potential somatic mutations in ctDNA, in combination with cfDNA levels, can help capture clinically relevant information beyond single genetic alterations and tumor fraction, potentially improving the accuracy of early detection and screening for breast cancer.
Recent advances in ctDNA testing technology have made it more accurate and reliable. ctDNA testing has several benefits, including early detection of cancer (detecting ctDNA at low levels )7; monitoring of tumor dynamics, therapeutic response, and residual disease 8; as well as analysis of the evolution of genetic or epigenetic alterations characterizing the tumor. 9 Its noninvasiveness, rapidity, and low cost allow for longitudinal monitoring of cancer in real time, potentially capturing tumor heterogeneity. 10,11
The liquid biopsy potentially can give more options for therapeutic monitoring for breast cancer and may mirror clinically relevant genetic alterations that occur in all tumor tissues. Liquid biopsy offers many advantages. It allows for the detection of minimal residual disease and micrometastatic disease that may be difficult to detect with a traditional tissue biopsy. 12 Liquid biopsy detects ctDNA that has been released into the bloodstream from multiple tumor regions and allows the possibility of identifying intratumoral heterogeneity and clonal evolution. 5 It can also detect small quantitative variations within the blood, enabling real-time surveillance.
The liquid biopsy can offer earlier and easier access to some tumor-based genetic information at any given timepoint and can replace a tumor tissue biopsy in some cases, helping to avoid delays and complications of a solid tumor invasive biopsy procedure. This is especially relevant in the metastatic setting, in which ctDNA might be the only available genetic material from tumors. 13 Tissue biopsy can only provide a static and spatially limited view of the disease at the time of sampling; ctDNA analysis could potentially reflect the genetic alterations that occur in all metastatic breast cancer sites over time. 14,15 Furthermore, machine learning of multi-gene signatures, obtained from ctDNA, can possibly identify complex biological features, including measures of tumor proliferation and estrogen receptor signaling, similar to direct tumor tissue DNA or RNA profiling. 16