Liquid biopsy in gastric cancer: A snapshot of the current state of the art

Abstract

Circulating tumor DNA (ctDNA) is nowadays considered a robust source to search for druggable tumoral genetic alterations, and in some specific settings liquid biopsy (LB) is already part of the diagnostics scenario and it has successfully implemented in the everyday practice. Three strengths make LB an extraordinary tool: i) to represent the complex molecular mosaicism that characterizes spatially heterogeneous malignancies; ii) to monitor in real-time the tumoral molecular landscape (i.e. to depict the longitudinal/temporal tumor evolution); iii) to ensure molecular profiling even in those cases in which tissue sampling is not feasible or not adequate. This review provides a snapshot of the current state of the art concerning ctDNA assay utility in gastric cancer (GC), testing its robustness as marker and seeking to understand the reasons for the delay in its application in clinical practice.

Keywords: CNAs; Circulating markers; Gastric cancer; Liquid biopsy; ctDNA.

Fig. 1

Principal molecular targets currently assessed in gastric cancer. Patients positive for HER2 expression are eligible for treatment with trastuzumab, a humanized recombinant monoclonal antibody able to bind to HER2 receptors, reducing its activity. According to the ToGA study, trastuzumab is used in combination with chemotherapy (fluorouracil plus cisplatin) in HER2-positive patients. Patients eligible for immunotherapy are selected on the basis of PD-L1 expression, calculated as CPS score and/or microsatellite status: MSI-high patients respond well to immunotherapy. The FIGHT trial investigated the activity of bemarituzumab as first-line treatment in metastatic patients harboring FGFR2 amplification or FGFR2b over-expression. The effect of the monoclonal antibody zolbetuximab against CLDN18.2 associated with chemotherapy (mFOLFOX6) was investigated in the SPOTLIGHT trial. Most of the cited molecular targets are almost mutually exclusive.

Fig. 2

Principal biomarkers currently investigated in blood from gastric cancer patients. Two different types of markers can be detected in blood: circulating tumor cells (CTC) and tumor-educated platelets (TEPs), in the plasma or serum isolated from blood three markers can be investigated: circulating tumor DNA (ctDNA), extracellular vesicles (EVs) and noncoding RNAs (ncRNAs).

Fig. 3

Analysis of ctDNA in gastric cancer. Principal advantages and issues hindering the introduction of ctDNA analysis in GC. Possible biomarkers to be tested and applications of LB applied to GC are summarized. Applications and biomarkers are enlisted starting from the more promising.

Fig. 4

Principal technologies for ctDNA analysis. Technologies for ctDNA analysis can be divided into two main groups: PCR and NGS-based technologies, that differ for LOD, number of analyzed genes ad turnaround time (TAT).