Gastric cancer (GC) is a global health challenge. With an estimated 1,089,103 new cases and 768,793 deaths in 2020, GC is the fifth most common type of cancer and the fourth leading cause of death worldwide [1]. Several molecular biomarkers for the treatment of GC, such as ERBB2 (also known as HER2) amplification and microsatellite instability (MSI)-high status, are applied in clinical practice [2]. ERBB2 is the first validated predictive biomarker for drug therapy and is overexpressed in 10%–20% of GC cases [3], and ERBB2-positive patients are candidates for trastuzumab treatment [4]. MSI-high is associated with a better prognosis and is a negative predictive marker for perioperative or adjuvant chemotherapy [5]. With the discovery of more molecular markers, molecular cancer DNA profiling has become a standard approach in oncology in the era of targeted therapy. However, traditional biopsy for molecular workup is an invasive procedure and is not always feasible [5].

Liquid biopsy for the analysis of cell-free DNA (cfDNA) from non-solid biological materials, including blood, urine, saliva, ascites, and pleural fluid samples, can be used to identify patients with specific tumor mutations more quickly and in a minimally invasive manner. Therefore, liquid biopsy may serve as an alternative to tissue biopsy [6, 7]. Increasing evidence suggests cfDNA may be a biomarker for diagnosis, prognosis, recurrence monitoring, and the identification of targetable alterations to predict sensitivity or resistance to GC treatments [8-10]. Table 1 lists ongoing clinical trials using liquid biopsy in the field of GC registered in ClinicalTrials.gov (https://clinicaltrials.gov/, accessed October 2, 2023). The ASCEND-Gastric study (NCT05224596) will evaluate the sensitivity and specificity of a combined cfDNA and protein biomarker-based assay for GC detection in participants at various clinical stages. Another study investigating the prognostic role of liquid biopsy in patients with locally advanced GC is underway (NCT04943406). Patients with a resectable tumor and below stage IV disease will be enrolled in this study, and liquid biopsies of peritoneal lavage fluid and plasma will be analyzed on multiple occasions, i.e., before curative gastrectomy, at hospital discharge, three months after surgery/at the completion of adjuvant therapy, and at disease recurrence, and overall and disease-free survival determined. In addition, next-generation sequencing (NGS)-based cfDNA assays to evaluate cfDNA positivity as a biomarker for monitoring minimal residual disease after radical gastrectomy (NCT05029869) are ongoing (Table 1). More multicenter studies and prospective evaluations in large clinical trials are necessary for the integration of liquid biopsy into GC diagnosis for precise clinical treatment.

In this issue of Annals of Laboratory Medicine, Kim, et al. [11] report the characteristics of somatic genomic alterations in patients diagnosed as having advanced or metastatic GC based on NGS-based cfDNA analysis using the Oncomine Pan-Cancer Cell-Free Assay (Thermo Fisher Scientific, Waltham, MA, USA) and AlphaLiquid 100 kit (IMBdx, Seoul, Korea). In this study of 81 patients with GC, 64.2% of patients (52/81) had tier I or II mutations, of whom 45 patients had mutations in genes amenable to potential targeted therapy and are in clinical trials. ERBB2 amplification was detected in 4.9% of patients (4/81). Among other biomarkers showing potential for targeted therapy, TP53 mutation (38.3%, 31/81) and FGFR2 amplification (6.2%, 5/81) were the most frequently detected. The study showed that NGS-based cfDNA analysis provides accurate and reliable information on somatic genomic alterations in patients with GC and may replace tissue biopsy as a diagnostic and prognostic tool.

Liquid biopsy is currently applied in clinical practice [12, 13]. While tissue biopsy is an important method for detecting somatic mutations, the development of cfDNA assays and their implementation in clinical practice should be recognized as a valuable option for patients who do not have adequate tissue quantities for mutation testing or who refuse or are unable to undergo tissue biopsy. In particular, NGS-based molecular cfDNA profiling may be a valuable tool for the diagnostic and prognostic assessment of patients with GC, allowing a broader use of currently approved targeted therapies and ensuring proper treatment for each patient.