Exosomal Liquid Biopsy for the Early Detection of Gastric Cancer

 The DESTINEX Multicenter Study

Silei Sui, MD, PhD^1,2; Caiming Xu, MD, PhD^1,3; Mitsuro Kanda, MD⁴; et al

Key Points

Question  What is the clinical utility of exosome-based microRNA as a liquid biopsy biomarker for early detection of gastric cancer?

Findings  In this multicenter case-control study of 809 specimens from 480 patients in the training and validation cohorts, the 10-microRNA signature Destinex assay demonstrated robust performance for early detection of gastric cancer, achieving high area under the curve values in both the training and validation cohorts. For early-stage (pT1) gastric cancer, Destinex achieved a high sensitivity and specificity in distinguishing gastric cancer in those with the disease vs those without it.

Meaning  These findings suggest that the Destinex assay could enhance the existing toolkit for gastric cancer screening, and its implementation is anticipated to improve patient outcomes significantly.

Abstract

Importance  Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide, primarily attributed to delayed detection. The invasive and cost-prohibitive nature of endoscopy for GC screening highlights the urgent need for noninvasive biomarkers.

Objective  To develop an exosome-based diagnostic signature to facilitate blood-based, early detection of patients with GC.

Design, Setting, and Participants  This was a multicenter, population-based, retrospective, case-control study that analyzed specimens collected between January 1, 2016, and December 30, 2020. The study encompassed the discovery, training, validation, and evaluation phases of biomarker development. This study was conducted at 4 major referral centers: Nagoya University Hospital in Japan and Ajou University Hospital, Asan Medical Center, and Samsung Medical Center in South Korea, providing a broad representation of advanced clinical care settings. The study included patients with GC, classified according to the TNM (tumor-node-metastasis) classification (8th edition), and controls without disease. Key sociodemographic data, including age and sex, were recorded for all participants. Data were analyzed from October 2022 to July 2024.

Exposures  Results were obtained from tissue and serum microRNA (miRNA) profiling and expression analysis. Frozen tissue collection and blood draws were conducted intraoperatively, preoperatively, and 3 months postoperatively.

Main Outcomes and Measures  Diagnostic performance of GC detection using an exosome-based miRNA signature.

Results  A total of 809 specimens from 480 patients (mean [SD] age, 61.9 [9.8] years; 336 male [70%]) in the training and validation cohorts were analyzed. A panel of 8 cell-free miRNAs and 10 exosomal miRNAs was initially developed in the discovery phase, which was subsequently reduced using machine learning algorithms to a panel of 8 cell-free and 9 exosomal miRNAs during the training phase. This 17-miRNA signature robustly identified GC with area under the curve (AUC) values of 96.3% (95% CI, 94.3%-98.4%) and 95.3% (95% CI, 92.8%-97.9%) in the training and validation cohorts, respectively. Additionally, 5 overlapping miRNAs were observed between cell-free and exosomal panels and exhibited a comparable efficacy in identifying patients with GC. Finally, we established a 10-miRNA signature (Destinex), which successfully identified early-stage (pT1) GC (AUC = 96.8%; 95% CI, 93.5%-100%). Finally, a significant decrease in miRNA expression levels in postsurgery serum specimens confirmed the robustness of the panel specificity.

Conclusion and Relevance  Results of this case-control study suggest that the Destinex assay was robust for early detection of GC, highlighting its potential for clinical application in the noninvasive identification of GC.

https://jamanetwork.com/journals/jamasurgery/fullarticle/2837074